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Andrews, Nancy Catherine

Positions:

Nanaline H. Duke Professor of Pediatrics

Pediatrics
School of Medicine

Dean of the School of Medicine

School of Medicine
School of Medicine

Professor of Pediatrics

Pediatrics
School of Medicine

Professor of Pharmacology & Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

B.S. 1980

B.S. — Yale University

M.S. 1980

M.S. — Yale University

Ph.D. 1985

Ph.D. — Massachusetts Institute of Technology

M.D. 1987

M.D. — Harvard University

News:

Grants:

Bridging the Gap to Enhance Clinical Research Program (BIGGER)

Administered By
Medicine, Infectious Diseases
AwardedBy
National Institutes of Health
Role
Advisor
Start Date
December 15, 2016
End Date
November 30, 2021

School of Medicine 2017 Biddle

Administered By
Pediatrics
AwardedBy
Mary Duke Biddle Foundation
Role
Principal Investigator
Start Date
January 01, 2017
End Date
December 31, 2017

NRSA Predoctoral Fellowship

Administered By
Sarah Stedman Nutrition & Metabolism Center
AwardedBy
National Institutes of Health
Role
Co-Sponsor
Start Date
July 01, 2014
End Date
June 30, 2017

Duke-UNC Clinical Hematology and Transfusion Research Career Development Program

Administered By
Medicine, Hematology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 28, 2006
End Date
April 30, 2017

Iron homeostasis in mammalian muscle

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 2011
End Date
March 31, 2016

Expansion of Animal Resources for Large Animals (Vivarium Expansion project)

Administered By
School of Medicine
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
March 04, 2010
End Date
March 03, 2015

Genes that modify Iron loading in mice

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
February 01, 2004
End Date
June 30, 2014

Identification of Novel Genes That Modulate Systemic Iron Homeostasis

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
August 01, 2009
End Date
September 30, 2013

Regulation of Iron Homeostasis

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
June 01, 1998
End Date
March 31, 2010

Erythroid Iron Transport

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 2008
End Date
March 31, 2009
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Awards:

Member, National Academy of Sciences. National Academy of Sciences.

Type
National
Awarded By
National Academy of Sciences
Date
January 01, 2015

Henry M. Stratton Medal. American Society of Hematology.

Type
National
Awarded By
American Society of Hematology
Date
January 01, 2013

Marion Spencer Fay Award. Institute for Women's Health and Leadership.

Type
National
Awarded By
Institute for Women's Health and Leadership
Date
January 01, 2013

Mentor Award for Basic Science. American Society of Hematology.

Type
International
Awarded By
American Society of Hematology
Date
January 01, 2011

Spirit Award . National Institute of Environmental Health Sciences.

Type
National
Awarded By
National Institute of Environmental Health Sciences
Date
January 01, 2011

Vanderbilt Prize in Biomedical Science. Vanderbilt University.

Type
National
Awarded By
Vanderbilt University
Date
January 01, 2010

President. American Society for Clinical Investigation (ASCI).

Type
National
Awarded By
American Society for Clinical Investigation (ASCI)
Date
January 01, 2009

Fellows. American Academy of Arts and Sciences.

Type
National
Awarded By
American Academy of Arts and Sciences
Date
January 01, 2007

Marcel Simon Award. International BioIron Society.

Type
International
Awarded By
International BioIron Society
Date
January 01, 2007

Fellow. American Association for the Advancement of Science.

Type
International
Awarded By
American Association for the Advancement of Science
Date
January 01, 2006

Member. Institute of Medicine of The National Academies.

Type
National
Awarded By
Institute of Medicine of The National Academies
Date
January 01, 2006

Member. American Pediatric Society.

Type
National
Awarded By
American Pediatric Society
Date
January 01, 2004

Member. Association of American Physicians (AAP).

Type
National
Awarded By
Association of American Physicians (AAP)
Date
January 01, 2004

E. Mead Johnson Award. Society for Pediatric Research.

Type
National
Awarded By
Society for Pediatric Research
Date
January 01, 2002

Outstanding Investigator Award in Basic Science. American Federation for Medical Research.

Type
National
Awarded By
American Federation for Medical Research
Date
January 01, 2000

Member. American Society for Clinical Investigation (ASCI).

Type
National
Awarded By
American Society for Clinical Investigation (ASCI)
Date
January 01, 1998

Investigator/Alumni Investigator. Howard Hughes Medical Institute.

Type
National
Awarded By
Howard Hughes Medical Institute
Date
January 01, 1993

Publications:

Disrupted iron homeostasis causes dopaminergic neurodegeneration in mice.

Disrupted brain iron homeostasis is a common feature of neurodegenerative disease. To begin to understand how neuronal iron handling might be involved, we focused on dopaminergic neurons and asked how inactivation of transport proteins affected iron homeostasis in vivo in mice. Loss of the cellular iron exporter, ferroportin, had no apparent consequences. However, loss of transferrin receptor 1, involved in iron uptake, caused neuronal iron deficiency, age-progressive degeneration of a subset of dopaminergic neurons, and motor deficits. There was gradual depletion of dopaminergic projections in the striatum followed by death of dopaminergic neurons in the substantia nigra. Damaged mitochondria accumulated, and gene expression signatures indicated attempted axonal regeneration, a metabolic switch to glycolysis, oxidative stress, and the unfolded protein response. We demonstrate that loss of transferrin receptor 1, but not loss of ferroportin, can cause neurodegeneration in a subset of dopaminergic neurons in mice.

Authors
Matak, P; Matak, A; Moustafa, S; Aryal, DK; Benner, EJ; Wetsel, W; Andrews, NC
MLA Citation
Matak, P, Matak, A, Moustafa, S, Aryal, DK, Benner, EJ, Wetsel, W, and Andrews, NC. "Disrupted iron homeostasis causes dopaminergic neurodegeneration in mice." Proceedings of the National Academy of Sciences of the United States of America 113.13 (March 2016): 3428-3435.
PMID
26929359
Source
epmc
Published In
Proceedings of the National Academy of Sciences of USA
Volume
113
Issue
13
Publish Date
2016
Start Page
3428
End Page
3435
DOI
10.1073/pnas.1519473113

A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency.

Patients with a combined immunodeficiency characterized by normal numbers but impaired function of T and B cells had a homozygous p.Tyr20His substitution in transferrin receptor 1 (TfR1), encoded by TFRC. The substitution disrupts the TfR1 internalization motif, resulting in defective receptor endocytosis and markedly increased TfR1 expression on the cell surface. Iron citrate rescued the lymphocyte defects, and expression of wild-type but not mutant TfR1 rescued impaired transferrin uptake in patient-derived fibroblasts. Tfrc(Y20H/Y20H) mice recapitulated the immunological defects of patients. Despite the critical role of TfR1 in erythrocyte development and function, patients had only mild anemia and only slightly increased TfR1 expression in erythroid precursors. We show that STEAP3, a metalloreductase expressed in erythroblasts, associates with TfR1 and partially rescues transferrin uptake in patient-derived fibroblasts, suggesting that STEAP3 may provide an accessory TfR1 endocytosis signal that spares patients from severe anemia. These findings demonstrate the importance of TfR1 in adaptive immunity.

Authors
Jabara, HH; Boyden, SE; Chou, J; Ramesh, N; Massaad, MJ; Benson, H; Bainter, W; Fraulino, D; Rahimov, F; Sieff, C; Liu, Z-J; Alshemmari, SH; Al-Ramadi, BK; Al-Dhekri, H; Arnaout, R; Abu-Shukair, M; Vatsayan, A; Silver, E; Ahuja, S; Davies, EG; Sola-Visner, M; Ohsumi, TK; Andrews, NC; Notarangelo, LD; Fleming, MD; Al-Herz, W; Kunkel, LM; Geha, RS
MLA Citation
Jabara, HH, Boyden, SE, Chou, J, Ramesh, N, Massaad, MJ, Benson, H, Bainter, W, Fraulino, D, Rahimov, F, Sieff, C, Liu, Z-J, Alshemmari, SH, Al-Ramadi, BK, Al-Dhekri, H, Arnaout, R, Abu-Shukair, M, Vatsayan, A, Silver, E, Ahuja, S, Davies, EG, Sola-Visner, M, Ohsumi, TK, Andrews, NC, Notarangelo, LD, Fleming, MD, Al-Herz, W, Kunkel, LM, and Geha, RS. "A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency." Nature genetics 48.1 (January 2016): 74-78.
PMID
26642240
Source
epmc
Published In
Nature Genetics
Volume
48
Issue
1
Publish Date
2016
Start Page
74
End Page
78
DOI
10.1038/ng.3465

Metabolic Catastrophe in Mice Lacking Transferrin Receptor in Muscle.

Transferrin receptor (Tfr1) is ubiquitously expressed, but its roles in non-hematopoietic cells are incompletely understood. We used a tissue-specific conditional knockout strategy to ask whether skeletal muscle required Tfr1 for iron uptake. We found that iron assimilation via Tfr1 was critical for skeletal muscle metabolism, and that iron deficiency in muscle led to dramatic changes, not only in muscle, but also in adipose tissue and liver. Inactivation of Tfr1 incapacitated normal energy production in muscle, leading to growth arrest and a muted attempt to switch to fatty acid β oxidation, using up fat stores. Starvation signals stimulated gluconeogenesis in the liver, but amino acid substrates became limiting and hypoglycemia ensued. Surprisingly, the liver was also iron deficient, and production of the iron regulatory hormone hepcidin was depressed. Our observations reveal a complex interaction between iron homeostasis and metabolism that has implications for metabolic and iron disorders.

Authors
Barrientos, T; Laothamatas, I; Koves, TR; Soderblom, EJ; Bryan, M; Moseley, MA; Muoio, DM; Andrews, NC
MLA Citation
Barrientos, T, Laothamatas, I, Koves, TR, Soderblom, EJ, Bryan, M, Moseley, MA, Muoio, DM, and Andrews, NC. "Metabolic Catastrophe in Mice Lacking Transferrin Receptor in Muscle." EBioMedicine 2.11 (November 2015): 1705-1717.
PMID
26870796
Source
epmc
Published In
EBioMedicine
Volume
2
Issue
11
Publish Date
2015
Start Page
1705
End Page
1717
DOI
10.1016/j.ebiom.2015.09.041

Lethal Cardiomyopathy in Mice Lacking Transferrin Receptor in the Heart.

Both iron overload and iron deficiency have been associated with cardiomyopathy and heart failure, but cardiac iron utilization is incompletely understood. We hypothesized that the transferrin receptor (Tfr1) might play a role in cardiac iron uptake and used gene targeting to examine the role of Tfr1 in vivo. Surprisingly, we found that decreased iron, due to inactivation of Tfr1, was associated with severe cardiac consequences. Mice lacking Tfr1 in the heart died in the second week of life and had cardiomegaly, poor cardiac function, failure of mitochondrial respiration, and ineffective mitophagy. The phenotype could only be rescued by aggressive iron therapy, but it was ameliorated by administration of nicotinamide riboside, an NAD precursor. Our findings underscore the importance of both Tfr1 and iron in the heart, and may inform therapy for patients with heart failure.

Authors
Xu, W; Barrientos, T; Mao, L; Rockman, HA; Sauve, AA; Andrews, NC
MLA Citation
Xu, W, Barrientos, T, Mao, L, Rockman, HA, Sauve, AA, and Andrews, NC. "Lethal Cardiomyopathy in Mice Lacking Transferrin Receptor in the Heart." Cell reports 13.3 (October 7, 2015): 533-545.
PMID
26456827
Source
epmc
Published In
Cell Reports
Volume
13
Issue
3
Publish Date
2015
Start Page
533
End Page
545
DOI
10.1016/j.celrep.2015.09.023

Noncanonical role of transferrin receptor 1 is essential for intestinal homeostasis.

Transferrin receptor 1 (Tfr1) facilitates cellular iron uptake through receptor-mediated endocytosis of iron-loaded transferrin. It is expressed in the intestinal epithelium but not involved in dietary iron absorption. To investigate its role, we inactivated the Tfr1 gene selectively in murine intestinal epithelial cells. The mutant mice had severe disruption of the epithelial barrier and early death. There was impaired proliferation of intestinal epithelial cell progenitors, aberrant lipid handling, increased mRNA expression of stem cell markers, and striking induction of many genes associated with epithelial-to-mesenchymal transition. Administration of parenteral iron did not improve the phenotype. Surprisingly, however, enforced expression of a mutant allele of Tfr1 that is unable to serve as a receptor for iron-loaded transferrin appeared to fully rescue most animals. Our results implicate Tfr1 in homeostatic maintenance of the intestinal epithelium, acting through a role that is independent of its iron-uptake function.

Authors
Chen, AC; Donovan, A; Ned-Sykes, R; Andrews, NC
MLA Citation
Chen, AC, Donovan, A, Ned-Sykes, R, and Andrews, NC. "Noncanonical role of transferrin receptor 1 is essential for intestinal homeostasis." Proceedings of the National Academy of Sciences of the United States of America 112.37 (September 2015): 11714-11719.
PMID
26324903
Source
epmc
Published In
Proceedings of the National Academy of Sciences of USA
Volume
112
Issue
37
Publish Date
2015
Start Page
11714
End Page
11719
DOI
10.1073/pnas.1511701112

Hungry irony.

Iron-deficient individuals experience a loss of appetite that can be restored with iron supplementation. It has been proposed that iron influences the satiety hormone leptin; however, a direct link between iron and leptin has remained elusive. In this issue of the JCI, Gao and colleagues demonstrate an inverse relationship between adipocyte iron and leptin that is mediated by iron-dependent activation of cAMP-responsive element binding protein (CREB), the transcription factor that represses leptin transcription. Together, the results of this study provide a mechanistic connection between dietary iron and the appetite-regulating hormone leptin.

Authors
Andrews, NC
MLA Citation
Andrews, NC. "Hungry irony." The Journal of clinical investigation 125.9 (September 2015): 3422-3423.
PMID
26301806
Source
epmc
Published In
Journal of Clinical Investigation
Volume
125
Issue
9
Publish Date
2015
Start Page
3422
End Page
3423
DOI
10.1172/jci83193

Research in academic medical centers: two threats to sustainable support.

Reductions in federal support and clinical revenue jeopardize biomedical research and, in turn, clinical medicine.

Authors
Levine, AS; Alpern, RJ; Andrews, NC; Antman, K; Balser, JR; Berg, JM; Davis, PB; Fitz, JG; Golden, RN; Goldman, L; Jameson, JL; Lee, VS; Polonsky, KS; Rappley, MD; Reece, EA; Rothman, PB; Schwinn, DA; Shapiro, LJ; Spiegel, AM
MLA Citation
Levine, AS, Alpern, RJ, Andrews, NC, Antman, K, Balser, JR, Berg, JM, Davis, PB, Fitz, JG, Golden, RN, Goldman, L, Jameson, JL, Lee, VS, Polonsky, KS, Rappley, MD, Reece, EA, Rothman, PB, Schwinn, DA, Shapiro, LJ, and Spiegel, AM. "Research in academic medical centers: two threats to sustainable support." Science translational medicine 7.289 (May 2015): 289fs22-.
PMID
26019216
Source
epmc
Published In
Science Translational Medicine
Volume
7
Issue
289
Publish Date
2015
Start Page
289fs22
DOI
10.1126/scitranslmed.aac5200

Women in Metabolism: Part I

MLA Citation
"Women in Metabolism: Part I." Cell Metabolism 21.5 (May 2015): 654-657.
Source
crossref
Published In
Cell Metabolism
Volume
21
Issue
5
Publish Date
2015
Start Page
654
End Page
657
DOI
10.1016/j.cmet.2015.04.017

INACTIVATION OF TRANSFERRIN RECEPTOR (TFR1) IN THE PANCREAS RESULTS IN PANCREATITIS AND DIABETES

Authors
Chen, A; Ned, RM; Donovan, A; Andrews, NC
MLA Citation
Chen, A, Ned, RM, Donovan, A, and Andrews, NC. "INACTIVATION OF TRANSFERRIN RECEPTOR (TFR1) IN THE PANCREAS RESULTS IN PANCREATITIS AND DIABETES." AMERICAN JOURNAL OF HEMATOLOGY 88.5 (May 2013): E197-E197.
Source
wos-lite
Published In
American Journal of Hematology
Volume
88
Issue
5
Publish Date
2013
Start Page
E197
End Page
E197

TRANSFERRIN RECEPTOR 1 (TFR1) IS REQUIRED FOR MAINTENANCE OF THE INTESTINAL EPITHELIUM

Authors
Chen, A; Ned, RM; Donovan, A; Andrews, NC
MLA Citation
Chen, A, Ned, RM, Donovan, A, and Andrews, NC. "TRANSFERRIN RECEPTOR 1 (TFR1) IS REQUIRED FOR MAINTENANCE OF THE INTESTINAL EPITHELIUM." AMERICAN JOURNAL OF HEMATOLOGY 88.5 (May 2013): E12-E13.
Source
wos-lite
Published In
American Journal of Hematology
Volume
88
Issue
5
Publish Date
2013
Start Page
E12
End Page
E13

Iron and copper in mitochondrial diseases.

Transition metals are frequently used as cofactors for enzymes and oxygen-carrying proteins that take advantage of their propensity to gain and lose single electrons. Metals are particularly important in mitochondria, where they play essential roles in the production of ATP and detoxification of reactive oxygen species. At the same time, transition metals (particularly Fe and Cu) can promote the formation of harmful radicals, necessitating meticulous control of metal concentration and subcellular compartmentalization. We summarize our current understanding of Fe and Cu in mammalian mitochondrial biology and discuss human diseases associated with aberrations in mitochondrial metal homeostasis.

Authors
Xu, W; Barrientos, T; Andrews, NC
MLA Citation
Xu, W, Barrientos, T, and Andrews, NC. "Iron and copper in mitochondrial diseases." Cell Metab 17.3 (March 5, 2013): 319-328.
PMID
23473029
Source
pubmed
Published In
Cell Metabolism
Volume
17
Issue
3
Publish Date
2013
Start Page
319
End Page
328
DOI
10.1016/j.cmet.2013.02.004

On soloists, symphonies, and transdisciplinary research

Authors
Andrews, NC; Murti, VN
MLA Citation
Andrews, NC, and Murti, VN. "On soloists, symphonies, and transdisciplinary research." Issues in Science and Technology 30.1 (January 1, 2013): 30-32.
Source
scopus
Published In
Issues in science and technology
Volume
30
Issue
1
Publish Date
2013
Start Page
30
End Page
32

Genetic Loss of Tmprss6 Increases Effective Erythropoiesis in a Mouse Model of beta-Thalassemia

Authors
Stagg, DB; Gardenghi, S; Rivella, S; Andrews, NC; Finberg, KE
MLA Citation
Stagg, DB, Gardenghi, S, Rivella, S, Andrews, NC, and Finberg, KE. "Genetic Loss of Tmprss6 Increases Effective Erythropoiesis in a Mouse Model of beta-Thalassemia." November 16, 2012.
Source
wos-lite
Published In
Blood
Volume
120
Issue
21
Publish Date
2012

Genetic Loss of Tmprss6 Increases Effective Erythropoiesis in a Mouse Model of beta-Thalassemia

Authors
Stagg, DB; Gardenghi, S; Rivella, S; Andrews, NC; Finberg, KE
MLA Citation
Stagg, DB, Gardenghi, S, Rivella, S, Andrews, NC, and Finberg, KE. "Genetic Loss of Tmprss6 Increases Effective Erythropoiesis in a Mouse Model of beta-Thalassemia." November 16, 2012.
Source
wos-lite
Published In
Blood
Volume
120
Issue
21
Publish Date
2012

Closing the iron gate.

Authors
Andrews, NC
MLA Citation
Andrews, NC. "Closing the iron gate." N Engl J Med 366.4 (January 26, 2012): 376-377.
PMID
22276828
Source
pubmed
Published In
The New England journal of medicine
Volume
366
Issue
4
Publish Date
2012
Start Page
376
End Page
377
DOI
10.1056/NEJMcibr1112780

Divalent metal transporter 1 regulates iron-mediated Ros and pancreatic β cell fate in response to cytokines

Reactive oxygen species (ROS) contribute to target-cell damage in inflammatory and iron-overload diseases. Little is known about iron transport regulation during inflammatory attack. Through a combination of in vitro and in vivo studies, we show that the proinflammatory cytokine IL-1β induces divalent metal transporter 1 (DMT1) expression correlating with increased β cell iron content and ROS production. Iron chelation and siRNA and genetic knockdown of DMT1 expression reduce cytokine-induced ROS formation and cell death. Glucose-stimulated insulin secretion in the absence of cytokines in Dmt1 knockout islets is defective, highlighting a physiological role of iron and ROS in the regulation of insulin secretion. Dmt1 knockout mice are protected against multiple low-dose streptozotocin and high-fat diet-induced glucose intolerance, models of type 1 and type 2 diabetes, respectively. Thus, β cells become prone to ROS-mediated inflammatory damage via aberrant cellular iron metabolism, a finding with potential general cellular implications. © 2012 Elsevier Inc.

Authors
Hansen, JB; Tonnesen, MF; Madsen, AN; Hagedorn, PH; Friberg, J; Grunnet, LG; Heller, RS; Nielsen, AO; Storling, J; Baeyens, L; Anker-Kitai, L; Qvortrup, K; Bouwens, L; Efrat, S; Aalund, M; Andrews, NC; Billestrup, N; Karlsen, AE; Holst, B; Pociot, F; Mandrup-Poulsen, T
MLA Citation
Hansen, JB, Tonnesen, MF, Madsen, AN, Hagedorn, PH, Friberg, J, Grunnet, LG, Heller, RS, Nielsen, AO, Storling, J, Baeyens, L, Anker-Kitai, L, Qvortrup, K, Bouwens, L, Efrat, S, Aalund, M, Andrews, NC, Billestrup, N, Karlsen, AE, Holst, B, Pociot, F, and Mandrup-Poulsen, T. "Divalent metal transporter 1 regulates iron-mediated Ros and pancreatic β cell fate in response to cytokines." Cell Metabolism 16.4 (2012): 449-461.
PMID
23000401
Source
scival
Published In
Cell Metabolism
Volume
16
Issue
4
Publish Date
2012
Start Page
449
End Page
461
DOI
10.1016/j.cmet.2012.09.001

Late stage erythroid precursor production is impaired in mice with chronic inflammation

Background We and others have shown previously that over-expression of hepcidin antimicrobial peptide, independently of inflammation, induces several features of anemia of inflammation and chronic disease, including hypoferremia, sequestration of iron stores and iron-restricted erythropoiesis. Because the iron-restricted erythropoiesis evident in hepcidin transgenic mice differs from the normocytic, normochromic anemia most often observed in anemia of inflammation, we tested the hypothesis that chronic inflammation may contribute additional features to anemia of inflammation which continue to impair erythropoiesis following the acute phase of inflammation in which hepcidin is active. Design and Methods We compared erythropoiesis and iron handling in mice with turpentine-induced sterile abscesses with erythropoiesis and iron handling in hepcidin transgenic mice. We compared erythrocyte indices, expression of genes in the hepcidin regulatory pathway, tissue iron distribution, expression of heme and iron transport genes in splenic macrophages, the phenotype of erythroid maturation and chloromethyl dichlorodihydrofluorescein diacetate, acetyl ester fluorescence. Results Mice with sterile abscesses exhibited an intense, acute inflammatory phase followed by a mild to moderate chronic inflammatory phase. We found that erythrocytes in mice with sterile abscesses were normocytic and normochromic in contrast to those in hepcidin transgenic mice. We also observed that although hypoferremia resolved in the late phases of inflammation, erythropoiesis remained suppressed, with evidence of inefficient maturation of erythroid precursors in the bone marrow of mice with sterile abscesses. Finally, we observed increased oxidative stress in erythroid progenitors and circulating erythrocytes of mice with sterile abscesses which was not evident in hepcidin transgenic mice. Conclusions Our results suggest that chronic inflammation inhibits late stages of erythroid production in the turpentine-induced sterile abscess model and induces features of impaired erythropoiesis which are distinct from those in hepcidin transgenic mice. ©2012 Ferrata Storti Foundation.

Authors
Prince, OD; Langdon, JM; Layman, AJ; Prince, IC; Sabogal, M; Mak, HH; Berger, AE; Cheadle, C; Chrest, FJ; Yu, Q; Andrews, NC; Xue, Q-L; Civin, CI; Walston, JD; Roy, CN
MLA Citation
Prince, OD, Langdon, JM, Layman, AJ, Prince, IC, Sabogal, M, Mak, HH, Berger, AE, Cheadle, C, Chrest, FJ, Yu, Q, Andrews, NC, Xue, Q-L, Civin, CI, Walston, JD, and Roy, CN. "Late stage erythroid precursor production is impaired in mice with chronic inflammation." Haematologica 97.11 (2012): 1648-1656.
PMID
22581006
Source
scival
Published In
Haematologica
Volume
97
Issue
11
Publish Date
2012
Start Page
1648
End Page
1656
DOI
10.3324/haematol.2011.053397

Mutation of Rubie, a novel long non-coding RNA located upstream of Bmp4, causes vestibular malformation in mice.

BACKGROUND: The vestibular apparatus of the vertebrate inner ear uses three fluid-filled semicircular canals to sense angular acceleration of the head. Malformation of these canals disrupts the sense of balance and frequently causes circling behavior in mice. The Epistatic circler (Ecl) is a complex mutant derived from wildtype SWR/J and C57L/J mice. Ecl circling has been shown to result from the epistatic interaction of an SWR-derived locus on chromosome 14 and a C57L-derived locus on chromosome 4, but the causative genes have not been previously identified. METHODOLOGY/PRINCIPAL FINDINGS: We developed a mouse chromosome substitution strain (CSS-14) that carries an SWR/J chromosome 14 on a C57BL/10J genetic background and, like Ecl, exhibits circling behavior due to lateral semicircular canal malformation. We utilized CSS-14 to identify the chromosome 14 Ecl gene by positional cloning. Our candidate interval is located upstream of bone morphogenetic protein 4 (Bmp4) and contains an inner ear-specific, long non-coding RNA that we have designated Rubie (RNA upstream of Bmp4 expressed in inner ear). Rubie is spliced and polyadenylated, and is expressed in developing semicircular canals. However, we discovered that the SWR/J allele of Rubie is disrupted by an intronic endogenous retrovirus that causes aberrant splicing and premature polyadenylation of the transcript. Rubie lies in the conserved gene desert upstream of Bmp4, within a region previously shown to be important for inner ear expression of Bmp4. We found that the expression patterns of Bmp4 and Rubie are nearly identical in developing inner ears. CONCLUSIONS/SIGNIFICANCE: Based on these results and previous studies showing that Bmp4 is essential for proper vestibular development, we propose that Rubie is the gene mutated in Ecl mice, that it is involved in regulating inner ear expression of Bmp4, and that aberrant Bmp4 expression contributes to the Ecl phenotype.

Authors
Roberts, KA; Abraira, VE; Tucker, AF; Goodrich, LV; Andrews, NC
MLA Citation
Roberts, KA, Abraira, VE, Tucker, AF, Goodrich, LV, and Andrews, NC. "Mutation of Rubie, a novel long non-coding RNA located upstream of Bmp4, causes vestibular malformation in mice." PLoS One 7.1 (2012): e29495-.
PMID
22253730
Source
pubmed
Published In
PloS one
Volume
7
Issue
1
Publish Date
2012
Start Page
e29495
DOI
10.1371/journal.pone.0029495

The channel kinase, TRPM7, is required for early embryonic development

Global disruption of transient receptor potential-melastatin-like 7 (Trpm7) in mice results in embryonic lethality before embryonic day 7. Using tamoxifen-inducible disruption of Trpm7 and multiple Cre recombinase lines, we show that Trpm7 deletion before and during organogenesis results in severe tissue-specific developmental defects. We find that Trpm7 is essential for kidney development from metanephric mesenchyme but not ureteric bud. Disruption of neural crest Trpm7 at early stages results in loss of pigment cells and dorsal root ganglion neurons. In contrast, late disruption of brainspecific Trpm7 after embryonic day 10.5 does not alter normal brain development. We developed induced pluripotent stem cells and neural stem (NS) cells in which Trpm7 disruption could be induced. Trpm7 -/- NS cells retained the capacities of self-renewal and differentiation into neurons and astrocytes. During in vitro differentiation of induced pluripotent stem cells to NS cells, Trpm7 disruption prevents the formation of the NS cell monolayer. The in vivo and in vitro results demonstrate a temporal requirement for the Trpm7 channel kinase during embryogenesis.

Authors
Jin, J; Wu, L-J; Jun, J; Cheng, X; Xu, H; Andrews, NC; Clapham, DE
MLA Citation
Jin, J, Wu, L-J, Jun, J, Cheng, X, Xu, H, Andrews, NC, and Clapham, DE. "The channel kinase, TRPM7, is required for early embryonic development." Proceedings of the National Academy of Sciences of the United States of America 109.5 (2012): E225-E233.
PMID
22203997
Source
scival
Published In
Proceedings of the National Academy of Sciences of USA
Volume
109
Issue
5
Publish Date
2012
Start Page
E225
End Page
E233
DOI
10.1073/pnas.1120033109

An iron-clad role for proteasomal degradation.

Authors
Andrews, NC
MLA Citation
Andrews, NC. "An iron-clad role for proteasomal degradation." Cell Metab 14.3 (September 7, 2011): 281-282.
PMID
21907132
Source
pubmed
Published In
Cell Metabolism
Volume
14
Issue
3
Publish Date
2011
Start Page
281
End Page
282
DOI
10.1016/j.cmet.2011.08.001

Skeletal muscle hemojuvelin is dispensable for systemic iron homeostasis.

Hepcidin, a hormone produced mainly by the liver, has been shown to inhibit both intestinal iron absorption and iron release from macrophages. Hemojuvelin, a glycophosphatidyl inositol-linked membrane protein, acts as a bone morphogenetic protein coreceptor to activate hepcidin expression through a SMAD signaling pathway in hepatocytes. In the present study, we show in mice that loss of hemojuvelin specifically in the liver leads to decreased liver hepcidin production and increased tissue and serum iron levels. Although it does not have any known function outside of the liver, hemojuvelin is expressed at very high levels in cardiac and skeletal muscle. To explore possible roles for hemojuvelin in skeletal muscle, we analyzed conditional knockout mice that lack muscle hemojuvelin. The mutant animals had no apparent phenotypic abnormalities. We found that systemic iron homeostasis and liver hepcidin expression were not affected by loss of hemojuvelin in skeletal muscle regardless of dietary iron content. We conclude that, in spite of its expression pattern, hemojuvelin is primarily important in the liver.

Authors
Chen, W; Huang, FW; de Renshaw, TB; Andrews, NC
MLA Citation
Chen, W, Huang, FW, de Renshaw, TB, and Andrews, NC. "Skeletal muscle hemojuvelin is dispensable for systemic iron homeostasis." Blood 117.23 (June 9, 2011): 6319-6325.
PMID
21493799
Source
pubmed
Published In
Blood
Volume
117
Issue
23
Publish Date
2011
Start Page
6319
End Page
6325
DOI
10.1182/blood-2010-12-327957

Tmprss6 is a genetic modifier of the Hfe-hemochromatosis phenotype in mice.

The hereditary hemochromatosis protein HFE promotes the expression of hepcidin, a circulating hormone produced by the liver that inhibits dietary iron absorption and macrophage iron release. HFE mutations are associated with impaired hepatic bone morphogenetic protein (BMP)/SMAD signaling for hepcidin production. TMPRSS6, a transmembrane serine protease mutated in iron-refractory iron deficiency anemia, inhibits hepcidin expression by dampening BMP/SMAD signaling. In the present study, we used genetic approaches in mice to examine the relationship between Hfe and Tmprss6 in the regulation of systemic iron homeostasis. Heterozygous loss of Tmprss6 in Hfe(-/-) mice reduced systemic iron overload, whereas homozygous loss caused systemic iron deficiency and elevated hepatic expression of hepcidin and other Bmp/Smad target genes. In contrast, neither genetic loss of Hfe nor hepatic Hfe overexpression modulated the hepcidin elevation and systemic iron deficiency of Tmprss6(-/-) mice. These results indicate that genetic loss of Tmprss6 increases Bmp/Smad signaling in an Hfe-independent manner that can restore Bmp/Smad signaling in Hfe(-/-) mice. Furthermore, these results suggest that natural genetic variation in the human ortholog TMPRSS6 might modify the clinical penetrance of HFE-associated hereditary hemochromatosis, raising the possibility that pharmacologic inhibition of TMPRSS6 could attenuate iron loading in this disorder.

Authors
Finberg, KE; Whittlesey, RL; Andrews, NC
MLA Citation
Finberg, KE, Whittlesey, RL, and Andrews, NC. "Tmprss6 is a genetic modifier of the Hfe-hemochromatosis phenotype in mice." Blood 117.17 (April 28, 2011): 4590-4599.
PMID
21355094
Source
pubmed
Published In
Blood
Volume
117
Issue
17
Publish Date
2011
Start Page
4590
End Page
4599
DOI
10.1182/blood-2010-10-315507

Transferrin is a major determinant of hepcidin expression in hypotransferrinemic mice

As a central regulator of iron metabolism, hepcidin inhibits dietary iron absorption and macrophage iron recycling. Its expression is regulated by multiple factors including iron availability and erythropoietic activity. To investigate the role of transferrin (Tf) in the regulation of hepcidin expression by these factors in vivo, we employed the hypotransferrinemic (hpx) mouse. These Tf-deficient mice have severe microcytic anemia, tissue iron overload, and hepcidin deficiency. To determine the relationship of Tf levels and erythropoiesis to hepcidin expression, we subjected hpx mutant and control mice to a number of experimental manipulations. Treatment of hpx mice with Tf injections corrected their anemia and restored hepcidin expression. To investigate the effect of erythropoiesis on hepcidin expression, we suppressed erythropoiesis with blood transfusions or myeloablation with chemotherapeutic drugs. Transfusion of hpx animals with wild-type red blood cells led to increased hepcidin expression, while hepcidin expression in myeloablated hpx mice increased only if Tf was administered postablation. These results suggest that hepcidin expression in hpx mice is regulated both by Tf-restricted erythropoiesis and by Tf through a mechanism independent of its role in erythropoiesis. © 2011 by The American Society of Hematology.

Authors
Bartnikas, TB; Andrews, NC; Fleming, MD
MLA Citation
Bartnikas, TB, Andrews, NC, and Fleming, MD. "Transferrin is a major determinant of hepcidin expression in hypotransferrinemic mice." Blood 117.2 (2011): 630-637.
PMID
20956801
Source
scival
Published In
Blood
Volume
117
Issue
2
Publish Date
2011
Start Page
630
End Page
637
DOI
10.1182/blood-2010-05-287359

Personalized medicine to anticipatory health

Authors
Andrews, NC
MLA Citation
Andrews, NC. "Personalized medicine to anticipatory health." Journal of Surgical Radiology 2.3 (2011): 220-223.
Source
scival
Published In
Journal of Surgical Radiology
Volume
2
Issue
3
Publish Date
2011
Start Page
220
End Page
223

Hepcidin induction by transgenic overexpression of Hfe does not require the Hfe cytoplasmic tail, but does require hemojuvelin

Authors
Schmidt, PJ; Andrews, NC; Fleming, MD
MLA Citation
Schmidt, PJ, Andrews, NC, and Fleming, MD. "Hepcidin induction by transgenic overexpression of Hfe does not require the Hfe cytoplasmic tail, but does require hemojuvelin." BLOOD 116.25 (December 16, 2010): 5679-5687.
PMID
20837779
Source
wos-lite
Published In
Blood
Volume
116
Issue
25
Publish Date
2010
Start Page
5679
End Page
5687
DOI
10.1182/blood-2010277954

Hepcidin as a Therapeutic Tool to Limit Iron Overload and Improve Anemia In beta-Thalassemia

Authors
Gardenghi, S; Ramos, P; Roy, CN; Andrews, NC; Nemeth, E; An, X; Narla, M; Ginzburg, Y; Rachmilewitz, EA; Giardina, P; Grady, RW; Rivella, S
MLA Citation
Gardenghi, S, Ramos, P, Roy, CN, Andrews, NC, Nemeth, E, An, X, Narla, M, Ginzburg, Y, Rachmilewitz, EA, Giardina, P, Grady, RW, and Rivella, S. "Hepcidin as a Therapeutic Tool to Limit Iron Overload and Improve Anemia In beta-Thalassemia." November 19, 2010.
Source
wos-lite
Published In
Blood
Volume
116
Issue
21
Publish Date
2010
Start Page
443
End Page
444

Tmprss6, An Inhibitor of Hepatic Bmp/Smad Signaling, Is Required for Hepcidin Suppression and Iron Loading In a Mouse Model of beta-Thalassemia

Authors
Finberg, KE; Whittlesey, RL; Rivella, S; Andrews, NC
MLA Citation
Finberg, KE, Whittlesey, RL, Rivella, S, and Andrews, NC. "Tmprss6, An Inhibitor of Hepatic Bmp/Smad Signaling, Is Required for Hepcidin Suppression and Iron Loading In a Mouse Model of beta-Thalassemia." November 19, 2010.
Source
wos-lite
Published In
Blood
Volume
116
Issue
21
Publish Date
2010
Start Page
75
End Page
75

The Serine Protease Tmprss6 Regulates Hepcidin Expression, but Its Loss Does Not Cause Systemic Iron Deficiency In the Fetal and Neonatal Periods

Authors
Wehbe, RM; Whittlesey, RL; Andrews, NC; Finberg, KE
MLA Citation
Wehbe, RM, Whittlesey, RL, Andrews, NC, and Finberg, KE. "The Serine Protease Tmprss6 Regulates Hepcidin Expression, but Its Loss Does Not Cause Systemic Iron Deficiency In the Fetal and Neonatal Periods." November 19, 2010.
Source
wos-lite
Published In
Blood
Volume
116
Issue
21
Publish Date
2010
Start Page
1728
End Page
1728

Ferrit(in)ing out new mechanisms in iron homeostasis.

Exquisite control of intestinal iron absorption prevents iron deficiency and toxic iron overload. Absorption is modulated by a circulating hormone, hepcidin, which inactivates the iron transporter ferroportin. In this issue of Cell Metabolism, Vanoaica and colleagues show that absorption is also regulated within the intestinal epithelium, through production of the iron-sequestering protein H-ferritin.

Authors
Andrews, NC
MLA Citation
Andrews, NC. "Ferrit(in)ing out new mechanisms in iron homeostasis." Cell Metab 12.3 (September 8, 2010): 203-204.
PMID
20816083
Source
pubmed
Published In
Cell Metabolism
Volume
12
Issue
3
Publish Date
2010
Start Page
203
End Page
204
DOI
10.1016/j.cmet.2010.08.011

Down-regulation of Bmp/Smad signaling by Tmprss6 is required for maintenance of systemic iron homeostasis.

Iron-refractory, iron-deficiency anemia (IRIDA) is a familial disorder characterized by iron deficiency anemia unresponsive to oral iron treatment but partially responsive to intravenous iron therapy. Previously, we showed that IRIDA patients harbor loss-of-function mutations in TMPRSS6, a type II transmembrane serine protease primarily expressed by the liver. Both humans and mice with TMPRSS6 mutations show inappropriately elevated levels of the iron-regulatory hormone hepcidin, suggesting that TMPRSS6 acts to negatively regulate hepcidin expression. Here we investigate the relationship between Tmprss6 and the bone morphogenetic protein (BMP)-Smad signaling pathway, a key pathway promoting hepcidin transcription in hepatocytes. We show that livers from mice deficient for Tmprss6 have decreased iron stores and decreased Bmp6 mRNA, but markedly increased mRNA for Id1, a target gene of Bmp6 signaling. In contrast, mice deficient for both Tmprss6 and hemojuvelin (Hjv), a BMP coreceptor that augments hepcidin expression in hepatocytes, showed markedly decreased hepatic levels of hepcidin and Id1 mRNA, markedly increased hepatic Bmp6 mRNA levels, and systemic iron overload similar to mice deficient for Hjv alone. These findings suggest that down-regulation of Bmp/Smad signaling by Tmprss6 is required for regulation of hepcidin expression and maintenance of systemic iron homeostasis.

Authors
Finberg, KE; Whittlesey, RL; Fleming, MD; Andrews, NC
MLA Citation
Finberg, KE, Whittlesey, RL, Fleming, MD, and Andrews, NC. "Down-regulation of Bmp/Smad signaling by Tmprss6 is required for maintenance of systemic iron homeostasis." Blood 115.18 (May 6, 2010): 3817-3826.
PMID
20200349
Source
pubmed
Published In
Blood
Volume
115
Issue
18
Publish Date
2010
Start Page
3817
End Page
3826
DOI
10.1182/blood-2009-05-224808

The Molecular Basis of Iron Metabolism

Authors
Andrews, NC; Ganz, T
MLA Citation
Andrews, NC, and Ganz, T. "The Molecular Basis of Iron Metabolism." (March 10, 2010): 169-178. (Chapter)
Source
scopus
Publish Date
2010
Start Page
169
End Page
178
DOI
10.1002/9781444318531.ch14

Can we keep the "academic" in academic medicine? 2009 American Society for Clinical Investigation Presidential Address.

Authors
Andrews, NC
MLA Citation
Andrews, NC. "Can we keep the "academic" in academic medicine? 2009 American Society for Clinical Investigation Presidential Address." J Clin Invest 120.1 (January 2010): 390-393.
PMID
20038792
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
120
Issue
1
Publish Date
2010
Start Page
390
End Page
393
DOI
10.1172/JCI41934

Hepcidin as a therapeutic tool to limit iron overload and improve anemia in β-thalassemic mice

Excessive iron absorption is one of the main features of β-thalassemia and can lead to severe morbidity and mortality. Serial analyses of β-thalassemic mice indicate that while hemoglobin levels decrease over time, the concentration of iron in the liver, spleen, and kidneys markedly increases. Iron overload is associated with low levels of hepcidin, a peptide that regulates iron metabolism by triggering degradation of ferroportin, an iron-transport protein localized on absorptive enterocytes as well as hepatocytes and macrophages. Patients with β-thalassemia also have low hepcidin levels. These observations led us to hypothesize that more iron is absorbed in β-thalassemia than is required for erythropoiesis and that increasing the concentration of hepcidin in the body of such patients might be therapeutic, limiting iron overload. Here we demonstrate that a moderate increase in expression of hepcidin in β-thalassemic mice limits iron overload, decreases formation of insoluble membrane-bound globins and reactive oxygen species, and improves anemia. Mice with increased hepcidin expression also demonstrated an increase in the lifespan of their red cells, reversal of ineffective erythropoiesis and splenomegaly, and an increase in total hemoglobin levels. These data led us to suggest that therapeutics that could increase hepcidin levels or act as hepcidin agonists might help treat the abnormal iron absorption in individuals with β-thalassemia and related disorders.

Authors
Gardenghi, S; Ramos, P; Marongiu, MF; Melchiori, L; Breda, L; Guy, E; Muirhead, K; Rao, N; Roy, CN; Andrews, NC; Nemeth, E; Follenzi, A; An, X; Mohandas, N; Ginzburg, Y; Rachmilewitz, EA; Giardina, PJ; Grady, RW; Rivella, S
MLA Citation
Gardenghi, S, Ramos, P, Marongiu, MF, Melchiori, L, Breda, L, Guy, E, Muirhead, K, Rao, N, Roy, CN, Andrews, NC, Nemeth, E, Follenzi, A, An, X, Mohandas, N, Ginzburg, Y, Rachmilewitz, EA, Giardina, PJ, Grady, RW, and Rivella, S. "Hepcidin as a therapeutic tool to limit iron overload and improve anemia in β-thalassemic mice." Journal of Clinical Investigation 120.12 (2010): 4466-4477.
Website
http://hdl.handle.net/10161/4327
PMID
21099112
Source
scival
Published In
Journal of Clinical Investigation
Volume
120
Issue
12
Publish Date
2010
Start Page
4466
End Page
4477
DOI
10.1172/JCI41717

Hepcidin induction by transgenic overexpression of Hfe does not require the Hfe cytoplasmic tail, but does require hemojuvelin

Mutations in HFE cause the most common form of hereditary hemochromatosis (HH).We previously showed that liver-specific, transgenic overexpression of murine Hfe stimulates production of the iron regulatory hormone hepcidin. Here, we developed several additional transgenic mouse strains to further interrogate the structural basis of HFE function in the pathophysiology of HH. We hypothesized that the small, cytoplasmic domain of HFE might be necessary for HFE-mediated induction of hepcidin.We demonstrate that, like the full-length protein, overexpression of Hfe proteins lacking the cytoplasmic domain leads to hepcidin induction, iron deficiency and a hypochromic, microcytic anemia. However, high-level expression of a liver-specific Hfe transgene carrying the mouse equivalent of the common HFE C282Y human disease-causing mutation (murine C294Y) did not cause iron deficiency. Furthermore, hepcidin induction by transgenes encoding both WT Hfe and Hfe lacking its cytoplasmic domain is greatly attenuated in the absence of hemojuvelin (Hjv). Our observations indicate that the extracellular and transmembrane domains of Hfe are sufficient, and Hjv is essential, for Hfe-mediated induction of hepcidin expression. © 2010 by The American Society of Hematology.

Authors
Schmidt, PJ; Andrews, NC; Fleming, MD
MLA Citation
Schmidt, PJ, Andrews, NC, and Fleming, MD. "Hepcidin induction by transgenic overexpression of Hfe does not require the Hfe cytoplasmic tail, but does require hemojuvelin." Blood 116.25 (2010): 5679-5687.
Source
scival
Published In
Blood
Volume
116
Issue
25
Publish Date
2010
Start Page
5679
End Page
5687
DOI
10.1182/blood-2010-04-277954

TRP channel regulates EGFR signaling in hair morphogenesis and skin barrier formation

A plethora of growth factors regulate keratinocyte proliferation and differentiation that control hair morphogenesis and skin barrier formation. Wavy hair phenotypes in mice result from naturally occurring loss-of-function mutations in the genes for TGF-α and EGFR. Conversely, excessive activities of TGF-α/EGFR result in hairless phenotypes and skin cancers. Unexpectedly, we found that mice lacking the Trpv3 gene also exhibit wavy hair coat and curly whiskers. Here we show that keratinocyte TRPV3, a member of the transient receptor potential (TRP) family of Ca2+-permeant channels, forms a signaling complex with TGF-α/EGFR. Activation of EGFR leads to increased TRPV3 channel activity, which in turn stimulates TGF-α release. TRPV3 is also required for the formation of the skin barrier by regulating the activities of transglutaminases, a family of Ca2+-dependent crosslinking enzymes essential for keratinocyte cornification. Our results show that a TRP channel plays a role in regulating growth factor signaling by direct complex formation. © 2010 Elsevier Inc.

Authors
Cheng, X; Jin, J; Hu, L; Shen, D; Dong, X-P; Samie, MA; Knoff, J; Eisinger, B; Liu, M-L; Huang, SM; Caterina, MJ; Dempsey, P; Michael, LE; Dlugosz, AA; Andrews, NC; Clapham, DE; Xu, H
MLA Citation
Cheng, X, Jin, J, Hu, L, Shen, D, Dong, X-P, Samie, MA, Knoff, J, Eisinger, B, Liu, M-L, Huang, SM, Caterina, MJ, Dempsey, P, Michael, LE, Dlugosz, AA, Andrews, NC, Clapham, DE, and Xu, H. "TRP channel regulates EGFR signaling in hair morphogenesis and skin barrier formation." Cell 141.2 (2010): 331-343.
PMID
20403327
Source
scival
Published In
Cell
Volume
141
Issue
2
Publish Date
2010
Start Page
331
End Page
343
DOI
10.1016/j.cell.2010.03.013

Proinflammatory state, hepcidin, and anemia in older persons

In patients with overt inflammatory diseases, up-regulated hepcidin impairs iron absorption and macrophage release, causing anemia. Whether the mild proinflammatory state of aging is associated with increased hepcidin is unknown. We characterized the relationships between urinary hepcidin, iron status, anemia, and inflammation in 582 patients 65 years or older participating in the InCHIANTI (Invecchiare in Chianti, "Aging in the Chianti Area") study, a population-based study of aging in Tuscany, Italy. Compared with nonanemic persons, urinary hepcidin (nanograms/milligram of urinary creatinine) was significantly lower in iron deficiency and inflammation anemia compared with no anemia or other anemia types. Urinary hepcidin was positively correlated with log(ferritin) and negatively correlated with the soluble transferrin receptor/log(ferritin) ratio but not correlated with markers of inflammation: interleukin-6 (IL-6), IL-1β, tumor necrosis factor-α, and C-reactive protein (CRP). Lower iron was significantly correlated with higher IL-6 and CRP. Adjusting for confounders, IL-6 and CRP remained significantly associated with serum iron, with no evidence that such a relationship was accounted for by variability in urinary hepcidin. In conclusion, elevated proinflammatory markers were associated with anemia and low iron status, but not with higher urinary hepcidin. Future studies should test whether hepcidin production becomes up-regulated only in situations of overt inflammation. © 2010 by The American Society of Hematology.

Authors
Ferrucci, L; Semba, RD; Guralnik, JM; Ershler, WB; Bandinelli, S; Patel, KV; Sun, K; Woodman, RC; Andrews, NC; Cotter, RJ; Ganz, T; Nemeth, E; Longo, DL
MLA Citation
Ferrucci, L, Semba, RD, Guralnik, JM, Ershler, WB, Bandinelli, S, Patel, KV, Sun, K, Woodman, RC, Andrews, NC, Cotter, RJ, Ganz, T, Nemeth, E, and Longo, DL. "Proinflammatory state, hepcidin, and anemia in older persons." Blood 115.18 (2010): 3810-3816.
PMID
20081092
Source
scival
Published In
Blood
Volume
115
Issue
18
Publish Date
2010
Start Page
3810
End Page
3816
DOI
10.1182/blood-2009-02-201087

Women: Diversity among leaders is there if you look

Authors
Andrews, NC; Kornbluth, S; Stokke, D
MLA Citation
Andrews, NC, Kornbluth, S, and Stokke, D. "Women: Diversity among leaders is there if you look." Nature 463.7281 (2010): 608--.
PMID
20130628
Source
scival
Published In
Nature
Volume
463
Issue
7281
Publish Date
2010
Start Page
608-
DOI
10.1038/463608d

Tmprss6 Is a Genetic Modifier of the Hfe-Hemochromatosis Phenotype in Mice

Authors
Finberg, KE; Whittlesey, R; Fleming, MD; Andrews, NC
MLA Citation
Finberg, KE, Whittlesey, R, Fleming, MD, and Andrews, NC. "Tmprss6 Is a Genetic Modifier of the Hfe-Hemochromatosis Phenotype in Mice." November 20, 2009.
Source
wos-lite
Published In
Blood
Volume
114
Issue
22
Publish Date
2009
Start Page
259
End Page
259

Build it and hope that enough of them will come.

Authors
Andrews, NC
MLA Citation
Andrews, NC. "Build it and hope that enough of them will come." J Clin Invest 119.10 (October 2009): 2860-2861.
PMID
20069718
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
119
Issue
10
Publish Date
2009
Start Page
2860
End Page
2861

ABCs of erythroid mitochondrial iron uptake.

Authors
Andrews, NC
MLA Citation
Andrews, NC. "ABCs of erythroid mitochondrial iron uptake." Proc Natl Acad Sci U S A 106.38 (September 22, 2009): 16012-16013.
PMID
19805253
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
106
Issue
38
Publish Date
2009
Start Page
16012
End Page
16013
DOI
10.1073/pnas.0909137106

Genes determining blood cell traits

Four genome-wide association studies report associations to a range of clinically relevant hematological traits. The candidate genes identified include many that are known to be important in iron homeostasis and red blood cell maturation. © 2009 Nature America, Inc. All rights reserved.

Authors
Andrews, NC
MLA Citation
Andrews, NC. "Genes determining blood cell traits." Nature Genetics 41.11 (2009): 1161-1162.
PMID
19862006
Source
scival
Published In
Nature Genetics
Volume
41
Issue
11
Publish Date
2009
Start Page
1161
End Page
1162
DOI
10.1038/ng1109-1161

Scara5 Is a Ferritin Receptor Mediating Non-Transferrin Iron Delivery

Developing organs require iron for a myriad of functions, but embryos deleted of the major adult transport proteins, transferrin or its receptor transferrin receptor1 (TfR1-/-), still initiate organogenesis, suggesting that non-transferrin pathways are important. To examine these pathways, we developed chimeras composed of fluorescence-tagged TfR1-/- cells and untagged wild-type cells. In the kidney, TfR1-/- cells populated capsule and stroma, mesenchyme and nephron, but were underrepresented in ureteric bud tips. Consistently, TfR1 provided transferrin to the ureteric bud, but not to the capsule or the stroma. Instead of transferrin, we found that the capsule internalized ferritin. Since the capsule expressed a novel receptor called Scara5, we tested its role in ferritin uptake and found that Scara5 bound serum ferritin and then stimulated its endocytosis from the cell surface with consequent iron delivery. These data implicate cell type-specific mechanisms of iron traffic in organogenesis, which alternatively utilize transferrin or non-transferrin iron delivery pathways. © 2009 Elsevier Inc. All rights reserved.

Authors
Li, JY; Paragas, N; Ned, RM; Qiu, A; Viltard, M; Leete, T; Drexler, IR; Chen, X; Sanna-Cherchi, S; Mohammed, F; Williams, D; Lin, CS; Schmidt-Ott, KM; Andrews, NC; Barasch, J
MLA Citation
Li, JY, Paragas, N, Ned, RM, Qiu, A, Viltard, M, Leete, T, Drexler, IR, Chen, X, Sanna-Cherchi, S, Mohammed, F, Williams, D, Lin, CS, Schmidt-Ott, KM, Andrews, NC, and Barasch, J. "Scara5 Is a Ferritin Receptor Mediating Non-Transferrin Iron Delivery." Developmental Cell 16.1 (2009): 35-46.
PMID
19154717
Source
scival
Published In
Developmental Cell
Volume
16
Issue
1
Publish Date
2009
Start Page
35
End Page
46
DOI
10.1016/j.devcel.2008.12.002

Iron is essential for neuron development and memory function in mouse hippocampus 1-3

Iron deficiency (ID) is the most prevalent micronutrient deficiency in the world and it affects neurobehavioral outcome. It is unclear whether the effect of dietary ID on the brain is due to the lack of neuronal iron or from other processes occurring in conjunction with ID (e.g. hypoxia due to anemia). We delineated the role of murine Slc11a2 [divalent metal ion transporter-1 (DMT-1)] in hippocampal neuronal iron uptake during development and memory formation. Camk2a gene promoter-driven cre recombinase (Cre) transgene (Camk2a-Cre) mice were mated with Slc11a2 flox/flox mice to obtain nonanemic Slc11a2 hipp/hipp (double mutant, hippocampal neuron-specific knockout of Slc11a2 hipp/hipp)mice, the first conditionally targeted model of iron uptake in the brain. Slc11a2 hipp/hipp mice had lower hippocampal iron content; altered developmental expression of genes involved in iron homeostasis, energy metabolism, and dendrite morphogenesis; reductions in markers for energy metabolism and glutamatergic neurotransmission on magnetic resonance spectroscopy; and altered pyramidal neuron dendrite morphology in area 1 of Ammon's Horn in the hippocampus. Slc11a2 hipp/hipp mice did not reach the criterion on a difficult spatial navigation test but were able to learn a spatial navigation task on an easier version of the Morris water maze (MWM). Learning of the visual cued task did not differ between the Slc11a2 WT/WT and Slc11a2 hipp/hipp mice. Slc11a2 WT/WT mice had upregulation of genes involved in iron uptake and metabolism in response to MWM training, and Slc11a2 hipp/hipp mice had differential expression of these genes compared with Slc11a2 WT/WT mice. Neuronal iron uptake by DMT-1 is essential for normal hippocampal neuronal development and Slc11a2 expression is induced by spatial memory training. Deletion of Slc11a2 disrupts hippocampal neuronal development and spatial memory behavior. © 2009 American Society for Nutrition.

Authors
Carlson, ES; Tkac, I; Magid, R; O'Connor, MB; Andrews, NC; Schallert, T; Gunshin, H; Georgieff, MK; Petryk, A
MLA Citation
Carlson, ES, Tkac, I, Magid, R, O'Connor, MB, Andrews, NC, Schallert, T, Gunshin, H, Georgieff, MK, and Petryk, A. "Iron is essential for neuron development and memory function in mouse hippocampus 1-3." Journal of Nutrition 139.4 (2009): 672-679.
PMID
19211831
Source
scival
Published In
The Journal of nutrition
Volume
139
Issue
4
Publish Date
2009
Start Page
672
End Page
679
DOI
10.3945/jn.108.096354

Increased Hepcidin Expression in Mice Affected by beta-Thalassemia Reduces Iron Overload with No Effect on Anemia

Authors
Gardenghi, S; Marongiu, MF; Muirhead, K; Ramos, P; Roy, CN; Andrews, NC; Nemeth, E; Follenzi, A; Rachmilewitz, E; Giardina, P; Grady, RW; Rivella, S
MLA Citation
Gardenghi, S, Marongiu, MF, Muirhead, K, Ramos, P, Roy, CN, Andrews, NC, Nemeth, E, Follenzi, A, Rachmilewitz, E, Giardina, P, Grady, RW, and Rivella, S. "Increased Hepcidin Expression in Mice Affected by beta-Thalassemia Reduces Iron Overload with No Effect on Anemia." BLOOD 112.11 (November 16, 2008): 53-53.
Source
wos-lite
Published In
Blood
Volume
112
Issue
11
Publish Date
2008
Start Page
53
End Page
53

Forging a field: the golden age of iron biology.

Authors
Andrews, NC
MLA Citation
Andrews, NC. "Forging a field: the golden age of iron biology." Blood 112.2 (July 15, 2008): 219-230. (Review)
PMID
18606887
Source
pubmed
Published In
Blood
Volume
112
Issue
2
Publish Date
2008
Start Page
219
End Page
230
DOI
10.1182/blood-2007-12-077388

Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA).

Iron deficiency is usually attributed to chronic blood loss or inadequate dietary intake. Here, we show that iron deficiency anemia refractory to oral iron therapy can be caused by germline mutations in TMPRSS6, which encodes a type II transmembrane serine protease produced by the liver that regulates the expression of the systemic iron regulatory hormone hepcidin. These findings demonstrate that TMPRSS6 is essential for normal systemic iron homeostasis in humans.

Authors
Finberg, KE; Heeney, MM; Campagna, DR; Aydinok, Y; Pearson, HA; Hartman, KR; Mayo, MM; Samuel, SM; Strouse, JJ; Markianos, K; Andrews, NC; Fleming, MD
MLA Citation
Finberg, KE, Heeney, MM, Campagna, DR, Aydinok, Y, Pearson, HA, Hartman, KR, Mayo, MM, Samuel, SM, Strouse, JJ, Markianos, K, Andrews, NC, and Fleming, MD. "Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA)." Nature genetics 40.5 (May 2008): 569-571.
PMID
18408718
Source
epmc
Published In
Nature Genetics
Volume
40
Issue
5
Publish Date
2008
Start Page
569
End Page
571
DOI
10.1038/ng.130

The science of climbing the academic ladder. Interview by Barbara Kantrowitz and Holly Peterson.

Authors
Andrews, N
MLA Citation
Andrews, N. "The science of climbing the academic ladder. Interview by Barbara Kantrowitz and Holly Peterson." Newsweek 152.15 (2008): 72--.
PMID
19004137
Source
scival
Published In
Newsweek
Volume
152
Issue
15
Publish Date
2008
Start Page
72-

Deletion of Trpm7 disrupts embryonic development and thymopoiesis without altering Mg2+ homeostasis

The gene transient receptor potential-melastatin-like 7 (Trpm7) encodes a protein that functions as an ion channel and a kinase. TRPM7 has been proposed to be required for cellular Mg2+ homeostasis in vertebrates. Deletion of mouse Trpm7 revealed that it is essential for embryonic development. Tissue-specific deletion of Trpm7 in the T cell lineage disrupted thymopoiesis, which led to a developmental block of thymocytes at the double-negative stage and a progressive depletion of thymic medullary cells. However, deletion of Trpm7 in T cells did not affect acute uptake of Mg2+ or the maintenance of total cellular Mg2+. Trpm7-deficient thymocytes exhibited dysregulated synthesis of many growth factors that are necessary for the differentiation and maintenance of thymic epithelial cells. The thymic medullary cells lost signal transducer and activator of transcription 3 activity, which accounts for their depletion when Trpm7 is disrupted in thymocytes.

Authors
Jin, J; Desai, BN; Navarro, B; Donovan, A; Andrews, NC; Clapham, DE
MLA Citation
Jin, J, Desai, BN, Navarro, B, Donovan, A, Andrews, NC, and Clapham, DE. "Deletion of Trpm7 disrupts embryonic development and thymopoiesis without altering Mg2+ homeostasis." Science 322.5902 (2008): 756-760.
PMID
18974357
Source
scival
Published In
Science
Volume
322
Issue
5902
Publish Date
2008
Start Page
756
End Page
760
DOI
10.1126/science.1163493

Hematopoietic-specific Stat5-null mice display microcytic hypochromic anemia associated with reduced transferrin receptor gene expression

Iron is essential for all cells but is toxic in excess, so iron absorption and distribution are tightly regulated. Serum iron is bound to transferrin and enters erythroid cells primarily via receptor-mediated endocytosis of the transferrin receptor (Tfr1). Tfr1 is essential for developing erythrocytes and reduced Tfr1 expression is associated with anemia. The transcription factors STAT5A/B are activated by many cytokines, including erythropoietin. Stat5aA/b -/- mice are severely anemic and die perinatally, but no link has been made to iron homeostasis. To study the function of STAT5A/B in vivo, we deleted the f floxed Stat5a/b locus in hematopoietic cells with a Tie2-Cre transgene. These mice exhibited microcytic, hypochromic anemia, as did lethally irradiated mice that received a transplant of Stat5a/b -/- fetal liver cells. Flow cytometry and RNA analyses of erythroid cells from mutant mice revealed a 50% reduction in Tfr1 mRNA and protein. We detected STAT5A/B binding sites in the first intron of the Tfr1 gene and found that expression of constitutively active STAT5A in an erythroid cell line increased Tfr1 levels. Chromatin immunoprecipitation experiments confirmed the binding of STAT5A/B to these sites. We conclude that STAT5A/B is an important regulator of iron update in erythroid progenitor cells via its control of Tfr1 transcription.

Authors
Zhu, B-M; McLaughlin, SK; Na, R; Liu, J; Cui, Y; Martin, C; Kimura, A; Robinson, GW; Andrews, NC; Hennighausen, L
MLA Citation
Zhu, B-M, McLaughlin, SK, Na, R, Liu, J, Cui, Y, Martin, C, Kimura, A, Robinson, GW, Andrews, NC, and Hennighausen, L. "Hematopoietic-specific Stat5-null mice display microcytic hypochromic anemia associated with reduced transferrin receptor gene expression." Blood 112.5 (2008): 2071-2080.
PMID
18552213
Source
scival
Published In
Blood
Volume
112
Issue
5
Publish Date
2008
Start Page
2071
End Page
2080
DOI
10.1182/blood-2007-12-127480

Deficiency of heme-regulated eIF2α kinase decreases hepcidin expression and splenic iron in HFE-/- mice

Heme-regulated eIF2α kinase (HRI) is essential for regulating globin translation in iron deficiency and in β-thalassemia. We investigated the role of heme-regulated eIF2α kinase in hemoglobin and red blood cell production as well as in iron homeostasis in a mouse model of iron overload. We show that HRI deficiency does not significantly affect red cell parameters of hemochromatosis (HFE-/-) mice. Importantly, heme-regulated eIF2α kinase deficiency exacerbates decreases in hepcidin expression and splenic macrophage iron in HFE-/- mice. Furthermore, the serum level of bone morphogenic protein 2, which positively regulates hepcidin, is reduced in heme-regulated eIF2α kinase deficiency, but not in HFE deficiency. ©2008 Ferrata Storti Foundation.

Authors
Liu, S; Suragani, RNVS; Han, A; Zhao, W; Andrews, NC; Chen, J-J
MLA Citation
Liu, S, Suragani, RNVS, Han, A, Zhao, W, Andrews, NC, and Chen, J-J. "Deficiency of heme-regulated eIF2α kinase decreases hepcidin expression and splenic iron in HFE-/- mice." Haematologica 93.5 (2008): 753-756.
PMID
18367482
Source
scival
Published In
Haematologica
Volume
93
Issue
5
Publish Date
2008
Start Page
753
End Page
756
DOI
10.3324/haematol.12175

The Transferrin Receptor Modulates Hfe-Dependent Regulation of Hepcidin Expression

Hemochromatosis is caused by mutations in HFE, a protein that competes with transferrin (TF) for binding to transferrin receptor 1 (TFR1). We developed mutant mouse strains to gain insight into the role of the Hfe/Tfr1 complex in regulating iron homeostasis. We introduced mutations into a ubiquitously expressed Tfr1 transgene or the endogenous Tfr1 locus to promote or prevent the Hfe/Tfr1 interaction. Under conditions favoring a constitutive Hfe/Tfr1 interaction, mice developed iron overload attributable to inappropriately low expression of the hormone hepcidin. In contrast, mice carrying a mutation that interferes with the Hfe/Tfr1 interaction developed iron deficiency associated with inappropriately high hepcidin expression. High-level expression of a liver-specific Hfe transgene in Hfe-/- mice was also associated with increased hepcidin production and iron deficiency. Together, these models suggest that Hfe induces hepcidin expression when it is not in complex with Tfr1. © 2008 Elsevier Inc. All rights reserved.

Authors
Schmidt, PJ; Toran, PT; Giannetti, AM; Bjorkman, PJ; Andrews, NC
MLA Citation
Schmidt, PJ, Toran, PT, Giannetti, AM, Bjorkman, PJ, and Andrews, NC. "The Transferrin Receptor Modulates Hfe-Dependent Regulation of Hepcidin Expression." Cell Metabolism 7.3 (2008): 205-214.
PMID
18316026
Source
scival
Published In
Cell Metabolism
Volume
7
Issue
3
Publish Date
2008
Start Page
205
End Page
214
DOI
10.1016/j.cmet.2007.11.016

Iron Homeostasis and Erythropoiesis

Erythrocytes require iron to perform their duty as oxygen carriers. Mammals have evolved a mechanism to maintain systemic iron within an optimal range that fosters erythroid development and function while satisfying other body iron needs. This chapter reviews erythroid iron uptake and utilization as well as systemic factors that influence iron availability. One of these factors is hepcidin, a circulating peptide hormone that maintains iron homeostasis. Elevated levels of hepcidin in the bloodstream effectively shut off iron absorption by disabling the iron exporter ferroportin. Conversely, low levels of circulating hepcidin allow ferroportin to export iron into the bloodstream. Aberrations in hepcidin expression or responsiveness to hepcidin result in disorders of iron deficiency and iron overload. It is clear that erythroid precursors communicate their iron needs to the liver to influence the production of hepcidin and thus the amount of iron available for use. However, the mechanism by which erythroid cells accomplish this remains unclear and is an area of active investigation. © 2008 Elsevier Inc. All rights reserved.

Authors
Wrighting, DM; Andrews, NC
MLA Citation
Wrighting, DM, and Andrews, NC. "Iron Homeostasis and Erythropoiesis." Current Topics in Developmental Biology 82 (2008): 141-167.
PMID
18282520
Source
scival
Published In
Current topics in developmental biology
Volume
82
Publish Date
2008
Start Page
141
End Page
167
DOI
10.1016/S0070-2153(07)00006-3

Climbing through medicine's glass ceiling.

Authors
Andrews, NC
MLA Citation
Andrews, NC. "Climbing through medicine's glass ceiling." N Engl J Med 357.19 (November 8, 2007): 1887-1889.
PMID
17989380
Source
pubmed
Published In
The New England journal of medicine
Volume
357
Issue
19
Publish Date
2007
Start Page
1887
End Page
1889
DOI
10.1056/NEJMp078198

The function of heme-regulated eIF2α kinase in murine iron homeostasis and macrophage maturation

Heme-regulated eIF2α kinase (HRI) plays an essential protective role in anemias of iron deficiency, erythroid protoporphyria, and β-thalassemia. In this study, we report that HRI protein is present in murine macrophages, albeit at a lower level than in erythroid precursors. Hri-/- mice exhibited impaired macrophage maturation and a weaker antiinflammatory response with reduced cytokine production upon LPS challenge. The level of production of hepcidin, an important player in the pathogenesis of the anemia of inflammation, was significantly decreased in Hri-/- mice, accompanied by decreased splenic macrophage iron content and increased serum iron content. Hepcidin expression was also significantly lower, with a concomitant increase in serum iron in Hri-/- mice upon LPS treatment. We also demonstrated an impairment of erythrophagocytosis by Hri-/- macrophages both in vitro and in vivo under chronic hemolytic anemia, providing evidence for the role of HRI in recycling iron from senescent red blood cells. This work demonstrates that HRI deficiency attenuates hepcidin expression and iron homeostasis in mice, indicating a potential role for HRI in the anemia of inflammation.

Authors
Liu, S; Suragani, RNVS; Wang, F; Han, A; Zhao, W; Andrews, NC; Chen, J-J
MLA Citation
Liu, S, Suragani, RNVS, Wang, F, Han, A, Zhao, W, Andrews, NC, and Chen, J-J. "The function of heme-regulated eIF2α kinase in murine iron homeostasis and macrophage maturation." Journal of Clinical Investigation 117.11 (2007): 3296-3305.
PMID
17932563
Source
scival
Published In
Journal of Clinical Investigation
Volume
117
Issue
11
Publish Date
2007
Start Page
3296
End Page
3305
DOI
10.1172/JCI32084

Genetic variation in Mon1a affects protein trafficking and modifies macrophage iron loading in mice

We undertook a quantitative trait locus (QTL) analysis in mice to identify modifier genes that might influence the severity of human iron disorders. We identified a strong QTL on mouse chromosome 9 that differentially affected macrophage iron burden in C57BL/10J and SWR/J mice. A C57BL/10J missense allele of an evolutionarily conserved gene, Mon1a, cosegregated with the QTL in congenic mouse lines. We present evidence that Mon1a is involved in trafficking of ferroportin, the major mammalian iron exporter, to the surface of iron-recycling macrophages. Differences in amounts of surface ferroportin correlate with differences in cellular iron content. Mon1a is also important for trafficking of cell-surface and secreted molecules unrelated to iron metabolism, suggesting that it has a fundamental role in the mammalian secretory apparatus. © 2007 Nature Publishing Group.

Authors
Wang, F; Paradkar, PN; Custodio, AO; Ward, DM; Fleming, MD; Campagna, D; Roberts, KA; Boyartchuk, V; Dietrich, WF; Kaplan, J; Andrews, NC
MLA Citation
Wang, F, Paradkar, PN, Custodio, AO, Ward, DM, Fleming, MD, Campagna, D, Roberts, KA, Boyartchuk, V, Dietrich, WF, Kaplan, J, and Andrews, NC. "Genetic variation in Mon1a affects protein trafficking and modifies macrophage iron loading in mice." Nature Genetics 39.8 (2007): 1025-1032.
PMID
17632513
Source
scival
Published In
Nature Genetics
Volume
39
Issue
8
Publish Date
2007
Start Page
1025
End Page
1032
DOI
10.1038/ng2059

A novel murine protein with no effect on iron homoeostasis is homologous with transferrin and is the putative inhibitor of carbonic anhydrase

In a search for genes that modify iron homoeostasis, a gene (1300017J02Rik) was located immediately upstream of the murine TF (transferrin) gene. However, expression of the 1300017J02Rik gene product was not responsive to a number of modulators of iron metabolism. Specifically, expression was not altered in mouse models of iron disorders including mice with deficiencies in the haemochromatosis protein Hfe, the recombination-activating protein, Rag, β2-microglobulin, TF, ceruloplasmin or Hb, or in mice with microcytic anaemia. Additionally, neither lipopolysaccharide nor hypoxia treatment resulted in any significant changes in the 1300017J02Rik expression level. The genomic DNA sequence suggested that the 1300017J02Rik gene product might be a protein equivalent to the pICA {porcine ICA [inhibitor of CA (carbonic anhydrase)]}. The coding region for the murine 1300017J02Rik gene was placed into the pNUT expression vector. Transformed BHK cells (baby-hamster kidney cells) were transfected with this plasmid, resulting in secretion of recombinant mICA (murine ICA) into the tissue culture medium. Following purification to homogeneity, the yield of mICA from the BHK cells was found to be considerably greater (at least 4-fold) than the yield of pICA from a previously reported Pichia pastoris (yeast) expression system. MS showed that the recombinant mICA was a glycoprotein that associated with CA in a 1:1 stoichiometry. Despite its high sequence similarity to TF, titration experiments showed that mICA was unable to bind iron specifically. Although enzymatic assays revealed that mICA was able to inhibit CA, it is unclear if this is its sole or even its major function since, to date, humans and other primates appear to lack functional ICA. Lastly, we note that this member of the TF superfamily is a relatively recent addition resulting from a tandem duplication event. © The Authors.

Authors
Wang, F; Lothrop, AP; James, NG; Griffiths, TAM; Lambert, LA; Leverence, R; Kaltashov, IA; Andrews, NC; MacGillivray, RTA; Mason, AB
MLA Citation
Wang, F, Lothrop, AP, James, NG, Griffiths, TAM, Lambert, LA, Leverence, R, Kaltashov, IA, Andrews, NC, MacGillivray, RTA, and Mason, AB. "A novel murine protein with no effect on iron homoeostasis is homologous with transferrin and is the putative inhibitor of carbonic anhydrase." Biochemical Journal 406.1 (2007): 85-95.
PMID
17511619
Source
scival
Published In
The Biochemical journal
Volume
406
Issue
1
Publish Date
2007
Start Page
85
End Page
95
DOI
10.1042/BJ20070384

Ineffective erythropoiesis in β-thalassemia is characterized by increased iron absorption mediated by down-regulation of hepcidin and up-regulation of ferroportin

Progressive iron overload is the most salient and ultimately fatal complication of β-thalassemia. However, little is known about the relationship among ineffective erythropoiesis (IE), the role of iron-regulatory genes, and tissue iron distribution in β-thalassemia. We analyzed tissue iron content and iron-regulatory gene expression in the liver, duodenum, spleen, bone marrow, kidney, and heart of mice up to 1 year old that exhibit levels of iron overload and anemia consistent with both β-thalassemia intermedia (th3/+) and major (th3/th3). Here we show, for the first time, that tissue and cellular iron distribution are abnormal and different in th3/+ and th3/th3 mice, and that transfusion therapy can rescue mice affected by β-thalassemia major and modify both the absorption and distribution of iron. Our study reveals that the degree of IE dictates tissue iron distribution and that IE and iron content regulate hepcidin (Hamp1) and other iron-regulatory genes such as Hfe and Cebpa. In young th3/+ and th3/th3 mice, low Hamp1 levels are responsible for increased iron absorption. However, in 1-year-old th3/+ animals, Hamp1 levels rise and it is rather the increase of ferroportin (Fpn1) that sustains iron accumulation, thus revealing a fundamental role of this iron transporter in the iron overload of β-thalassemia. © 2007 by The American Society of Hematology.

Authors
Gardenghi, S; Marongiu, MF; Ramos, P; Guy, E; Breda, L; Chadburn, A; Liu, Y; Amariglio, N; Rechavi, G; Rachmilewitz, EA; Breuer, W; Cabantchik, ZI; Wrighting, DM; Andrews, NC; Sousa, MD; Giardina, PJ; Grady, RW; Rivella, S
MLA Citation
Gardenghi, S, Marongiu, MF, Ramos, P, Guy, E, Breda, L, Chadburn, A, Liu, Y, Amariglio, N, Rechavi, G, Rachmilewitz, EA, Breuer, W, Cabantchik, ZI, Wrighting, DM, Andrews, NC, Sousa, MD, Giardina, PJ, Grady, RW, and Rivella, S. "Ineffective erythropoiesis in β-thalassemia is characterized by increased iron absorption mediated by down-regulation of hepcidin and up-regulation of ferroportin." Blood 109.11 (2007): 5027-5035.
PMID
17299088
Source
scival
Published In
Blood
Volume
109
Issue
11
Publish Date
2007
Start Page
5027
End Page
5035
DOI
10.1182/blood-2006-09-048868

Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance

Systemic iron balance is regulated by hepcidin, a peptide hormone secreted by the liver. By decreasing cell surface expression of the iron exporter ferroportin, hepcidin decreases iron absorption from the intestine and iron release from reticuloendothelial stores. Hepcidin excess has been implicated in the pathogenesis of anemia of chronic disease, while hepcidin deficiency has a key role in the pathogenesis of the iron overload disorder hemochromatosis. We have recently shown that hemojuvelin is a coreceptor for bone morphogenetic protein (BMP) signaling and that BMP signaling positively regulates hepcidin expression in liver cells in vitro. Here we show that BMP-2 administration increases hepcidin expression and decreases serum iron levels in vivo. We also show that soluble hemojuvelin (HJV.Fc) selectively inhibits BMP induction of hepcidin expression in vitro and that administration of HJV.Fc decreases hepcidin expression, increases ferroportin expression, mobilizes splenic iron stores, and increases serum iron levels in vivo. These data support a role for modulators of the BMP signaling pathway in treating diseases of iron overload and anemia of chronic disease.

Authors
Babitt, JL; Huang, FW; Xia, Y; Sidis, Y; Andrews, NC; Lin, HY
MLA Citation
Babitt, JL, Huang, FW, Xia, Y, Sidis, Y, Andrews, NC, and Lin, HY. "Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance." Journal of Clinical Investigation 117.7 (2007): 1933-1939.
PMID
17607365
Source
scival
Published In
Journal of Clinical Investigation
Volume
117
Issue
7
Publish Date
2007
Start Page
1933
End Page
1939
DOI
10.1172/JCI31342

Of mice and iron: Ferroportin disease

Authors
Andrews, NC
MLA Citation
Andrews, NC. "Of mice and iron: Ferroportin disease." Blood 109.10 (2007): 4115--.
Source
scival
Published In
Blood
Volume
109
Issue
10
Publish Date
2007
Start Page
4115-
DOI
10.1182/blood-2007-02-075739

Hepcidin antimicrobial peptide transgenic mice exhibit features of the anemia of inflammation

The anemia of inflammation is an acquired disorder affecting patients with a variety of medical conditions, and it is characterized by changes in iron homeostasis and erythropoiesis. Mounting evidence suggests that hepcidin antimicrobial peptide plays a primary role in the pathogenesis of the anemia of inflammation. To evaluate which features of this anemia can be attributed to hepcidin, we have generated mice carrying a tetracycline-regulated hepcidin transgene. Expression of the hepcidin transgene resulted in down-regulation of endogenous hepcidin mRNA. The transgenic mice developed a mild-to-moderate anemia associated with iron deficiency and ironrestricted erythropoiesis. Similar to the anemia of inflammation, iron accumulated in tissue macrophages, whereas a relative paucity of iron was found in the liver. Circulating erythrocytes in transgenic animals had normal survival rates, but transgenic animals had an impaired response to erythropoietin. Thus, hepcidin transgenic mice recapitulate each of the key features of anemia of inflammation in human patients and serve as a useful model of this prevalent disorder. © 2007 by The American Society of Hematology.

Authors
Roy, CN; Mak, HH; Akpan, I; Losyev, G; Zurakowski, D; Andrews, NC
MLA Citation
Roy, CN, Mak, HH, Akpan, I, Losyev, G, Zurakowski, D, and Andrews, NC. "Hepcidin antimicrobial peptide transgenic mice exhibit features of the anemia of inflammation." Blood 109.9 (2007): 4038-4044.
PMID
17218383
Source
scival
Published In
Blood
Volume
109
Issue
9
Publish Date
2007
Start Page
4038
End Page
4044
DOI
10.1182/blood-2006-10-051755

Transferrin receptor 1 is a cellular receptor for New World haemorrhagic fever arenaviruses

At least five arenaviruses cause viral haemorrhagic fevers in humans. Lassa virus, an Old World arenavirus, uses the cellular receptor α-dystroglycan to infect cells. Machupo, Guanarito, Junin and Sabia viruses are New World haemorrhagic fever viruses that do not use α-dystroglycan. Here we show a specific, high-affinity association between transferrin receptor 1 (TfR1) and the entry glycoprotein (GP) of Machupo virus. Expression of human TfR1, but not human transferrin receptor 2, in hamster cell lines markedly enhanced the infection of viruses pseudotyped with the GP of Machupo, Guanarito and Junin viruses, but not with those of Lassa or lymphocytic choriomeningitis viruses. An anti-TfR1 antibody efficiently inhibited the replication of Machupo, Guanarito, Junin and Sabia viruses, but not that of Lassa virus. Iron depletion of culture medium enhanced, and iron supplementation decreased, the efficiency of infection by Junin and Machupo but not Lassa pseudoviruses. These data indicate that TfR1 is a cellular receptor for New World haemorrhagic fever arenaviruses. ©2007 Nature Publishing Group.

Authors
Radoshitzky, SR; Abraham, J; Spiropoulou, CF; Kuhn, JH; Nguyen, D; Li, W; Nagel, J; Schmidt, PJ; Nunberg, JH; Andrews, NC; Farzan, M; Choe, H
MLA Citation
Radoshitzky, SR, Abraham, J, Spiropoulou, CF, Kuhn, JH, Nguyen, D, Li, W, Nagel, J, Schmidt, PJ, Nunberg, JH, Andrews, NC, Farzan, M, and Choe, H. "Transferrin receptor 1 is a cellular receptor for New World haemorrhagic fever arenaviruses." Nature 446.7131 (2007): 92-96.
PMID
17287727
Source
scival
Published In
Nature
Volume
446
Issue
7131
Publish Date
2007
Start Page
92
End Page
96
DOI
10.1038/nature05539

Iron homeostasis

Iron is needed by all mammalian cells but is toxic in excess. Specialized transport mechanisms conduct iron across cellular membranes. These are regulated to ensure homeostasis both systemically in living organisms and within individual cells. Over the past decade, major advances have been made in identifying and characterizing the proteins involved in the transport, handling, and homeostatic regulation of iron. Molecular understanding of these processes has provided important insights into the pathophysiology of human iron disorders. Copyright © 2007 by Annual Reviews. All rights reserved.

Authors
Andrews, NC; Schmidt, PJ
MLA Citation
Andrews, NC, and Schmidt, PJ. "Iron homeostasis." Annual Review of Physiology 69 (2007): 69-85.
PMID
17014365
Source
scival
Published In
Annual Review of Physiology
Volume
69
Publish Date
2007
Start Page
69
End Page
85
DOI
10.1146/annurev.physiol.69.031905.164337

When Is a Heme Transporter Not a Heme Transporter? When It's a Folate Transporter

Essential nutrients enter the body through a variety of specific transporter molecules expressed in the intestinal epithelium. A recent paper by Qiu et al. (2006) elegantly demonstrates that one of these transporters, previously thought to carry heme, is in fact an important folate transporter. © 2007 Elsevier Inc. All rights reserved.

Authors
Andrews, NC
MLA Citation
Andrews, NC. "When Is a Heme Transporter Not a Heme Transporter? When It's a Folate Transporter." Cell Metabolism 5.1 (2007): 5-6.
PMID
17189201
Source
scival
Published In
Cell Metabolism
Volume
5
Issue
1
Publish Date
2007
Start Page
5
End Page
6
DOI
10.1016/j.cmet.2006.12.004

Iron metabolism

Iron is an essential element that is toxic when it accumulates in excess. Intricate regulatory mechanisms have evolved to maintain iron homeostasis within cells and between different tissues of complex organisms. This chapter discusses the proteins involved in iron transport and storage, and their regulation in health and disease. © 2006 Humana Press Inc.

Authors
Andrews, NC
MLA Citation
Andrews, NC. "Iron metabolism." (December 1, 2006): 848-853. (Chapter)
Source
scopus
Publish Date
2006
Start Page
848
End Page
853
DOI
10.1007/978-1-59259-963-9_87

Hereditary hemochromatosis protein, HFE, interaction with transferrin receptor 2 suggests a molecular mechanism for mammalian iron sensing

HFE and transferrin receptor 2 (TFR2) are membrane proteins integral to mammalian iron homeostasis and associated with human hereditary hemochromatosis. Here we demonstrate that HFE and TFR2 interact in cells, that this interaction is not abrogated by disease-associated mutations of HFE and TFR2, and that TFR2 competes with TFR1 for binding to HFE. We propose a new model for the mechanism of iron status sensing that results in the regulation of iron homeostasis. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.

Authors
Goswami, T; Andrews, NC
MLA Citation
Goswami, T, and Andrews, NC. "Hereditary hemochromatosis protein, HFE, interaction with transferrin receptor 2 suggests a molecular mechanism for mammalian iron sensing." Journal of Biological Chemistry 281.39 (2006): 28494-28498.
PMID
16893896
Source
scival
Published In
The Journal of biological chemistry
Volume
281
Issue
39
Publish Date
2006
Start Page
28494
End Page
28498
DOI
10.1074/jbc.C600197200

Interleukin-6 induces hepcidin expression through STAT3

Iron homeostasis is maintained through meticulous regulation of circulating hepcidin levels. Hepcidin levels that are inappropriately low or high result in iron overload or iron deficiency, respectively. Although hypoxia, erythroid demand, iron, and inflammation are all known to influence hepcidin expression, the mechanisms responsible are not well defined. In this report we show that the inflammatory cytokine interleukin-6 (IL-6) directly regulates hepcidin through induction and subsequent promoter binding of signal transducer and activator of transcription 3 (STAT3). STAT3 is necessary and sufficient for the IL-6 responsiveness of the hepcidin promoter. Our findings provide a mechanism by which hepcidin can be regulated by inflammation or, in the absence of inflammatory stimuli, by alternative mechanisms leading to STAT3 activation. © 2006 by The American Society of Hematology.

Authors
Wrighting, DM; Andrews, NC
MLA Citation
Wrighting, DM, and Andrews, NC. "Interleukin-6 induces hepcidin expression through STAT3." Blood 108.9 (2006): 3204-3209.
PMID
16835372
Source
scival
Published In
Blood
Volume
108
Issue
9
Publish Date
2006
Start Page
3204
End Page
3209
DOI
10.1182/blood-2006-06-027631

Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression

Hepcidin is a key regulator of systemic iron homeostasis. Hepcidin deficiency induces iron overload, whereas hepcidin excess induces anemia. Mutations in the gene encoding hemojuvelin (HFE2, also known as HJV) cause severe iron overload and correlate with low hepcidin levels, suggesting that hemojuvelin positively regulates hepcidin expression. Hemojuvelin is a member of the repulsive guidance molecule (RGM) family, which also includes the bone morphogenetic protein (BMP) coreceptors RGMA and DRAGON (RGMB). Here, we report that hemojuvelin is a BMP coreceptor and that hemojuvelin mutants associated with hemochromatosis have impaired BMP signaling ability. Furthermore, BMP upregulates hepatocyte hepcidin expression, a process enhanced by hemojuvelin and blunted in Hfe2-/- hepatocytes. Our data suggest a mechanism by which HFE2 mutations cause hemochromatosis: hemojuvelin dysfunction decreases BMP signaling, thereby lowering hepcidin expression. © 2006 Nature Publishing Group.

Authors
Babitt, JL; Huang, FW; Wrighting, DM; Xia, Y; Sidis, Y; Samad, TA; Campagna, JA; Chung, RT; Schneyer, AL; Woolf, CJ; Andrews, NC; Lin, HY
MLA Citation
Babitt, JL, Huang, FW, Wrighting, DM, Xia, Y, Sidis, Y, Samad, TA, Campagna, JA, Chung, RT, Schneyer, AL, Woolf, CJ, Andrews, NC, and Lin, HY. "Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression." Nature Genetics 38.5 (2006): 531-539.
PMID
16604073
Source
scival
Published In
Nature Genetics
Volume
38
Issue
5
Publish Date
2006
Start Page
531
End Page
539
DOI
10.1038/ng1777

The ins and outs of iron homeostasis

Iron is an essential element that is toxic when it accumulates in excess. Intricate regulatory mechanisms have evolved to maintain iron homeostasis within cells and between different tissues of complex organisms. This review discusses the proteins involved in iron transport and storage and their regulation in health and disease. ©2006 Int. Union Physiol. Sci./Am. Physiol. Soc.

Authors
Donovan, A; Roy, CN; Andrews, NC
MLA Citation
Donovan, A, Roy, CN, and Andrews, NC. "The ins and outs of iron homeostasis." Physiology 21.2 (2006): 115-123.
PMID
16565477
Source
scival
Published In
Physiology (Bethesda, Md.)
Volume
21
Issue
2
Publish Date
2006
Start Page
115
End Page
123
DOI
10.1152/physiol.00052.2005

Chronic hepcidin induction causes hyposideremia and alters the pattern of cellular iron accumulation in hemochromatotic mice

We report the generation of a tetracyclineregulated (Tet ON) transgenic mouse model for acute and chronic expression of the iron regulatory peptide hepcidin in the liver. We demonstrate that short-term and long-term tetracycline-dependent activation of hepcidin in adult mice leads to hypoferremia and iron-limited erythropoiesis, respectively. This clearly establishes the key role of hepcidin in regulating the extracellular iron concentration. We previously demonstrated that, when expressed early in fetal development, constitutive transgenic hepcidin expression prevented iron accumulation in an Hfe-/- mouse model of hemochromatosis. We now explore the effect of chronic hepcidin expression in adult Hfe-/- mice that have already developed liver iron overload. We demonstrate that induction of chronic hepcidin expression in 2-month-old Hfe-/- mice alters their pattern of cellular iron accumulation, leading to increased iron in tissue macrophages and duodenal cells but less iron in hepatocytes. These hepcidin-induced changes in the pattern of cellular iron accumulation are associated with decreased expression of the iron exporter ferroportin in macrophages but no detectable alteration of ferroportin expression in the hepatocytes. We speculate that this change in iron homeostasis could offer a therapeutic advantage by protecting against damage to parenchymal cells. © 2006 by The American Society of Hematology.

Authors
Viatte, L; Nicolas, G; Lou, D-Q; Bennoun, M; Lesbordes-Brion, J-C; Canonne-Hergaux, F; Schönig, K; Bujard, H; Kahn, A; Andrews, NC; Vaulont, S
MLA Citation
Viatte, L, Nicolas, G, Lou, D-Q, Bennoun, M, Lesbordes-Brion, J-C, Canonne-Hergaux, F, Schönig, K, Bujard, H, Kahn, A, Andrews, NC, and Vaulont, S. "Chronic hepcidin induction causes hyposideremia and alters the pattern of cellular iron accumulation in hemochromatotic mice." Blood 107.7 (2006): 2952-2958.
PMID
16339398
Source
scival
Published In
Blood
Volume
107
Issue
7
Publish Date
2006
Start Page
2952
End Page
2958
DOI
10.1182/blood-2005-10-4071

Iron Absorption

Authors
Andrews, NC
MLA Citation
Andrews, NC. "Iron Absorption." Physiology of the Gastrointestinal Tract 2 (2006): 1983-1992.
Source
scival
Published In
Physiology of the Gastrointestinal Tract
Volume
2
Publish Date
2006
Start Page
1983
End Page
1992
DOI
10.1016/B978-012088394-3/50081-7

The role of duodenal cytochrome b in intestinal iron absorption remains unclear [2] (multiple letters)

Authors
Frazer, DM; Wilkins, SJ; Vulpe, CD; Anderson, GJ; Andrews, NC; Gunshin, H
MLA Citation
Frazer, DM, Wilkins, SJ, Vulpe, CD, Anderson, GJ, Andrews, NC, and Gunshin, H. "The role of duodenal cytochrome b in intestinal iron absorption remains unclear [2] (multiple letters)." Blood 106.13 (2005): 4413-4414.
PMID
16326980
Source
scival
Published In
Blood
Volume
106
Issue
13
Publish Date
2005
Start Page
4413
End Page
4414
DOI
10.1182/blood-2005-07-2923

Iron in skin of mice with three etiologies of systemic iron overload

In human hemochromatosis, tissue toxicity is a function of tissue iron levels. Despite reports of skin toxicity in hemochromatosis, little is known about iron levels in skin of individuals with systemic iron overload. We measured skin iron and studied skin histology in three mouse models of systemic iron overload: mice with a deletion of the hemochromatosis (Hfe) gene, mice fed a high iron diet, and mice given parenteral injections of iron. In Hfe -/- mice, iron content in the epidermis and dermis was unexpectedly the same as in Hfe+/+ mice, and there were no histological abnormalities detected after 30 wk. A high iron diet produced increased iron in the epidermis of both normal and Hfe-/- animals; a high diet increased iron in the dermis only in Hfe-/- mice. Increased skin iron was not associated with other histological changes, even after 19 wk. Parenteral administration of iron produced increased iron in the epidermis and dermis, and gave the skin a bronze hue. These results show that the amount and distribution of iron in the skin depends on the etiology of iron overload. It appears that neither Hfe deletion nor elevated skin iron alone can account for cutaneous manifestations reportedly seen in humans with hereditary hemochromatosis. Copyright © 2005 by The Society for Investigative Dermatology, Inc.

Authors
Adams, BD; Lazova, R; Andrews, NC; Milstone, LM
MLA Citation
Adams, BD, Lazova, R, Andrews, NC, and Milstone, LM. "Iron in skin of mice with three etiologies of systemic iron overload." Journal of Investigative Dermatology 125.6 (2005): 1200-1205.
PMID
16354190
Source
scival
Published In
Journal of Investigative Dermatology
Volume
125
Issue
6
Publish Date
2005
Start Page
1200
End Page
1205
DOI
10.1111/j.0022-202X.2005.23949.x

Understanding heme transport

Authors
Andrews, NC
MLA Citation
Andrews, NC. "Understanding heme transport." New England Journal of Medicine 353.23 (2005): 2508-2509.
PMID
16339100
Source
scival
Published In
The New England journal of medicine
Volume
353
Issue
23
Publish Date
2005
Start Page
2508
End Page
2509
DOI
10.1056/NEJMcibr053987

Analysis of the E399D mutation in SLC11A2 (mutiple letters)

Authors
Gunshin, H; Jin, J; Fujiwara, Y; Andrews, NC; Mims, M; Prchal, J
MLA Citation
Gunshin, H, Jin, J, Fujiwara, Y, Andrews, NC, Mims, M, and Prchal, J. "Analysis of the E399D mutation in SLC11A2 (mutiple letters)." Blood 106.6 (2005): 2221-2222.
PMID
16140868
Source
scival
Published In
Blood
Volume
106
Issue
6
Publish Date
2005
Start Page
2221
End Page
2222
DOI
10.1182/blood-2005-03-1192

A mutation in Sec15l1 causes anemia in hemoglobin deficit (hbd) mice

Hemoglobin deficit (hbd) mice carry a spontaneous mutation that impairs erythroid iron assimilation but does not cause other defects. Normal delivery of iron to developing erythroid precursors is highly dependent on the transferrin cycle. Through genetic mapping and complementation experiments, we show that the hbd mutation is an in-frame deletion of a conserved exon of the mouse gene Sec15l1, encoding one of two Sec15 proteins implicated in the mammalian exocyst complex. Sec15l1 is linked to the transferrin cycle through its interaction with Rab11, a GTPase involved in vesicular trafficking. We propose that inactivation of Sec15l1 alters recycling of transferrin cycle endosomes and increases the release of transferrin receptor exocytic vesicles. This in turn decreases erythroid iron uptake. Determining the molecular basis of the hbd phenotype provides new insight into the intricate mechanisms necessary for normal erythroid iron uptake and the function of a mammalian exocyst protein. © 2005 Nature Publishing Group.

Authors
Lim, JE; Jin, O; Bennett, C; Morgan, K; Wang, F; III, CCT; Fleming, MD; Andrews, NC
MLA Citation
Lim, JE, Jin, O, Bennett, C, Morgan, K, Wang, F, III, CCT, Fleming, MD, and Andrews, NC. "A mutation in Sec15l1 causes anemia in hemoglobin deficit (hbd) mice." Nature Genetics 37.11 (2005): 1270-1273.
PMID
16227995
Source
scival
Published In
Nature Genetics
Volume
37
Issue
11
Publish Date
2005
Start Page
1270
End Page
1273
DOI
10.1038/ng1659

Cybrd1 (duodenal cytochrome b) is not necessary for dietary iron absorption in mice

Mammalian nonheme iron absorption requires reduction of dietary iron for uptake by the divalent metal ion transport system in the intestine. This was thought to be mediated by duodenal cytochrome b (Cybrd1), a ferric reductase enzyme resident on the luminal surface of intestinal absorptive cells. To test its importance in vivo, we inactivated the murine Cybrd1 gene and assessed tissue iron stores in Cybrd1-null mice. We found that loss of Cybrd1 had little or no impact on body iron stores, even in the setting of iron deficiency. We conclude that other mechanisms must be available for the reduction of dietary iron. © 2005 by The American Society of Hematology.

Authors
Gunshin, H; Starr, CN; DiRenzo, C; Fleming, MD; Jin, J; Greer, EL; Sellers, VM; Galica, SM; Andrews, NC
MLA Citation
Gunshin, H, Starr, CN, DiRenzo, C, Fleming, MD, Jin, J, Greer, EL, Sellers, VM, Galica, SM, and Andrews, NC. "Cybrd1 (duodenal cytochrome b) is not necessary for dietary iron absorption in mice." Blood 106.8 (2005): 2879-2883.
PMID
15961514
Source
scival
Published In
Blood
Volume
106
Issue
8
Publish Date
2005
Start Page
2879
End Page
2883
DOI
10.1182/blood-2005-02-0716

A mouse model of juvenile hemochromatosis

Hereditary hemochromatosis is an iron-overload disorder resulting from mutations in proteins presumed to be involved in the maintenance of iron homeostasis. Mutations in hemojuvelin (HJV) cause severe, early-onset juvenile hemochromatosis. The normal function of HJV is unknown. Juvenile hemochromatosis patients have decreased urinary levels of hepcidin, a peptide hormone that binds to the cellular iron exporter ferroportin, causing its internalization and degradation. We have disrupted the murine Hjv gene and shown that Hjv -/- mice have markedly increased iron deposition in liver, pancreas, and heart but decreased iron levels in tissue macrophages. Hepcidin mRNA expression was decreased in Hjv-/- mice. Accordingly, ferroportin expression detected by immunohistochemistry was markedly increased in both intestinal epithelial cells and macrophages. We propose that excess, unregulated ferroportin activity in these cell types leads to the increased intestinal iron absorption and plasma iron levels characteristic of the juvenile hemochromatosis phenotype.

Authors
Huang, FW; Pinkus, JL; Pinkus, GS; Fleming, MD; Andrews, NC
MLA Citation
Huang, FW, Pinkus, JL, Pinkus, GS, Fleming, MD, and Andrews, NC. "A mouse model of juvenile hemochromatosis." Journal of Clinical Investigation 115.8 (2005): 2187-2191.
PMID
16075059
Source
scival
Published In
Journal of Clinical Investigation
Volume
115
Issue
8
Publish Date
2005
Start Page
2187
End Page
2191
DOI
10.1172/JCI25049

Case 21-2005: A four-week-old male infant with jaundice and thrombocytopenia

Authors
Andrews, NC; Anupindi, S; Badizadegan, K
MLA Citation
Andrews, NC, Anupindi, S, and Badizadegan, K. "Case 21-2005: A four-week-old male infant with jaundice and thrombocytopenia." New England Journal of Medicine 353.2 (2005): 189-198.
PMID
16014889
Source
scival
Published In
The New England journal of medicine
Volume
353
Issue
2
Publish Date
2005
Start Page
189
End Page
198
DOI
10.1056/NEJMcpc059016

Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver

Solute carrier family 11, member 2 (SLC11A2) is the only transmembrane iron transporter known to be involved in cellular iron uptake. It is widely expressed and has been postulated to play important roles in intestinal iron absorption, erythroid iron utilization, hepatic iron accumulation, placental iron transfer, and other processes. Previous studies have suggested that other transporters might exist, but their physiological significance remained uncertain. To define the activities of Slc11a2 in vivo, we inactivated the murine gene that encodes it globally and selectively. We found that fetal Slc11a2 is not needed for materno-fetal iron transfer but that Slc11a2 activity is essential for intestinal non-heme iron absorption after birth. Slc11a2 is also required for normal hemoglobin production during the development of erythroid precursors. However, hepatocytes and most other cells must have an alternative, as-yet-unknown, iron uptake mechanism. We previously showed that Slc11a2 serves as the primary portal for intestinal iron entry in hemochromatosis. However, inactivation of murine Hfe ameliorates the phenotype of animals lacking Slc11a2.

Authors
Gunshin, H; Fujiwara, Y; Custodio, AO; DiRenzo, C; Robine, S; Andrews, NC
MLA Citation
Gunshin, H, Fujiwara, Y, Custodio, AO, DiRenzo, C, Robine, S, and Andrews, NC. "Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver." Journal of Clinical Investigation 115.5 (2005): 1258-1266.
PMID
15849611
Source
scival
Published In
Journal of Clinical Investigation
Volume
115
Issue
5
Publish Date
2005
Start Page
1258
End Page
1266
DOI
10.1172/JCI200524356

Molecular control of iron metabolism

As described in this volume, our knowledge of mammalian iron metabolism has advanced dramatically over the past decade. While basic physiological concepts were described through elegant experiments in the 1950s and 1960s, many molecular details remained unknown. Modern techniques in genetics, biochemistry and molecular biology have allowed for the identification and characterization of most, but probably not all, of the key molecules that move iron into, out of, and between cells. Insight into the complex regulation of these iron transport proteins has been accelerated through the identification of hemochromatosis disease genes. Although much of the information has been gleaned from experiments in animal models, it is likely that it can be directly extrapolated to humans. © 2004 Elsevier Ltd. All rights reserved.

Authors
Andrews, NC
MLA Citation
Andrews, NC. "Molecular control of iron metabolism." Best Practice and Research: Clinical Haematology 18.2 SPEC. ISS. (2005): 159-169.
PMID
15737882
Source
scival
Published In
Best Practice & Research: Clinical Haematology
Volume
18
Issue
2 SPEC. ISS.
Publish Date
2005
Start Page
159
End Page
169
DOI
10.1016/j.beha.2004.10.004

Haptoglobin modifies the hemochromatosis phenotype in mice

Classic hereditary hemochromatosis (HH) is a common genetic disorder of iron metabolism caused by a mutation in the HFE gene. Whereas the prevalence of the mutation is very high, the clinical penetrance of the disease is low, suggesting that the HFE mutation is a necessary but not sufficient cause of clinical HH. Several candidate modifier genes have been proposed in mice and humans, including haptoglobin. Haptoglobin is the plasma protein with the highest binding affinity for hemoglobin. It delivers free plasma hemoglobin to the reticuloendothelial system, thus reducing loss of hemoglobin through the glomeruli and allowing heme-iron recycling. To gain insight into the role of haptoglobin as a modifier gene in HH, we used Hfe and haptoglobin double-null mice. Here, we show that Hfe and haptoglobin compound mutant mice accumulate significantly less hepatic iron than Hfe-null mice, thus demonstrating that haptoglobin-mediated heme-iron recovery may contribute significantly to iron loading in HH. © 2005 by The American Society of Hematology.

Authors
Tolosano, E; Fagoonee, S; Garuti, C; Valli, L; Andrews, NC; Altruda, F; Pietrangelo, A
MLA Citation
Tolosano, E, Fagoonee, S, Garuti, C, Valli, L, Andrews, NC, Altruda, F, and Pietrangelo, A. "Haptoglobin modifies the hemochromatosis phenotype in mice." Blood 105.8 (2005): 3353-3355.
PMID
15613548
Source
scival
Published In
Blood
Volume
105
Issue
8
Publish Date
2005
Start Page
3353
End Page
3355
DOI
10.1182/blood-2004-07-2814

The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis

Ferroportin (SLC40A1) is an iron transporter postulated to play roles in intestinal iron absorption and cellular iron release. Hepcidin, a regulatory peptide, binds to ferroportin and causes it to be internalized and degraded. If ferroportin is the major cellular iron exporter, ineffective hepcidin function could explain manifestations of human hemochromatosis disorders. To investigate this, we inactivated the murine ferroportin (Fpn) gene globally and selectively. Embryonic lethality of Fpnnull/null animals indicated that ferroportin is essential early in development. Rescue of embryonic lethality through selective inactivation of ferroportin in the embryo proper suggested that ferroportin has an important function in the extraembryonic visceral endoderm. Ferroportin-deficient animals accumulated iron in enterocytes, macrophages, and hepatocytes, consistent with a key role for ferroportin in those cell types. Intestine-specific inactivation of ferroportin confirmed that it is critical for intestinal iron absorption. These observations define the major sites of ferroportin activity and give insight into hemochromatosis. © 2005 Elsevier Inc. All rights reserved.

Authors
Donovan, A; Lima, CA; Pinkus, JL; Pinkus, GS; Zon, LI; Robine, S; Andrews, NC
MLA Citation
Donovan, A, Lima, CA, Pinkus, JL, Pinkus, GS, Zon, LI, Robine, S, and Andrews, NC. "The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis." Cell Metabolism 1.3 (2005): 191-200.
PMID
16054062
Source
scival
Published In
Cell Metabolism
Volume
1
Issue
3
Publish Date
2005
Start Page
191
End Page
200
DOI
10.1016/j.cmet.2005.01.003

Anemia of inflammation: The hepcidin link

Purpose of review: The anemia of inflammation has been associated for nearly two decades with elevated cytokine levels, but the primary mediator of this condition was unknown. Recently hepcidin antimicrobial peptide has emerged as the hormone that links the type II acute phase response to iron handling and erythropoiesis. Recent findings: Hepcidin antimicrobial peptide likely modulates iron transport from macrophages and enterocytes to red blood cell precursors as a consequence of its interaction with SLC40A1/ferroportin, the only known transporter that facilitates iron egress. Insights into the regulation of hepcidin antimicrobial peptide expression by known iron metabolic proteins such as HFE, hemojuvelin, and transferrin receptor 2 are expanding the understanding of the genetic circuitry that controls iron absorption and utilization. Summary: Increasingly, experiments suggest the hepatocyte is not just the iron storage depot but is the 'command central' for the maintenance of iron homeostasis. It receives multiple signals related to iron balance and responds via transcriptional control of hepcidin antimicrobial peptide. © 2005 Lippincott Williams & Wilkins.

Authors
Roy, CN; Andrews, NC
MLA Citation
Roy, CN, and Andrews, NC. "Anemia of inflammation: The hepcidin link." Current Opinion in Hematology 12.2 (2005): 107-111.
PMID
15725899
Source
scival
Published In
Current Opinion in Hematology
Volume
12
Issue
2
Publish Date
2005
Start Page
107
End Page
111
DOI
10.1097/00062752-200503000-00001

Pathophysiologic mechanisms of anemia of chronic disease.

Anemia of chronic disease (ACD) is a prevalent condition commonly observed in patients with chronic infections, cancer, trauma, and inflammatory disorders. In this article, Dr Andrews examines new research findings that enhance the understanding of the pathophysiologic mechanisms of ACD. After a brief review of iron homeostasis and a look at ACD in a historical context, she explores the significance of hepcidin, a recently discovered hormone involved in iron metabolism, and discusses a new hypothesis that connects hepcidin to the pathogenesis of ACD. Dr Andrews also examines the link between ACD and hereditary hemochromatosis, 2 disorders that on the surface may seem quite different but have in common the involvement of hepcidin in their pathogenesis.

Authors
Andrews, NC
MLA Citation
Andrews, NC. "Pathophysiologic mechanisms of anemia of chronic disease." Postgraduate medicine 116.5 Suppl Anemia (November 2004): 17-22.
PMID
19667680
Source
epmc
Published In
Postgraduate Medicine
Volume
116
Issue
5 Suppl Anemia
Publish Date
2004
Start Page
17
End Page
22
DOI
10.3810/pgm.11.2004.suppl36.250

Probing the iron pool. Focus on "Detection of intracellular iron by its regulatory effect"

Authors
Andrews, NC
MLA Citation
Andrews, NC. "Probing the iron pool. Focus on "Detection of intracellular iron by its regulatory effect"." American Journal of Physiology - Cell Physiology 287.6 56-6 (2004): C1537-C1538.
PMID
15525686
Source
scival
Published In
American Journal of Physiology - Cell Physiology
Volume
287
Issue
6 56-6
Publish Date
2004
Start Page
C1537
End Page
C1538
DOI
10.1152/ajpcell.00435.2004

Identification of a novel mutation (C321X) in HJV

Juvenile hemochromatosis is a rare autosomal recessive disorder characterized by the early onset of severe iron overload. We report the occurrence of compound heterozygous mutations in hemojuvelin (HJV), including a termination codon, in a patient with juvenile hemochromatosis but no family history of iron disorders. © 2004 by The American Society of Hematology.

Authors
Huang, FW; Rubio-Aliaga, I; Kushner, JP; Andrews, NC; Fleming, MD
MLA Citation
Huang, FW, Rubio-Aliaga, I, Kushner, JP, Andrews, NC, and Fleming, MD. "Identification of a novel mutation (C321X) in HJV." Blood 104.7 (2004): 2176-2177.
PMID
15138164
Source
scival
Published In
Blood
Volume
104
Issue
7
Publish Date
2004
Start Page
2176
End Page
2177
DOI
10.1182/blood-2004-01-0400

Pathophysiologic mechanisms of anemia of chronic disease.

Anemia of chronic disease (ACD) is a prevalent condition commonly observed in patients with chronic infections, cancer, trauma, and inflammatory disorders. In this article, Dr Andrews examines new research findings that enhance the understanding of the pathophysiologic mechanisms of ACD. After a brief review of iron homeostasis and a look at ACD in a historical context, she explores the significance of hepcidin, a recently discovered hormone involved in iron metabolism, and discusses a new hypothesis that connects hepcidin to the pathogenesis of ACD. Dr Andrews also examines the link between ACD and hereditary hemochromatosis, 2 disorders that on the surface may seem quite different but have in common the involvement of hepcidin in their pathogenesis.

Authors
Andrews, NC
MLA Citation
Andrews, NC. "Pathophysiologic mechanisms of anemia of chronic disease." Postgraduate medicine 116.5 Suppl Anemia (2004): 17-22.
Source
scival
Published In
Postgraduate Medicine
Volume
116
Issue
5 Suppl Anemia
Publish Date
2004
Start Page
17
End Page
22
DOI
10.3810/pgm.11.2004.suppl36.250

Iron homeostasis and inherited iron overload disorders: An overview

Knowledge of iron metabolism has increased markedly in recent years and resulted in new insights into genetic iron overload disorders. Mutations in at least five distinct genes are known to cause iron overload. This has facilitated and complicated the job of clinicians who evaluate patients who have biochemical or clinical signs of iron-related diseases. The situation is even more complex for pediatric patients who are deemed to be at risk for iron overload because of an affected relative.

Authors
Heeney, MM; Andrews, NC
MLA Citation
Heeney, MM, and Andrews, NC. "Iron homeostasis and inherited iron overload disorders: An overview." Hematology/Oncology Clinics of North America 18.6 SPEC.ISS. (2004): 1379-1403.
PMID
15511621
Source
scival
Published In
Hematology/Oncology Clinics of North America
Volume
18
Issue
6 SPEC.ISS.
Publish Date
2004
Start Page
1379
End Page
1403
DOI
10.1016/j.hoc.2004.06.018

An Hfe-dependent pathway mediates hyposideremia in response to lipopolysaccharide-induced inflammation in mice

Inflammation influences iron balance in the whole organism. A common clinical manifestation of these changes is anemia of chronic disease (ACD; also called anemia of inflammation). Inflammation reduces duodenal iron absorption and increases macrophage iron retention, resulting in low serum iron concentrations (hyposideremia). Despite the protection hyposideremia provides against proliferating microorganisms, this 'iron withholding' reduces the iron available to maturing red blood cells and eventually contributes to the development of anemia. Hepcidin antimicrobial peptide (Hamp) is a hepatic defensin-like peptide hormone that inhibits duodenal iron absorption and macrophage iron release. Hamp is part of the type II acute phase response and is thought to have a crucial regulatory role in sequestering iron in the context of ACD. Mice with deficiencies in the hemochromatosis gene product, Hfe, mounted a general inflammatory response after injection of lipopolysaccharide but lacked appropriate Hamp expression and did not develop hyposideremia. These data suggest a previously unidentified role for Hfe in innate immunity and ACD.

Authors
Roy, CN; Custodio, ÁO; Graaf, JD; Schneider, S; Akpan, I; Montross, LK; Sanchez, M; Gaudino, A; Hentze, MW; Andrews, NC; Muckenthaler, MU
MLA Citation
Roy, CN, Custodio, ÁO, Graaf, JD, Schneider, S, Akpan, I, Montross, LK, Sanchez, M, Gaudino, A, Hentze, MW, Andrews, NC, and Muckenthaler, MU. "An Hfe-dependent pathway mediates hyposideremia in response to lipopolysaccharide-induced inflammation in mice." Nature Genetics 36.5 (2004): 481-485.
PMID
15098034
Source
scival
Published In
Nature Genetics
Volume
36
Issue
5
Publish Date
2004
Start Page
481
End Page
485
DOI
10.1038/ng1350

Transferrin is required for early T-cell differentiation

Transferrin, the major plasma iron carrier, mediates iron entry into cells through interaction with its receptor. Several in vitro studies have demonstrated that transferrin plays an essential role in lymphocyte division, a role attributed to its iron transport function. In the present study we used hypotransferrinaemic (Trfhpx/bpx) mice to investigate the possible involvement of transferrin in T lymphocyte differentiation in vivo. The absolute number of thymocytes was substantially reduced in Trfhpx/hpx mice, a result that could not be attributed to increased apoptosis. Moreover, the proportions of the four major thymic subpopulations were maintained and the percentage of dividing cells was not reduced. A leaky block in the differentiation of CD4- CD8- CD3- CB44 - CD25+ (TN3) into CD4- CD8- CD3- CD44- CB25- (TN4) cells was observed. In addition, a similar impairment of early thymocyte differentiation was observed in mice with reduced levels of transferrin receptor. The present study demonstrates, for the first time, that transferrin itself or a pathway triggered by the interaction of transferrin with its receptor is essential for normal early T-cell differentiation in vivo.

Authors
Macedo, MF; Sousa, MD; Ned, RM; Mascarenhas, C; Andrews, NC; Correia-Neves, M
MLA Citation
Macedo, MF, Sousa, MD, Ned, RM, Mascarenhas, C, Andrews, NC, and Correia-Neves, M. "Transferrin is required for early T-cell differentiation." Immunology 112.4 (2004): 543-549.
PMID
15270724
Source
scival
Published In
Immunology
Volume
112
Issue
4
Publish Date
2004
Start Page
543
End Page
549
DOI
10.1111/j.1365-2567.2004.01915.x

Balancing acts: Molecular control of mammalian iron metabolism

Iron is ubiquitous in the environment and in biology. The study of iron biology focuses on physiology and homeostasis - understanding how cells and organisms regulate their iron content, how diverse tissues orchestrate iron allocation, and how dysregulated iron homeostasis leads to common hematological, metabolic, and neurodegenerative diseases. This has provided novel insights into gene regulation and unveiled remarkable links to the immune system.

Authors
Hentze, MW; Muckenthaler, MU; Andrews, NC
MLA Citation
Hentze, MW, Muckenthaler, MU, and Andrews, NC. "Balancing acts: Molecular control of mammalian iron metabolism." Cell 117.3 (2004): 285-297.
PMID
15109490
Source
scival
Published In
Cell
Volume
117
Issue
3
Publish Date
2004
Start Page
285
End Page
297
DOI
10.1016/S0092-8674(04)00343-5

Complexity of CNC Transcription Factors As Revealed by Gene Targeting of the Nrf3 Locus

Cap'n'collar (CNC) family basic leucine zipper transcription factors play crucial roles in the regulation of mammalian gene expression and development. To determine the in vivo function of the CNC protein Nrf3 (NF-E2-related factor 3), we generated mice deficient in this transcription factor. We performed targeted disruption of two Nrf3 exons coding for CNC homology, basic DNA-binding, and leucine zipper dimerization domains. Nrf3 null mice developed normally and revealed no obvious phenotypic differences compared to wild-type animals. Nrf3-/- mice were fertile, and gross anatomy as well as behavior appeared normal. The mice showed normal age progression and did not show any apparent additional phenotype during their life span. We observed no differences in various blood parameters and chemistry values. We infected wild-type and Nrf3-/- mice with acute lymphocytic choriomeningitis virus and found no differences in these animals with respect to their number of virus-specific CD8 and CD4 T cells as well as their B-lymphocyte response. To determine whether the mild phenotype of Nrf3 null animals is due to functional redundancy, we generated mice deficient in multiple CNC factors. Contrary to our expectations, an absence of Nrf3 does not seem to cause additional lethality in compound Nrf3-/-/Nrf2-/- and Nrf3 -/-/p45-/- mice. We hypothesize that the role of Nrf3 in vivo may become apparent only after appropriate challenge to the mice.

Authors
Derjuga, A; Gourley, TS; Holm, TM; Heng, HHQ; Shivdasani, RA; Ahmed, R; Andrews, NC; Blank, V
MLA Citation
Derjuga, A, Gourley, TS, Holm, TM, Heng, HHQ, Shivdasani, RA, Ahmed, R, Andrews, NC, and Blank, V. "Complexity of CNC Transcription Factors As Revealed by Gene Targeting of the Nrf3 Locus." Molecular and Cellular Biology 24.8 (2004): 3286-3294.
PMID
15060151
Source
scival
Published In
Molecular and Cellular Biology
Volume
24
Issue
8
Publish Date
2004
Start Page
3286
End Page
3294
DOI
10.1128/MCB.24.8.3286-3294.2004

Anemia of inflammation: The cytokine-hepcidin link

The anemia of inflammation, commonly observed in patients with chronic infections, malignancy, trauma, and inflammatory disorders, is a well-known clinical entity. Until recently, we understood little about its pathogenesis. It now appears that the inflammatory cytokine IL-6 induces production of hepcidin, an iron-regulatory hormone that may be responsible for most or all of the features of this disorder (see the related article beginning on page 1271).

Authors
Andrews, NC
MLA Citation
Andrews, NC. "Anemia of inflammation: The cytokine-hepcidin link." Journal of Clinical Investigation 113.9 (2004): 1251-1253.
PMID
15124013
Source
scival
Published In
Journal of Clinical Investigation
Volume
113
Issue
9
Publish Date
2004
Start Page
1251
End Page
1253
DOI
10.1172/JCI200421441

Contributions of β2-microglobulin-dependent molecules and lymphocytes to iron regulation: Insights from HfeRag1-/- and β2mRag1 -/- double knock-out mice

Genetic causes of hereditary hemochromatosis (HH) include mutations in the HFE gene, coding for a β2-microglobulin (β2m)-associated major histocompatibility complex class I-like protein. However, iron accumulation in patients with HH can be highly variable. Previously, analysis of β2mRag1-/- double-deficient mice, lacking all β2m-dependent molecules and lymphocytes, demonstrated increased iron accumulation in the pancreas and heart compared with β2m single knock-out mice. To evaluate whether the observed phenotype in β2mRag1-/- mice was due solely to the absence of Hfe or to other β2m-dependent molecules, we generated HfeRag1-/- double-deficient mice. Our studies revealed that introduction of Rag1 deficiency in Hfe knock-out mice leads to heightened iron overload, mainly in the liver, whereas the heart and pancreas are relatively spared compared with β2mRag1-/- mice. These results suggest that other β2m-interacting protein(s) may be involved in iron regulation and that in the absence of functional Hfe molecules lymphocyte numbers may influence iron overload severity. © 2004 by The American Society of Hematology.

Authors
Miranda, CJ; Makui, H; Andrews, NC; Santos, MM
MLA Citation
Miranda, CJ, Makui, H, Andrews, NC, and Santos, MM. "Contributions of β2-microglobulin-dependent molecules and lymphocytes to iron regulation: Insights from HfeRag1-/- and β2mRag1 -/- double knock-out mice." Blood 103.7 (2004): 2847-2849.
PMID
14656877
Source
scival
Published In
Blood
Volume
103
Issue
7
Publish Date
2004
Start Page
2847
End Page
2849
DOI
10.1182/blood-2003-09-3300

Hepcidin, a candidate modifier of the hemochromatosis phenotype in mice

Hereditary hemochromatosis (HH) type I is a disorder of iron metabolism caused by a mutation in the HFE gene. Whereas the prevalence of the mutation is very high, its penetrance seems very low. The goal of our study was to determine whether hepcidin, a recently identified iron-regulatory peptide, could be a genetic modifier contributing to the HH phenotype. In mice, deficiency of either HFE (Hfe-/-) or hepcidin (Usf2-/-) is associated with the same pattern of iron overload observed in patients with HH. We intercrossed Hfe-/- and Usf2+/- mice and asked whether hepcidin deficiency increased the iron burden in Hfe-/- mice. Our results showed that, indeed, liver iron accumulation was greater in the Hfe-/-Usf2+/- mice than in mice lacking Hfe alone. This result, in agreement with recent findings in humans, provides a genetic explanation for some variability of the HH phenotype. © 2004 by The American Society of Hematology.

Authors
Nicolas, G; Andrews, NC; Kahn, A; Vaulont, S
MLA Citation
Nicolas, G, Andrews, NC, Kahn, A, and Vaulont, S. "Hepcidin, a candidate modifier of the hemochromatosis phenotype in mice." Blood 103.7 (2004): 2841-2843.
PMID
14656876
Source
scival
Published In
Blood
Volume
103
Issue
7
Publish Date
2004
Start Page
2841
End Page
2843
DOI
10.1182/blood-2003-09-3358

A spontaneous, recurrent mutation in divalent metal transporter-1 exposes a calcium entry pathway

Divalent metal transporter-1 (DMT1/DCT1/Nramp2) is the major Fe 2+ transporter mediating cellular iron uptake in mammals. Phenotypic analyses of animals with spontaneous mutations in DMT1 indicate that it functions at two distinct sites, transporting dietary iron across the apical membrane of intestinal absorptive cells, and transporting endosomal iron released from transferrin into the cytoplasm of erythroid precursors. DMT1 also acts as a proton-dependent transporter for other heavy metal ions including Mn2+, Co2+, and Cu2, but not for Mg 2+ or Ca2+. A unique mutation in DMT1, G185R, has occurred spontaneously on two occasions in microcytic (mk) mice and once in Belgrade (b) rats. This mutation severely impairs the iron transport capability of DMT1, leading to systemic iron deficiency and anemia. The repeated occurrence of the G185R mutation cannot readily be explained by hypermutability of the gene. Here we show that G185R mutant DMT1 exhibits a new, constitutive Ca2+ permeability, suggesting a gain of function that contributes to remutation and the mk and b phenotypes.

Authors
Xu, H; Jin, J; DeFelice, LJ; Andrews, NC; Clapham, DE
MLA Citation
Xu, H, Jin, J, DeFelice, LJ, Andrews, NC, and Clapham, DE. "A spontaneous, recurrent mutation in divalent metal transporter-1 exposes a calcium entry pathway." PLoS Biology 2.3 (2004).
PMID
15024413
Source
scival
Published In
PLoS Biology
Volume
2
Issue
3
Publish Date
2004
DOI
10.1371/journal.pbio.0020050

The molecular regulation of iron metabolism

Mammalian iron homeostasis requires meticulous control of proteins involved in intestinal iron absorption and tissue iron management. Recent studies in animal models have provided important insights into iron physiology. This review describes our current understanding of the regulation of iron trafficking and its perturbation in genetic iron disorders. © 2004 The European Hematology Association All rights reserved.

Authors
Donovan, A; Andrews, NC
MLA Citation
Donovan, A, and Andrews, NC. "The molecular regulation of iron metabolism." Hematology Journal 5.5 (2004): 373-380.
PMID
15448662
Source
scival
Published In
Hematology Journal
Volume
5
Issue
5
Publish Date
2004
Start Page
373
End Page
380
DOI
10.1038/sj.thj.6200540

Transferrin receptor 1 is differentially required in lymphocyte development

Transferrin receptor (TfR) facilitates cellular iron uptake by mediating endocytosis of its ligand, iron-loaded transferrin. Although TfR is widely believed to be important for iron acquisition by all mammalian cells, direct experimental evidence is lacking. We have previously shown that mouse embryos homozygous for a disrupted transferrin receptor allele (TfR-/-) die of anemia before embryonic day 12.5, although most other embryonic tissues appear to be developing normally. Here, we have investigated the importance of TfR postnatally, by using TfR-/- embryonic stem cells to produce chimeric animals. We find that TfR-/- embryonic stem cells give rise to most tissues and organs, but do not contribute to hematopoietic tissues on a wild-type C57BL/6J background, indicating that both adult erythropoiesis and lymphopoiesis require TfR. On an immunodeficient RAG2-/- background, TfR-/- B-cell development proceeds at least to the IgM+ stage, although significantly fewer IgM+ cells are present in peripheral lymphoid organs. Conversely, T cells lacking TfR are arrested very early in their development, at the CD4-8-3- stage. These results indicate that TfR is necessary for the normal maturation of thymocytes, but that B-cell development is less severely affected by the absence of TfR. © 2003 by The American Society of Hematology.

Authors
Ned, RM; Swat, W; Andrews, NC
MLA Citation
Ned, RM, Swat, W, and Andrews, NC. "Transferrin receptor 1 is differentially required in lymphocyte development." Blood 102.10 (2003): 3711-3718.
PMID
12881306
Source
scival
Published In
Blood
Volume
102
Issue
10
Publish Date
2003
Start Page
3711
End Page
3718
DOI
10.1182/blood-2003-04-1086

Hfe deficiency increases susceptibility to cardiotoxicity and exacerbates changes in iron metabolism induced by doxorubicin

The clinical use of doxorubicin (DOX), an anthracycline chemotherapeutic agent, is limited by cardiotoxicity. The possible involvement of iron in DOX-induced cardiotoxicity became evident from studies in which iron chelators were shown to be cardioprotective. Iron overload is found in hereditary hemochromatosis, a genetic disorder prevalent in individuals of European descent. We hypothesized that Hfe deficiency may increase susceptibility to DOX-induced toxicity. Acute cardiotoxicity and iron changes were studied after treatment with DOX in Hfe knock-out (Hfe-/-) mice and wild-type mice. DOX-induced iron metabolism changes were intensified in Hfe-/- mice, which accumulated significantly more iron in the heart, liver, and pancreas, but less in the spleen compared with wild-type mice. In addition, Hfe-deficient mice exhibited significantly greater sensitivity to DOX-induced elevations in serum creatine kinase and aspartate aminotransferase. Increased mortality after chronic DOX treatment was observed in Hfe-/- mice and Hfe +/- mice compared with wild-type mice. DOX-treated Hfe-/- mice had a higher degree of mitochondrial damage and iron deposits in the heart than did wild-type mice. These data demonstrate that Hfe deficiency in mice increases susceptibility to DOX-induced cardiotoxicity and suggest that genetic mutations related to defects in iron metabolism may contribute to its cardiotoxicity in humans. © 2003 by The American Society of Hematology.

Authors
Miranda, CJ; Makui, H; Soares, RJ; Bilodeau, M; Mui, J; Vali, H; Bertrand, R; Andrews, NC; Santos, MM
MLA Citation
Miranda, CJ, Makui, H, Soares, RJ, Bilodeau, M, Mui, J, Vali, H, Bertrand, R, Andrews, NC, and Santos, MM. "Hfe deficiency increases susceptibility to cardiotoxicity and exacerbates changes in iron metabolism induced by doxorubicin." Blood 102.7 (2003): 2574-2580.
PMID
12805055
Source
scival
Published In
Blood
Volume
102
Issue
7
Publish Date
2003
Start Page
2574
End Page
2580
DOI
10.1182/blood-2003-03-0869

Probucol prevents early coronary heart disease and death in the high-density lipoprotein receptor SR-BI/apolipoprotein E double knockout mouse

Mice with homozygous null mutations in the high-density lipoprotein receptor SR-BI (scavenger receptor class B, type I) and apolipoprotein E genes fed a low-fat diet exhibit a constellation of pathologies shared with human atherosclerotic coronary heart disease (CHD): hypercholesterolemia, occlusive coronary atherosclerosis, myocardial infarctions, cardiac dysfunction (heart enlargement, reduced systolic function and ejection fraction, and ECG abnormalities), and premature death (mean age 6 weeks). They also exhibit a block in RBC maturation and abnormally high plasma unesterified-to-total cholesterol ratio (0.8) with associated abnormal lipoprotein morphology (lamellar/vesicular and stacked discoidal particles reminiscent of those in lecithin/cholesterol acyltransferase deficiency and cholestasis). Treatment with the lipid-lowering, antiatherosclerosis, and antioxidation drug probucol extended life to as long as 60 weeks (mean 36 weeks), and at 5-6 weeks of age, virtually completely reversed the cardiac and most RBC pathologies and corrected the unesterified to total cholesterol ratio (0.3) and associated distinctive abnormal lipoprotein morphologies. Manipulation of the timing of administration and withdrawal of probucol could control the onset of death and suggested that critical pathological changes usually occurred in untreated double knockout mice between ≈3 (weaning) and 5 weeks of age and that probucol delayed heart failure even after development of substantial CHD. The ability of probucol treatment to modulate pathophysiology in the double knockout mice enhances the potential of this murine system for analysis of the pathophysiology of CHD and preclinical testing of new approaches for the prevention and treatment of cardiovascular disease.

Authors
Braun, A; Zhang, S; Miettinen, HE; Ebrahim, S; Holm, TM; Vasile, E; Post, MJ; Yoerger, DM; Picard, MH; Krieger, JL; Andrews, NC; Simons, M; Krieger, M
MLA Citation
Braun, A, Zhang, S, Miettinen, HE, Ebrahim, S, Holm, TM, Vasile, E, Post, MJ, Yoerger, DM, Picard, MH, Krieger, JL, Andrews, NC, Simons, M, and Krieger, M. "Probucol prevents early coronary heart disease and death in the high-density lipoprotein receptor SR-BI/apolipoprotein E double knockout mouse." Proceedings of the National Academy of Sciences of the United States of America 100.12 (2003): 7283-7288.
PMID
12771386
Source
scival
Published In
Proceedings of the National Academy of Sciences of the United States of America
Volume
100
Issue
12
Publish Date
2003
Start Page
7283
End Page
7288
DOI
10.1073/pnas.1237725100

Regulatory defects in liver and intestine implicate abnormal hepcidin and Cybrd1 expression in mouse hemochromatosis

Individuals with hereditary hemochromatosis suffer from systemic iron overload due to duodenal hyperabsorption. Most cases arise from a founder mutation in HFE(845G→A; ref. 2) that results in the amino-acid substitution C282Y and prevents the association of HFE with β2-microglobulin. Mice homozygous with respect to a null allele of Hfe (Hfe-/-) or homozygous with respect to the orthologous 882G→A mutation (Hfe845A/845A) develop iron overload that recapitulates hereditary hemochromatosis in humans, confirming that hereditary hemochromatosis arises from loss of HFE function. Much work has focused on an exclusive role for the intestine in hereditary hemochromatosis. HFE deficiency in intestinal crypt cells is thought to cause intestinal iron deficiency and greater expression of iron transporters such as SLC11A2 (also called DMT1, DCT1 and NRAMP2) and SLC11A3 (also called IREG1, ferroportin and MTP1; ref. 3). Published data on the expression of these transporters in the duodenum of HFE-deficient mice and humans are contradictory. In this report, we used a custom microarray to assay changes in duodenal and hepatic gene expression in Hfe-deficient mice. We found unexpected alterations in the expression of Slc39a1 (mouse ortholog of SLC11A3) and Cybrd1, which encode key iron transport proteins, and Hamp (hepcidin antimicrobial peptide), a hepatic regulator of iron transport. We propose that inappropriate regulatory cues from the liver underlie greater duodenal iron absorption, possibly involving the ferric reductase Cybrd1.

Authors
Muckenthaler, M; Roy, CN; Custodio, ÁO; Miñana, B; DeGraaf, J; Montross, LK; Andrews, NC; Hentze, MW
MLA Citation
Muckenthaler, M, Roy, CN, Custodio, ÁO, Miñana, B, DeGraaf, J, Montross, LK, Andrews, NC, and Hentze, MW. "Regulatory defects in liver and intestine implicate abnormal hepcidin and Cybrd1 expression in mouse hemochromatosis." Nature Genetics 34.1 (2003): 102-107.
PMID
12704390
Source
scival
Published In
Nature Genetics
Volume
34
Issue
1
Publish Date
2003
Start Page
102
End Page
107
DOI
10.1038/ng1152

Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis

Hereditary hemochromatosis is a prevalent genetic disorder of iron hyperabsorption leading to hyperferremia, tissue iron deposition and complications including cirrhosis, hepatocarcinoma, cardiomyopathy and diabetes. Most individuals affected with hereditary hemochromatosis are homozygous with respect to a missense mutation that disrupts the conformation of HFE, an atypical HLA class I molecule (ref. 1; OMIM 235200). Mice lacking Hfe2-4 or producing a C282Y mutant Hfe protein3 develop hyperferremia and have high hepatic iron levels. In both humans and mice, hereditary hemochromatosis is associated with a paucity of iron in reticuloendothelial cells. It has been suggested that HFE modulates uptake of transferrinbound iron by undifferentiated intestinal crypt cells, thereby programming the absorptive capacity of enterocytes derived from these cells5,6; however, this model is unproven and controversial7,8. Hepcidin, a peptide hormone (HAMP; OMIM 606464), seems to act in the same regulatory pathway as HFE. Although expression of mouse Hamp is normally greater during iron overload, Hfe-/- mice have inappropriately low expression of Hamp. We crossed Hfe-/- mice with transgenic mice overexpressing Hamp and found that Hamp inhibited the iron accumulation normally observed in the Hfe-/- mice. This argues against the crypt programming model and suggests that failure of Hamp induction contributes to the pathogenesis of hemochromatosis, providing a rationale for the use of HAMP in the treatment of this disease.

Authors
Nicolas, G; Viatte, L; Lou, D-Q; Bennoun, M; Beaumont, C; Kahn, A; Andrews, NC; Vaulont, S
MLA Citation
Nicolas, G, Viatte, L, Lou, D-Q, Bennoun, M, Beaumont, C, Kahn, A, Andrews, NC, and Vaulont, S. "Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis." Nature Genetics 34.1 (2003): 97-101.
PMID
12704388
Source
scival
Published In
Nature Genetics
Volume
34
Issue
1
Publish Date
2003
Start Page
97
End Page
101
DOI
10.1038/ng1150

2002 E. Mead Johnson Award for research in pediatrics lecture: The molecular biology of the anemia of chronic disease: A hypothesis

The anemia of chronic disease is a common disorder that afflicts patients with a wide variety of inflammatory conditions including arthritis, malignancies, infections, and inflammatory bowel disease. It results in significant morbidity and may be severe enough to require blood transfusions. The pathogenesis of anemia of chronic disease is not fully understood, but poor maintenance of red blood cell mass has been observed at three levels: 1) iron is not efficiently recycled from reticuloendothelial macrophages to erythroid precursors, 2) erythroid precursors respond poorly to erythropoietin, and 3) red blood cell survival is decreased. Whether each of these changes is related to the same effector of the inflammatory process is unknown. We have had the opportunity to investigate severe anemia of chronic disease in an unusual group of patients with glycogen storage disease type 1a. We found that anemia was directly related to the presence of large hepatic adenomas that inappropriately produced a new peptide hormone, hepcidin. Hepcidin has recently been identified as part of the innate immune response and is a key regulator of cellular iron egress. Based on our findings in this patient group, we propose a central role for hepcidin in anemia of chronic disease, linking the inflammatory process with iron recycling and erythropoiesis. We present a hypothesis based on our findings.

Authors
Roy, CN; Weinstein, DA; Andrews, NC
MLA Citation
Roy, CN, Weinstein, DA, and Andrews, NC. "2002 E. Mead Johnson Award for research in pediatrics lecture: The molecular biology of the anemia of chronic disease: A hypothesis." Pediatric Research 53.3 (2003): 507-512.
PMID
12595602
Source
scival
Published In
Pediatric Research
Volume
53
Issue
3
Publish Date
2003
Start Page
507
End Page
512
DOI
10.1203/01.PDR.0000049513.67410.2D

Animal models of hereditary iron transport disorders

Authors
Andrews, NC
MLA Citation
Andrews, NC. "Animal models of hereditary iron transport disorders." Advances in Experimental Medicine and Biology 509 (2003): 1-17.
PMID
12572986
Source
scival
Published In
Advances in experimental medicine and biology
Volume
509
Publish Date
2003
Start Page
1
End Page
17

Iron metabolism in mice with partial frataxin deficiency

Friedreich ataxia (FRDA), the most common autosomal recessive inherited ataxic disorder, is the consequence of deficiency of the mitochondrial protein frataxin, typically caused by homozygous intronic GAA expansions in the corresponding gene. The yeast frataxin homologue (yfh1p) is required for cellular respiration. Yfh1p appears to regulate mitochondrial iron homeostasis and protect from free radical toxicity. Complete loss of frataxin in knockout mice leads to early embryonic lethality, indicating an important role for frataxin during development. Heterozygous littermates with partial frataxin deficiency are apparently healthy and have no obvious phenotype. Here we evaluate iron metabolism and sensitivity to dietary and parenteral iron loading in heterozygote frataxin knockout mice (Fx+/-). Iron concentrations in the liver, heart, pancreas and spleen, and cellular iron distribution patterns were compared between wild type and Fx+/- mice. Response to parenteral iron challenge was not different between Fx+/- mice and wild type littermates, while sporadic iron deposits were observed in the hearts of dietary iron-loaded Fx+/- mice. Finally, we evaluated the effect of partial frataxin deficiency on susceptibility to cardiac damage in the mouse model of hereditary hemochromatosis (HH), the Hfe knockout mice. HH, an iron overload disease, is one of the most frequent genetic diseases in populations of European origin. By breeding Hfe-/- with Fx+/- mice, we obtained compound mutant mice lacking both Hfe and one frataxin allele. Sparse iron deposits in areas of mild to moderate cardiac fibrosis were found in the majority of these mice. However, they did not develop any neurological symptoms. Our studies indicate an association between frataxin deficiency, iron deposits and cardiac fibrosis, but no obvious association between iron accumulation and neurodegeneration similar to FRDA could be detected in our model. In addition, these results suggest that frataxin mutations may have a modifier role in HH, that predisposes to cardiomyopathy.

Authors
Santos, MM; Miranda, CJ; Levy, JE; Montross, LK; Cossée, M; Sequeiros, J; Andrews, N; Koenig, M; Pandolfo, M
MLA Citation
Santos, MM, Miranda, CJ, Levy, JE, Montross, LK, Cossée, M, Sequeiros, J, Andrews, N, Koenig, M, and Pandolfo, M. "Iron metabolism in mice with partial frataxin deficiency." Cerebellum 2.2 (2003): 146-153.
PMID
12880182
Source
scival
Published In
Cerebellum
Volume
2
Issue
2
Publish Date
2003
Start Page
146
End Page
153
DOI
10.1080/14734220309408

Inappropriate expression of hepcidin is associated with iron refractory anemia: Implications for the anemia of chronic disease

The anemia of chronic disease is a prevalent, poorly understood condition that afflicts patients with a wide variety of diseases, including infections, malignancies, and rheumatologic disorders. It is characterized by a blunted erythropoietin response by erythroid precursors, decreased red blood cell survival, and a defect in iron absorption and macrophage iron retention, which interrupts iron delivery to erythroid precursor cells. We noted that patients with large hepatic adenomas had severe iron refractory anemia similar to that observed in anemia of chronic disease. This anemia resolved spontaneously after adenoma resection or liver transplantation. We investigated the role of the adenomas in the pathogenesis of the anemia and found that they produce inappropriately high levels of hepcidin mRNA. Hepcidin is a peptide hormone that has been implicated in controlling the release of iron from cells. We conclude that hepcidin plays a major, causative role in the anemia observed in our subgroup of patients with hepatic adenomas, and we speculate that it is important in the pathogenesis of the anemia of chronic disease in general. © 2002 by The American Society of Hematology.

Authors
Weinstein, DA; Roy, CN; Fleming, MD; Loda, MF; Wolfsdorf, JI; Andrews, NC
MLA Citation
Weinstein, DA, Roy, CN, Fleming, MD, Loda, MF, Wolfsdorf, JI, and Andrews, NC. "Inappropriate expression of hepcidin is associated with iron refractory anemia: Implications for the anemia of chronic disease." Blood 100.10 (2002): 3776-3781.
PMID
12393428
Source
scival
Published In
Blood
Volume
100
Issue
10
Publish Date
2002
Start Page
3776
End Page
3781
DOI
10.1182/blood-2002-04-1260

A genetic view of iron homeostasis

Inherited disorders of iron metabolism are invariably disorders of iron balance or distribution. This review describes the proteins known to be involved in establishing and maintaining iron balance, and discusses regulation of iron homeostasis in the context of three cell types: intestinal enterocytes, reticuloendothelial macrophages, and hepatocytes. It emphasizes information gleaned from the use of genetic analyses, particularly in mice, and poses new questions to help advance our understanding of iron balance. Copyright 2002, Elsevier Science (USA). All rights reserved.

Authors
Andrews, NC
MLA Citation
Andrews, NC. "A genetic view of iron homeostasis." Seminars in Hematology 39.4 (2002): 227-234.
PMID
12382197
Source
scival
Published In
Seminars in Hematology
Volume
39
Issue
4
Publish Date
2002
Start Page
227
End Page
234
DOI
10.1053/shem.2002.35632

Regulation of iron absorption in Hfe mutant mice

Hereditary hemochromatosis is most commonly caused by homozygosity for a point mutation (C282Y) in the human hemochromatosis gene (HFE). The mechanism by which HFE regulates iron absorption is not known, but the C282Y mutation results in loss of cell surface expression of the human hemachromatosis protein (HFE) and hyperabsorption of iron by the duodenal enterocyte. Mice homozygous for a deletion in the mouse hemochromatosis gene (Hfe) or a mutation equivalent to that seen in human hereditary hemochromatosis (C282Y) were compared with wild-type animals for their ability to regulate iron absorption. Both mutant strains hyperabsorbed 59Fe administered by gavage. Feeding a diet supplemented with carbonyl iron resulted in a more than 5-fold reduction of 59Fe absorption in both wild-type and mutant mouse strains. Similarly, the iron loading associated with age in Hfe mutant mice resulted in nearly a 4-fold reduction in iron absorption. When mice were stimulated to absorb iron either by depleting iron stores or by inducing erythropoiesis, wild type and Hfe mutant strains increased absorption to similar levels, approximately 5-fold over control values. Our data indicate that Hfe mutant mice retain the ability to regulate iron absorption. Mouse hemachromatosis protein (Hfe) plays a minor role in down-regulation but does not influence the up-regulation of iron absorption. © 2002 by The American Society of Hematology.

Authors
Ajioka, RS; Levy, JE; Andrews, NC; Kushner, JP
MLA Citation
Ajioka, RS, Levy, JE, Andrews, NC, and Kushner, JP. "Regulation of iron absorption in Hfe mutant mice." Blood 100.4 (2002): 1465-1469.
PMID
12149232
Source
scival
Published In
Blood
Volume
100
Issue
4
Publish Date
2002
Start Page
1465
End Page
1469
DOI
10.1182/blood-2001-11-0037

Metal transporters and disease

Iron and copper are essential nutrients that must be meticulously regulated to exploit their usefulness in biological reactions while protecting against their tendency to promote formation of toxic free-radicals. This review summarizes recently described steps in the transport of these metals, and explores how defects in these steps lead to human diseases including hemochromatosis, Menkes disease and Wilson disease.

Authors
Andrews, NC
MLA Citation
Andrews, NC. "Metal transporters and disease." Current Opinion in Chemical Biology 6.2 (2002): 181-186.
PMID
12039002
Source
scival
Published In
Current Opinion in Chemical Biology
Volume
6
Issue
2
Publish Date
2002
Start Page
181
End Page
186
DOI
10.1016/S1367-5931(02)00307-1

The other physician-scientist problem: Where have all the young girls gone?

Authors
Andrews, NC
MLA Citation
Andrews, NC. "The other physician-scientist problem: Where have all the young girls gone?." Nature Medicine 8.5 (2002): 439-441.
PMID
11984578
Source
scival
Published In
Nature Medicine
Volume
8
Issue
5
Publish Date
2002
Start Page
439
End Page
441
DOI
10.1038/nm0502-439

Failure of red blood cell maturation in mice with defects in the high-density lipoprotein receptor SR-BI

Mammalian erythrocytes undergo a unique maturation process in which they discard their nuclei and organelles and assume a flexible biconcave shape. We found that altered plasma lipoprotein metabolism can profoundly influence these events. Abnormal erythrocyte morphology was observed in hypercholesterolemic mice lacking the high-density lipoprotein receptor SR-BI. This was exacerbated by feeding mice a highcholesterol diet or, more dramatically, by inactivating the apolipoprotein E gene. Erythrocytes from SR-BI-/-lapolipoprotein E-/- mice and SR-BI-/- mice that were fed cholesterol had markedly Increased membrane cholesterol. Their morphology appeared immature, with macrocytosis, irregular shape, and large autophagolysosomes. Autophagolysosomes from SR-BI-/-lapolipoprotein E-/- erythrocytes were expelled when the erythrocytes were transfused into wildtype animals or incubated in vitro with normolipidemic serum or the cholesterol-sequestering agent methyl cyclodextrin. We propose that autophagocytosis and phagolysosome expulsion are essential steps in erythroid maturation and that expulsion is inhibited in the presence of markedly increased cellular cholesterol. © 2002 by The American Society of Hematology.

Authors
Holm, TM; Braun, A; Trigatti, BL; Brugnara, C; Sakamoto, M; Krieger, M; Andrews, NC
MLA Citation
Holm, TM, Braun, A, Trigatti, BL, Brugnara, C, Sakamoto, M, Krieger, M, and Andrews, NC. "Failure of red blood cell maturation in mice with defects in the high-density lipoprotein receptor SR-BI." Blood 99.5 (2002): 1817-1824.
PMID
11861300
Source
scival
Published In
Blood
Volume
99
Issue
5
Publish Date
2002
Start Page
1817
End Page
1824
DOI
10.1182/blood.V99.5.1817

Iron-dependent regulation of the divalent metal ion transporter

The first step in intestinal iron absorption is mediated by the H+-coupled Fe2+ transporter called divalent cation transporter 1/divalent metal ion transporter 1 (DCT1/DMT1) (also known as natural resistance-associated macrophage protein 2). DCT1/DMT1 mRNA levels in the duodenum strongly increase in response to iron depletion. To study the mechanism of iron-dependent DCT1/DMT1 mRNA regulation, we investigated the endogenous expression of DCT1/DMT1 mRNA in various cell types. We found that only the iron responsive element (IRE)-containing form, which corresponds to one of two splice forms of DCT1/DMT1, is responsive to iron treatment and this responsiveness was cell type specific. We also examined the interaction of the putative 3′-UTR IRE with iron responsive binding proteins (IRP1 and IRP2), and found that IRP1 binds to the DCT1/DMT1-IRE with higher affinity compared to IRP2. This differential binding of IRP1 and IRP2 was also reported for the IREs of transferrin receptors, erythroid 5-aminolevulinate synthase and mitochondrial aconitase. We propose that regulation of DCT1/DMT1 mRNA by iron involves post-transcriptional regulation through the binding of IRP1 to the transporter's IRE, as well as other as yet unknown factors. © 2001 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.

Authors
Gunshin, H; Allerson, CR; Polycarpou-Schwarz, M; Rofts, A; Rogers, JT; Kishi, F; Hentze, MW; Rouault, TA; Andrews, NC; Hediger, MA
MLA Citation
Gunshin, H, Allerson, CR, Polycarpou-Schwarz, M, Rofts, A, Rogers, JT, Kishi, F, Hentze, MW, Rouault, TA, Andrews, NC, and Hediger, MA. "Iron-dependent regulation of the divalent metal ion transporter." FEBS Letters 509.2 (2001): 309-316.
PMID
11741608
Source
scival
Published In
FEBS Letters
Volume
509
Issue
2
Publish Date
2001
Start Page
309
End Page
316
DOI
10.1016/S0014-5793(01)03189-1

Recent advances in disorders of iron metabolism: Mutations, mechanisms and modifiers

The spectrum of known disorders of iron metabolism has expanded dramatically over the past few years. Identification of HFE, the gene most commonly mutated in patients with hereditary hemochromatosis, has allowed molecular diagnosis and paved the way for identification of other genes, such as TFR2, that are important in non-HFE-associated iron overload. There are clearly several other, unidentified, iron overload disease genes yet to be found. In parallel, our understanding of iron transport has expanded through identification of Fpn1/Ireg1/MTP1, Sfxn1 and Dcytb. Ongoing studies of Friedreich's ataxia, sideroblastic anemia, aceruloplasminemia and neurodegeneration with brain-iron accumulation are clarifying the role for iron in the nervous system. Finally, as the number of known iron metabolic genes increases and their respective functions are ascertained, new opportunities have arisen to identify genetic modifiers of iron homeostasis.

Authors
Roy, CN; Andrews, NC
MLA Citation
Roy, CN, and Andrews, NC. "Recent advances in disorders of iron metabolism: Mutations, mechanisms and modifiers." Human Molecular Genetics 10.20 (2001): 2181-2186.
PMID
11673399
Source
scival
Published In
Human Molecular Genetics
Volume
10
Issue
20
Publish Date
2001
Start Page
2181
End Page
2186

A mutation in a mitochondrial transmembrane protein is responsible for the pleiotropic hematological and skeletal phenotype of flexed-tail (f/f) mice

We have studied the flexed-tail (f) mouse to gain insight into mammalian mitochondrial iron metabolism. Flexed-tail animals have axial skeletal abnormalities and a transient embryonic and neonatal anemia characterized by pathologic intramitochondrial iron deposits in erythrocytes. Mitochondrial iron accumulation is the hallmark of sideroblastic anemias, which typically result from defects in heme biosynthesis or other pathways that lead to abnormal erythroid mitochondrial iron utilization. To clone the f gene, we used positional cloning techniques, and identified a frameshift mutation in a mitochondrial transmembrane protein. The mutated gene, Sfxn1, is the prototype of a novel family of evolutionarily conserved proteins present in eukaryotes.

Authors
Fleming, MD; Campagna, DR; Haslett, JN; III, CCT; Andrews, NC
MLA Citation
Fleming, MD, Campagna, DR, Haslett, JN, III, CCT, and Andrews, NC. "A mutation in a mitochondrial transmembrane protein is responsible for the pleiotropic hematological and skeletal phenotype of flexed-tail (f/f) mice." Genes and Development 15.6 (2001): 652-657.
PMID
11274051
Source
scival
Published In
Genes & development
Volume
15
Issue
6
Publish Date
2001
Start Page
652
End Page
657
DOI
10.1101/gad.873001

Mining copper transport genes

Authors
Andrews, NC
MLA Citation
Andrews, NC. "Mining copper transport genes." Proceedings of the National Academy of Sciences of the United States of America 98.12 (2001): 6543-6545.
PMID
11390990
Source
scival
Published In
Proceedings of the National Academy of Sciences of the United States of America
Volume
98
Issue
12
Publish Date
2001
Start Page
6543
End Page
6545
DOI
10.1073/pnas.131192498

Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene

Hemochromatosis is a progressive iron overload disorder that is prevalent among individuals of European descent. It is usually inherited in an autosomal-recessive pattern and associated with missense mutations in HFE, an atypical major histocompatibility class I gene. Recently, we described a large family with autosomal-dominant hemochromatosis not linked to HFE and distinguished by early iron accumulation in reticuloendothelial cells. Through analysis of a large pedigree, we have determined that this disease maps to 2q32. The gene encoding ferroportin (SLC11A3), a transmembrane iron export protein, lies within a candidate interval defined by highly significant lod scores. We show that the iron-loading phenotype in autosomal-dominant hemochromatosis is associated with a nonconservative missense mutation in the ferroportin gene. This missense mutation, converting alanine to aspartic acid at residue 77 (A77D), was not seen in samples from 100 unaffected control individuals. We propose that partial loss of ferroportin function leads to an imbalance in iron distribution and a consequent increase in tissue iron accumulation.

Authors
Montosi, G; Donovan, A; Totaro, A; Garuti, C; Pignatti, E; Cassanelli, S; Trenor, CC; Gasparini, P; Andrews, NC; Pietrangelo, A
MLA Citation
Montosi, G, Donovan, A, Totaro, A, Garuti, C, Pignatti, E, Cassanelli, S, Trenor, CC, Gasparini, P, Andrews, NC, and Pietrangelo, A. "Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene." Journal of Clinical Investigation 108.4 (2001): 619-623.
PMID
11518736
Source
scival
Published In
Journal of Clinical Investigation
Volume
108
Issue
4
Publish Date
2001
Start Page
619
End Page
623
DOI
10.1172/JCI200113468

Expression of the DMT1 (NRAMP2/DCT1) iron transporter in mice with genetic iron overload disorders

Iron overload is highly prevalent, but its molecular pathogenesis is poorly understood. Recently, DMT1 was shown to be a major apical iron transporter in absorptive cells of the duodenum. In vivo, it is the only transporter known to be important for the uptake of dietary non-heme iron from the gut lumen. The expression and subcellular localization of DMT1 protein in 3 mouse models of iron overload were examined: Hypotransferrinemic (Trfhpx) mice, Hfe knockout mice, and B2m knockout mice. Interestingly, in Trfhpx homozygotes, DMT1 expression was strongly induced in the villus brush border when compared to control animals. This suggests that DMT1 expression is increased in response to iron deficiency in the erythron, even in the setting of systemic iron overload. In contrast, no increase was seen in DMT1 expression in animals with iron overload resembling human hemochromatosis. Therefore, it does not appear that changes in DMT1 levels are primarily responsible for iron loading in hemochromatosis. © 2001 by The American Society of Hematology.

Authors
Canonne-Hergaux, F; Levy, JE; Fleming, MD; Montross, LK; Andrews, NC; Gros, P
MLA Citation
Canonne-Hergaux, F, Levy, JE, Fleming, MD, Montross, LK, Andrews, NC, and Gros, P. "Expression of the DMT1 (NRAMP2/DCT1) iron transporter in mice with genetic iron overload disorders." Blood 97.4 (2001): 1138-1140.
PMID
11159549
Source
scival
Published In
Blood
Volume
97
Issue
4
Publish Date
2001
Start Page
1138
End Page
1140
DOI
10.1182/blood.V97.4.1138

A mouse model of familial porphyria cutanea tarda

Approximately one-third of patients with porphyria cutanea tarda (PCT), the most common porphyria in humans, inherit a single mutant allele of the uroporphyrinogen decarboxylase (URO-D) gene. PCT associated with URO-D mutations is designated familial PCT. The phenotype is characterized by a photosensitive dermatosis with hepatic accumulation and urinary excretion of uroporphyrin and hepta-carboxylic porphyrins. Most heterozygotes for URO-D mutations do not express a porphyric phenotype unless hepatic siderosis is present. Hemochromatosis gene (HFE) mutations are frequently found when the phenotype is expressed. We used homologous recombination to disrupt one allele of murine URO-D. URO-D+/- mice had half-wild type (wt) URO-D protein and enzymatic activity in all tissues but did not accumulate hepatic porphyrins, indicating that half-normal URO-D activity is not rate limiting. When URO-D+/- mice were injected with iron-dextran and given drinking water containing δ-aminolevulinic acid for 21 days, hepatic porphyrins accumulated, and hepatic URO-D activity was reduced to 20% of wt. We bred mice homozygous for an HFE gene disruption (HFE-/-) to URO-D+/- mice, generating mice with the URO-D+/-/HFE-/- genotype. These animals developed a porphyric phenotype by 14 weeks of age without ALA supplementation, and URO-D activity was reduced to 14% of wt. These data indicate that iron overload alone is sufficient to reduce URO-D activity to rate-limiting levels in URO-D+/- mice. The URO-D+/- mouse serves as an excellent model of familial PCT and affords the opportunity to define the mechanism by which iron influences URO-D activity.

Authors
Phillips, JD; Jackson, LK; Bunting, M; Franklin, MR; Thomas, KR; Levy, JE; Andrews, NC; Kushner, JP
MLA Citation
Phillips, JD, Jackson, LK, Bunting, M, Franklin, MR, Thomas, KR, Levy, JE, Andrews, NC, and Kushner, JP. "A mouse model of familial porphyria cutanea tarda." Proceedings of the National Academy of Sciences of the United States of America 98.1 (2001): 259-264.
PMID
11134514
Source
scival
Published In
Proceedings of the National Academy of Sciences of USA
Volume
98
Issue
1
Publish Date
2001
Start Page
259
End Page
264
DOI
10.1073/pnas.011481398

Uroporphyria in Hfe mutant mice given 5-aminolevulinate: A new model of Fe-mediated porphyria cutanea tarda

Porphyria cutanea tarda (PCT), a liver disease with skin lesions caused by excess liver production of uroporphyrin (URO), is associated with consumption of alcoholic beverages or estrogens, and moderate iron overload. Recently, it has been shown that many PCT patients carry mutations in the HFE gene, which is responsible for hereditary hemochromatosis. Mice homozygous for either the null mutation in the Hfe gene or the C282Y missense mutation rapidly accumulate hepatic parenchymal iron similar to patients with hemochromatosis. Here we investigated whether disruption of the murine Hfe gene would result in hepatic uroporphyria. Mice homozygous for the Hfe-null mutation accumulated high levels of hepatic URO when fed 5-aminolevulinate (ALA). Hfe (+/-) mice also accumulated hepatic URO when fed ALA, but at a much slower rate. The amount of accumulated URO in the null mutant mice was similar to that in wild-type mice treated with iron carbonyl in the diet, or injected with iron dextran. Iron in both wildtype and Hfe (+/-) mice was mostly in Kupffer cells. In contrast, Hfe (-/-) mice had considerable parenchymal iron deposition as well, in a pattern similar to that observed in wild-type mice treated with iron carbonyl. URO accumulation was accompanied by 84% and 33% decreases in hepatic uroporphyrinogen decarboxylase activities in Hfe (-/-) and Hfe (+/-) mice, respectively. No increases in CYP1A2 or other cytochrome P450s were detected in the Hfe-null mutant mice. We conclude that this experimental model of uroporphyria is a valid model for further investigations into the mechanism of PCT.

Authors
Sinclair, PR; Gorman, N; Walton, HS; Bement, WJ; Sinclair, JF; Gerhard, GS; Szakacs, JG; Andrews, NC; Levy, JE
MLA Citation
Sinclair, PR, Gorman, N, Walton, HS, Bement, WJ, Sinclair, JF, Gerhard, GS, Szakacs, JG, Andrews, NC, and Levy, JE. "Uroporphyria in Hfe mutant mice given 5-aminolevulinate: A new model of Fe-mediated porphyria cutanea tarda." Hepatology 33.2 (2001): 406-412.
PMID
11172342
Source
scival
Published In
Hepatology
Volume
33
Issue
2
Publish Date
2001
Start Page
406
End Page
412
DOI
10.1053/jhep.2001.21409

Expression of stimulator of Fe transport is not enhanced in Hfe knockout mice

Hfe knockout (-/-) mice recapitulate many of the biochemical abnormalities of hereditary hemochromatosis (HH), but the molecular mechanisms involved in the etiology of iron overload in HH remain poorly understood. It was found previously that livers of patients with HH contained 5-fold higher SFT (stimulator of Fe transport) mRNA levels relative to subjects without HH. Because this observation suggests a possible role for SFT in HH, we investigated SFT mRNA expression in Hfe-/- mice. The 4- and 10-wk-old Hfe-/- mice do not have elevated levels of hepatic SFT transcripts relative to age-matched Hfe+/+ mice, despite having 2.2- and 3.3-fold greater hepatic nonheme iron concentrations, respectively. Northern blot analyses of various mouse tissues revealed that SFT is widely expressed. The novel observation that SFT transcripts are abundant in brain prompted a comparison of SFT transcript levels and nonheme iron levels in the brains of Hfe+/+ and Hfe-/- mice. Neither SFT mRNA levels nor nonheme iron levels differed between groups. Further comparisons of Hfe-/- and Hfe+/+ mouse tissues revealed no significant differences in SFT mRNA levels in duodenum, the site of increased iron absorption in HH. Important distinctions between Hfe-/- mice and HH patients include not only differences in the relative rate and magnitude of iron loading but also the lack of fibrosis and phlebotomy treatment in the knockout animals.

Authors
Knutson, MD; Levy, JE; Andrews, NC; Wessling-Resnick, M
MLA Citation
Knutson, MD, Levy, JE, Andrews, NC, and Wessling-Resnick, M. "Expression of stimulator of Fe transport is not enhanced in Hfe knockout mice." Journal of Nutrition 131.5 (2001): 1459-1464.
PMID
11340100
Source
scival
Published In
Journal of Nutrition
Volume
131
Issue
5
Publish Date
2001
Start Page
1459
End Page
1464

Disorders of iron metabolism.

Authors
Conrad, ME; Umbreit, JN
MLA Citation
Conrad, ME, and Umbreit, JN. "Disorders of iron metabolism." The New England journal of medicine 342.17 (April 2000): 1293-1294. (Letter)
PMID
10787338
Source
epmc
Published In
The New England journal of medicine
Volume
342
Issue
17
Publish Date
2000
Start Page
1293
End Page
1294
DOI
10.1056/nejm200004273421716

Iron metabolism: iron deficiency and iron overload.

Iron is an essential cofactor in a variety of cellular processes. Except for a few unusual bacterial species, iron is indispensable for living organisms. However, free iron is toxic because of its propensity to induce the formation of dangerous free radicals. Consequently, iron balance is tightly regulated. Disorders of iron homeostasis are among the most common afflictions of humans. This review discusses inherited iron deficiency and iron overload disorders and recent insights into their pathophysiology.

Authors
Andrews, NC
MLA Citation
Andrews, NC. "Iron metabolism: iron deficiency and iron overload." Annual review of genomics and human genetics 1 (January 2000): 75-98. (Review)
PMID
11701625
Source
epmc
Published In
Annual Review of Genomics and Human Genetics
Volume
1
Publish Date
2000
Start Page
75
End Page
98
DOI
10.1146/annurev.genom.1.1.75

The molecular defect in hypotransferrinemic mice

Hypotransferrinemic (Trf(hpx/hpx)) mice have a severe deficiency in serum transferrin (Trf) as the result of a spontaneous mutation linked to the murine Trf locus. They are born alive, but before weaning, die from severe anemia if they are not treated with exogenous Trf or red blood cell transfusions. We have determined the molecular basis of the hpx mutation. It results from a single point mutation, which alters an invariable nucleotide in the splice donor site after exon 16 of the Trf gene. No normal Trf messenger RNA (mRNA) is made from the hpx allele. A small amount of mRNA results from the usage of cryptic splice sites within exon 16. The predominant cryptic splice site produces a Trf mRNA carrying a 27-base pair (bp), in-frame deletion. Less than 1% of normal levels of a Trf-like protein is found in the serum of Trf(hpx)/hpx) mice, most likely resulting from translation of the internally deleted mRNA. Despite their severe Trf deficiency, however, Trf(hpx/hpx) mice initially treated with transferrin injections can survive after weaning without any further treatment. They have massive tissue iron overload develop in all nonhematopoietic tissues, while they continue to have severe iron deficiency anemia. Their liver iron burden is 100-fold greater than that of wild-type mice and 15- to 20-fold more than that of mice lacking the hemochromatosis gene, Hfe. Trf(hpx/hpx) mice thus provide an additional model with a defined molecular defect for the study of genetic iron disorders. (C) 2000 by The American Society of Hematology.

Authors
III, CCT; Campagna, DR; Sellers, VM; Andrews, NC; Fleming, MD
MLA Citation
III, CCT, Campagna, DR, Sellers, VM, Andrews, NC, and Fleming, MD. "The molecular defect in hypotransferrinemic mice." Blood 96.3 (2000): 1113-1118.
PMID
10910930
Source
scival
Published In
Blood
Volume
96
Issue
3
Publish Date
2000
Start Page
1113
End Page
1118

Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter

Defects in iron absorption and utilization lead to iron deficiency and overload disorders. Adult mammals absorb iron through the duodenum, whereas embryos obtain iron through placental transport. Iron uptake from the intestinal lumen through the apical surface of polarized duodenal enterocytes is mediated by the divalent metal transporter, DMT1 (refs 1-3). A second transporter has been postulated to export iron across the basolateral surface to the circulation. Here we have used positional cloning to identify the gene responsible for the hypochromic anaemia of the zebrafish mutant weissherbst. The gene, ferroportin1, encodes a multiple-transmembrane domain protein, expressed in the yolk sac, that is a candidate for the elusive iron exporter. Zebrafish ferroportin1 is required for the transport of iron from maternally derived yolk stores to the circulation and functions as an iron exporter when expressed in Xenopus oocytes. Human Ferroportin1 is found at the basal surface of placental syncytiotrophoblasts, suggesting that it also transports iron from mother to embryo. Mammalian Ferroportin1 is expressed at the basolateral surface of duodenal enterocytes and could export cellular iron into the circulation. We propose that Ferroportin1 function may be perturbed in mammalian disorders of iron deficiency or overload.

Authors
Donovan, A; Brownlie, A; Zhou, Y; Shepard, J; Pratt, SJ; Moynihan, J; Paw, BH; Drejer, A; Barut, B; Zapata, A; Law, TC; Brugnara, C; Lux, SE; Pinkus, GS; Pinkus, JL; Kingsley, PD; Palls, J; Fleming, MD; Andrews, NC; Zon, LI
MLA Citation
Donovan, A, Brownlie, A, Zhou, Y, Shepard, J, Pratt, SJ, Moynihan, J, Paw, BH, Drejer, A, Barut, B, Zapata, A, Law, TC, Brugnara, C, Lux, SE, Pinkus, GS, Pinkus, JL, Kingsley, PD, Palls, J, Fleming, MD, Andrews, NC, and Zon, LI. "Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter." Nature 403.6771 (2000): 776-781.
PMID
10693807
Source
scival
Published In
Nature
Volume
403
Issue
6771
Publish Date
2000
Start Page
776
End Page
781
DOI
10.1038/35001596

Genes that modify the hemochromatosis phenotype in mice

Hereditary hemochromatosis (HH) is a prevalent human disease caused by a mutation in HFE, which encodes an atypical HLA class I protein involved in regulation of intestinal iron absorption. To gain insight into the pathogenesis of hemochromatosis, we have bred Hfe knockout mice to strains carrying other mutations that impair normal iron metabolism. Compound mutant mice lacking both Hfe and its interacting protein, beta-2 microglobulin (B2m), deposit more tissue iron than mice lacking Hfe only, suggesting that another B2m-interacting protein may be involved in iron regulation. Hfe knockout mice carrying mutations in the iron transporter DMT1 fail to load iron, indicating that hemochromatosis involves iron flux through DMT1. Similarly, compound mutants deficient in both Hfe and hephaestin (Heph) show less iron loading than do Hfe knockout mice, indicating that iron absorption in hemochromatosis involves the function of Heph as well. Finally, compound mutants lacking Hfe and the transferrin receptor accumulate more tissue iron than do mice lacking Hfe alone, consistent with the idea that interaction between these two proteins contributes to the control of normal iron absorption. In addition to providing insight into the pathogenesis of HH, our results suggest that each of these genes might be a candidate modifier of the human hemochromatosis phenotype.

Authors
Levy, JE; Montross, LK; Andrews, NC
MLA Citation
Levy, JE, Montross, LK, and Andrews, NC. "Genes that modify the hemochromatosis phenotype in mice." Journal of Clinical Investigation 105.9 (2000): 1209-1216.
PMID
10791995
Source
scival
Published In
Journal of Clinical Investigation
Volume
105
Issue
9
Publish Date
2000
Start Page
1209
End Page
1216
DOI
10.1172/JCI9635

Iron metabolism: Iron deficiency and iron overload

Iron is an essential cofactor in a variety of cellular processes. Except for a few unusual bacterial species, iron is indispensable for living organisms. However, free iron is toxic because of its propensity to induce the formation of dangerous free radicals. Consequently, iron balance is tightly regulated. Disorders of iron homeostasis are among the most common afflictions of humans. This review discusses inherited iron deficiency and iron overload disorders and recent insights into their pathophysiology.

Authors
Andrews, NC
MLA Citation
Andrews, NC. "Iron metabolism: Iron deficiency and iron overload." Annual Review of Genomics and Human Genetics 1.2000 (2000): 75-98.
Source
scival
Published In
Annual Review of Genomics and Human Genetics
Volume
1
Issue
2000
Publish Date
2000
Start Page
75
End Page
98

Intestinal iron absorption: Current concepts circa 2000

Iron is essential for all mammalian cells, and particularly needed for the production of erythrocyte haemoglobin. However, excess iron is toxic, and tissue iron concentrations must be strictly regulated. This regulation occurs at the sites of entrance of iron into the body: in the placenta before birth, and the small intestine after birth. Although iron homeostasis has been intensively studied for half a century, the molecular details have only recently begun to emerge. This review will cover current information on intestinal iron absorption.

Authors
Andrews, NC
MLA Citation
Andrews, NC. "Intestinal iron absorption: Current concepts circa 2000." Digestive and Liver Disease 32.1 (2000): 56-61.
PMID
10975756
Source
scival
Published In
Digestive and Liver Disease
Volume
32
Issue
1
Publish Date
2000
Start Page
56
End Page
61

Inherited iron overload disorders

Iron is an essential nutrient that is highly toxic in excess. Normal iron balance is maintained primarily by regulation of intestinal absorption of the metal from the diet. Iron overload generally results from a chronic increase in intestinal absorption. During the past 5 years, it has become apparent that there are at least eight inherited disorders of iron metabolism characterized by the toxic accumulation of iron. This review provides an update for pediatricians on the clinical features and pathogenesis of these disorders. (C) 2000 Lippincott Williams and Witkins, Inc.

Authors
Andrews, NC
MLA Citation
Andrews, NC. "Inherited iron overload disorders." Current Opinion in Pediatrics 12.6 (2000): 596-602.
PMID
11106282
Source
scival
Published In
Current Opinion in Pediatrics
Volume
12
Issue
6
Publish Date
2000
Start Page
596
End Page
602
DOI
10.1097/00008480-200012000-00015

Comparison of the interactions of transferrin receptor and transferrin receptor 2 with transferrin and the hereditary hemochromatosis protein HFE

The transferrin receptor (TfR) interacts with two proteins important for iron metabolism, transferrin (Tf) and HFE, the protein mutated in hereditary hemochromatosis. A second receptor for Tf, TfR2, was recently identified and found to be functional for iron uptake in transfected cells (Kawabata, H., Germain, R. S., Vuong, P. T., Nakamaki, T., Said, J. W., and Koeffler, H. P. (2000) J. Biol. Chem. 275, 16618-16625). TfR2 has a pattern of expression and regulation that is distinct from TfR, and mutations in TfR2 have been recognized as the cause of a non-HFE linked form of hemochromatosis (Camaschella, C., Roetto, A., Cali, A., De Gobbi, M., Garozzo, G., Carella, M., Majorano, N., Totaro, A., and Gasparini, P. (2000) Nat. Genet. 25, 14-15). To investigate the relationship between TfR, TfR2, Tf, and HFE, we performed a series of binding experiments using soluble forms of these proteins. We find no detectable binding between TfR2 and HFE by co-immunoprecipitation or using a surface plasmon resonance-based assay. The affinity of TfR2 for iron-loaded Tf was determined to be 27 nM, 25-fold lower than the affinity of TfR for Tf. These results imply that HFE regulates Tf-mediated iron uptake only from the classical TfR and that TfR2 does not compete for HFE binding in cells expressing both forms of TfR.

Authors
Jr, APW; Bennett, MJ; Sellers, VM; Andrews, NC; Enns, CA; Bjorkman, PJ
MLA Citation
Jr, APW, Bennett, MJ, Sellers, VM, Andrews, NC, Enns, CA, and Bjorkman, PJ. "Comparison of the interactions of transferrin receptor and transferrin receptor 2 with transferrin and the hereditary hemochromatosis protein HFE." Journal of Biological Chemistry 275.49 (2000): 38135-38138.
PMID
11027676
Source
scival
Published In
The Journal of biological chemistry
Volume
275
Issue
49
Publish Date
2000
Start Page
38135
End Page
38138
DOI
10.1074/jbc.C000664200

Iron metabolism and absorption

Iron is an essential nutrient for animals living in an oxygen-rich environment. It greatly enhances the oxygen-carrying capacity of aqueous solutions as the active center in hemoglobin, facilitating oxygen delivery to tissues. Because it accepts and loses electrons readily, iron confers redox activity on the cytochromes of the respiratory chain and on numerous other enzymes. Yet, its utility is balanced by a risk of toxicity. Free iron catalyzes the formation of free radicals that damage cell membranes, proteins and DNA. To exploit the useful properties of iron, while avoiding its toxicity, most living organisms have developed meticulously regulated mechanisms for iron transport and storage. Specialized proteins sequester extracellular and intracellular iron and mediate transport of iron across cellular membranes. Iron balance is regulated by systemic homeostatic mechanisms that we are only beginning to understand. This review describes our current understanding of iron metabolism in mammals.

Authors
Andrews, NC
MLA Citation
Andrews, NC. "Iron metabolism and absorption." Reviews in Clinical and Experimental Hematology 4.4 (2000): 283-301.
Source
scival
Published In
Reviews in Clinical and Experimental Hematology
Volume
4
Issue
4
Publish Date
2000
Start Page
283
End Page
301
DOI
10.1046/j.1468-0734.2000.00021.x

The Nramp2/DMT1 iron transporter is induced in the duodenum of microcytic anemia mk mice but is not properly targeted to the intestinal brush border

Microcytic anemia (mk) mice and Belgrade (b) rats are severely iron deficient because of impaired intestinal iron absorption and defective iron metabolism in peripheral tissues. Both animals carry a glycine to arginine substitution at position 185 in the iron transporter known as Nramp2/DMT1 (divalent metal transporter 1). DMT1 messenger RNA (mRNA) and protein expression has been examined in the gastrointestinal tract of mk mice. Northern blot analysis indicates that, by comparison to mk/+ heterozygotes, mk/mk homozygotes show a dramatic increase in the level of DMT1 mRNA in the duodenum. This increase in RNA expression is paralleled by a concomitant increase of the 100-kd DMT1 isoform I protein expression in the duodenum. Immunohistochemical analyses show that, as for normal mice on a low-iron diet, DMT1 expression in enterocytes of mk/mk mice is restricted to the duodenum. However, and in contrast to normal enterocytes, little if any expression of DMT1 is seen at the apical membrane in mk/mk mice. These results suggest that the G185R mutation, which was shown to impair the transport properties of DMT1, also affects the membrane targeting of the protein in mk/mk enterocytes. This loss of function of DMT1 is paralleled by a dramatic increase in expression of the defective protein in mk/mk mice. This is consistent with a feedback regulation of DMT1 expression by iron stores. (C) 2000 by The American Society of Hematology.

Authors
Canonne-Hergaux, F; Fleming, MD; Levy, JE; Gauthier, S; Ralph, T; Picard, V; Andrews, NC; Gros, P
MLA Citation
Canonne-Hergaux, F, Fleming, MD, Levy, JE, Gauthier, S, Ralph, T, Picard, V, Andrews, NC, and Gros, P. "The Nramp2/DMT1 iron transporter is induced in the duodenum of microcytic anemia mk mice but is not properly targeted to the intestinal brush border." Blood 96.12 (2000): 3964-3970.
PMID
11090085
Source
scival
Published In
Blood
Volume
96
Issue
12
Publish Date
2000
Start Page
3964
End Page
3970

Iron homeostasis: Insights from genetics and animal models

Disorders that perturb iron balance are among the most prevalent human diseases, but until recently iron transport remained poorly understood. Over the past five years, genetic studies of patients with inherited iron homeostasis disorders and the analysis of mutant mice, rats and zebrafish have helped to identify several important iron-transport proteins. With information being mined from the genomes of four species, the study of iron metabolism has benefited enormously from positional-cloning efforts. Complementing the genomic strategy, targeted mutagenesis in mice has produced new models of human iron diseases. The animal models described in this review offer valuable tools for investigating iron homeostasis in vivo.

Authors
Andrews, NC
MLA Citation
Andrews, NC. "Iron homeostasis: Insights from genetics and animal models." Nature Reviews Genetics 1.3 (2000): 208-217.
PMID
11252750
Source
scival
Published In
Nature Reviews Genetics
Volume
1
Issue
3
Publish Date
2000
Start Page
208
End Page
217

Ectopic expression of transcription factor NF-E2 alters the phenotype of erythroid and monoblastoid cells

In this study, regulation of transcription factor NF-E2 was examined in differentiating erythroid and myeloid cells, and the impact of raising NF-E2 concentrations within these cell types was assessed. NF-E2 was expressed in the J2E erythroid cell line, but the levels increased only marginally during erythropoietin-induced differentiation. In contrast, rare myeloid variants of J2E cells did not express NF-E2. Although NF-E2 was present in M1 monoblastoid cells, it was undetectable as these cells matured into macrophages. Compared with erythroid cells, transcription of the NF-E2 gene was reduced, and the half-life of the mRNA was significantly shorter in monocytoid cells. Ectopic expression of NF-E2 had a profound impact upon the J2E cells; morphologically mature erythroid cells spontaneously emerged in culture, but the cells failed to synthesize hemoglobin, even in the presence of erythropoietin. Although proliferation and viability increased in the NF-E2-transfected J2E cells, their responsiveness to erythropoietin was severely diminished. Strikingly, increasing the expression of NF-E2 in M1 cells produced sublines that contained erythroid or immature megakaryocytic cells. Finally, overexpression of NF-E2 in primary hemopoietic progenitors from fetal liver increased erythroid colony formation in the absence of erythropoietin. These data demonstrate that elevated NF-E2 (i) had a dominant effect on the phenotype and maturation of J2E erythroid cells, (ii) was able to reprogram the M1 monocytoid line, and (iii) promoted the development of erythroid colonies by normal progenitors.

Authors
Sayer, MS; Tilbrook, PA; Ingley, A; Spadaccini, E; Sarna, MK; Williams, JH; Andrews, NC; Klinken, SP
MLA Citation
Sayer, MS, Tilbrook, PA, Ingley, A, Spadaccini, E, Sarna, MK, Williams, JH, Andrews, NC, and Klinken, SP. "Ectopic expression of transcription factor NF-E2 alters the phenotype of erythroid and monoblastoid cells." Journal of Biological Chemistry 275.33 (2000): 25292-25298.
PMID
10842186
Source
scival
Published In
Journal of Biological Chemistry
Volume
275
Issue
33
Publish Date
2000
Start Page
25292
End Page
25298
DOI
10.1074/jbc.M908695199

Disorders of iron metabolism

Authors
Andrews, NC
MLA Citation
Andrews, NC. "Disorders of iron metabolism." New England Journal of Medicine 341.26 (1999): 1986-1995.
PMID
10607817
Source
scival
Published In
The New England journal of medicine
Volume
341
Issue
26
Publish Date
1999
Start Page
1986
End Page
1995
DOI
10.1056/NEJM199912233412607

The iron transporter DMT1

Divalent metal transporter 1 (DMT1) is the first mammalian transmembrane iron transporter to be identified. In 1997, parallel experiments from two groups provided compelling evidence of its function. Fleming and colleagues identified mutations in DMT1 (formerly known as Nramp2 and DCT1) in mice and rats with defects in intestinal iron absorption and red blood cell iron utilization. Gunshin and co-workers (H Gunshin, B MacKenzie, UV Berger, Y Gunshin, MF Romero, WF Boron, S Nussberger, JL Gollan, MA Hediger, Cloning and characterization of a mammalian proton-coupled metal-ion transporter, Nature 388 (1997) 482-488.) isolated DMT1 through an expression cloning strategy looking for mRNAs that stimulated iron uptake by Xenopus oocytes. Taken together, these data indicate that the twelve transmembrane domain protein DMT1 transfers iron across the apical surface of intestinal cells and out of transferrin cycle endosomes. Human DMT1 may be a good target for pharmacological intervention in patients with iron overload disorders attributable to increased iron absorption. Copyright (C) 1999 Elsevier Science Ltd.

Authors
Andrews, NC
MLA Citation
Andrews, NC. "The iron transporter DMT1." International Journal of Biochemistry and Cell Biology 31.10 (1999): 991-994.
PMID
10582331
Source
scival
Published In
The International Journal of Biochemistry & Cell Biology
Volume
31
Issue
10
Publish Date
1999
Start Page
991
End Page
994
DOI
10.1016/S1357-2725(99)00065-5

Iron transport across biologic membranes

Iron is essential for life, but is toxic in excess. Nearly all organisms have therefore developed regulated mechanisms for efficient transport of iron into cells. This paper reviews the current understanding of iron transport, focusing on valuable lessons from studies of yeast iron transport and the discovery of the first mammalian transmembrane iron transporter.

Authors
Andrews, NC; Fleming, MD; Gunshin, H
MLA Citation
Andrews, NC, Fleming, MD, and Gunshin, H. "Iron transport across biologic membranes." Nutrition Reviews 57.4 (1999): 114-123.
PMID
10228348
Source
scival
Published In
Nutrition Reviews
Volume
57
Issue
4
Publish Date
1999
Start Page
114
End Page
123

The C282Y mutation causing hereditary hemochromatosis does not produce a null allele

Targeted mutagenesis was used to produce two mutations in the murine hemochromatosis gene (Hfe) locus. The first mutation deletes a large portion of the coding sequence, generating a null allele. The second mutation introduces a missense mutation (C282Y) into the Hfe locus, but otherwise leaves the gene intact. This mutation is identical to the disease-causing mutation in patients with hereditary hemochromatosis. Mice carrying each of the two mutations were bred and analyzed. Homozygosity for either mutation results in postnatal iron loading. The effects of the null mutation are more severe than the effects of the C282Y mutation. Mice heterozygous for either mutation accumulate more iron than normal controls. Interestingly, although liver iron stores are greatly increased, splenic iron is decreased. We conclude that the C282Y mutation does not result in a null allele.

Authors
Levy, JE; Montross, LK; Cohen, DE; Fleming, MD; Andrews, NC
MLA Citation
Levy, JE, Montross, LK, Cohen, DE, Fleming, MD, and Andrews, NC. "The C282Y mutation causing hereditary hemochromatosis does not produce a null allele." Blood 94.1 (1999): 9-11.
PMID
10381492
Source
scival
Published In
Blood
Volume
94
Issue
1
Publish Date
1999
Start Page
9
End Page
11

Transferrin receptor is necessary for development of erythrocytes and the nervous system

Plasma iron circulates bound to transferrin (Trf), which solubilizes the ferric ion and attenuates its reactivity. Diferric Trf interacts with cell- surface Trf receptor (Trfr) to undergo receptor-mediated endocytosis into specialized endosomes. Endosomal acidification leads to iron release, and iron is transported out of the endosome through the activity of divalent metal transporter 1 (DMT1, formerly Nramp2), a transmembrane iron transporter that functions only at low pH (ref. 1). Trf and Trfr then return to the cell surface for reuse, completing a highly efficient cycle. Although the Trf cycle is assumed to be the general mechanism for cellular iron uptake, this has not been validated experimentally. Mice with hypotransferrinaemia (hpx) have little or no plasma Trf (refs 2,3). They have severe anaemia, indicating that the Trf cycle is essential for iron uptake by erythroid cells. Other hpx tissues, however, are generally normal, and there is a paradoxical increase in intestinal iron absorption and iron storage. To test the hypothesis that the Trf cycle has unique importance for erythropoiesis, we disrupted the Trfr gene in mice. This results in elimination of the Trf cycle, but leaves other Trf functions intact. Mice lacking Trfr have a more severe phenotype than hpx mice, affecting both erythropoiesis and neurologic development. Furthermore, haploinsufficiency for Trfr results in impaired erythroid development and abnormal iron homeostasis.

Authors
Levy, JE; Jin, O; Fujiwara, Y; Kuo, F; Andrews, NC
MLA Citation
Levy, JE, Jin, O, Fujiwara, Y, Kuo, F, and Andrews, NC. "Transferrin receptor is necessary for development of erythrocytes and the nervous system." Nature Genetics 21.4 (1999): 396-399.
PMID
10192390
Source
scival
Published In
Nature Genetics
Volume
21
Issue
4
Publish Date
1999
Start Page
396
End Page
399
DOI
10.1038/7727

Commentary on: Ferrokinetics in the syndrome of familial hypoferremic microcytic anemia with iron malabsorption

Authors
Andrews, NC; Fleming, MD
MLA Citation
Andrews, NC, and Fleming, MD. "Commentary on: Ferrokinetics in the syndrome of familial hypoferremic microcytic anemia with iron malabsorption." Journal of Pediatric Hematology/Oncology 21.5 (1999): 353-355.
PMID
10524446
Source
scival
Published In
Journal of Pediatric Hematology/Oncology
Volume
21
Issue
5
Publish Date
1999
Start Page
353
End Page
355
DOI
10.1097/00043426-199909000-00004

Molecular insights into mechanisms of iron transport

The past 3 years have witnessed extraordinary progress in our understanding of mammalian iron transport and homeostasis. The first transmembrane iron transporter has been found. Mutations in this protein, in two animal models with iron-transport defects, have helped to define the roles of this protein in vivo. The gene defective in patients with hereditary hemochromatosis has been identified, and much has been learned about the structure and function of its gene product. Finally, our ability to make a molecular diagnosis of hereditary hemochromatosis has called attention to new iron-loading disorders, including African iron overload and juvenile hemochromatosis.

Authors
Andrews, NC; Fleming, MD; Levy, JE
MLA Citation
Andrews, NC, Fleming, MD, and Levy, JE. "Molecular insights into mechanisms of iron transport." Current Opinion in Hematology 6.2 (1999): 61-64.
PMID
10088633
Source
scival
Published In
Current Opinion in Hematology
Volume
6
Issue
2
Publish Date
1999
Start Page
61
End Page
64
DOI
10.1097/00062752-199903000-00001

Mammalian iron transport: An unexpected link between metal homeostasis and host defense

Iron deficiency and iron overload disorders are common in clinical practice. Both can result from perturbations in the flux of iron across the absorptive intestinal enterocyte. Until recently iron transport has been poorly understood. In 1997 two independent cloning strategies identified Nramp2 (DCT1) as the first mammalian transmembrane iron transporter. In this review we discuss evidence that Nramp-related proteins play essential roles in metal homeostasis and host defense.

Authors
Fleming, MD; Andrews, NC
MLA Citation
Fleming, MD, and Andrews, NC. "Mammalian iron transport: An unexpected link between metal homeostasis and host defense." Journal of Laboratory and Clinical Medicine 132.6 (1998): 464-468.
PMID
9851735
Source
scival
Published In
Journal of Laboratory and Clinical Medicine
Volume
132
Issue
6
Publish Date
1998
Start Page
464
End Page
468

p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities

We describe the cloning of p63, a gene at chromosome 3q27-29 that bears strong homology to the tumor suppressor p53 and to the related gene, p73. p63 was detected in a variety of human and mouse tissues, including proliferating basal cells of epithelial layers in the epidermis, cervix, urothelium, and prostate. Unlike p53, the p63 gene encodes multiple isotypes with remarkably divergent abilities to transactivate p53 reporter genes and induce apoptosis. Importantly, the predominant p63 isotypes in many epithelial tissues lack an acidic N terminus corresponding to the transactivation domain of p53. We demonstrate that these truncated p63 variants can act as dominant-negative agents toward transactivation by p53 and p63, and we suggest the possibility of physiological interactions among members of the p53 family.

Authors
Yang, A; Kaghad, M; Wang, Y; Gillett, E; Fleming, MD; Dötsch, V; Andrews, NC; Caput, D; McKeon, F
MLA Citation
Yang, A, Kaghad, M, Wang, Y, Gillett, E, Fleming, MD, Dötsch, V, Andrews, NC, Caput, D, and McKeon, F. "p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities." Molecular Cell 2.3 (1998): 305-316.
PMID
9774969
Source
scival
Published In
Molecular Cell
Volume
2
Issue
3
Publish Date
1998
Start Page
305
End Page
316

Iron is hot: An update on the pathophysiology of hemochromatosis

Authors
Andrews, NC; Levy, JE
MLA Citation
Andrews, NC, and Levy, JE. "Iron is hot: An update on the pathophysiology of hemochromatosis." Blood 92.6 (1998): 1845-1851.
PMID
9731040
Source
scival
Published In
Blood
Volume
92
Issue
6
Publish Date
1998
Start Page
1845
End Page
1851

The G185R mutation disrupts function of the iron transporter Nramp2

Microcytic anemia (mk) mice and Belgrade (b) rats have severe into deficiency anemia due to defects in intestinal iron transport and erythroid iron utilization. Both animal mutants carry the same missense mutation in Nramp2, the first mammalian iron transporter to be identified. This mutation, in which glycine 185 is changed to arginine (G185R), occurs within predicted transmembrane domain 4 of the protein. We have performed site-directed mutagenesis of murine Nramp2, focusing on amino acids of transmembrane domain 4 that are highly conserved among Nramp-like proteins. We have expressed each mutant form in transfected cells and examined iron transport function, subcellular localization, and protein amounts. All tested forms of Nramp2 localize to the plasma membrane and to transferrin-containing endosomes. Most transmembrane domain 4 mutations affect the amount of protein detected and consequently show diminished iron transport. The G185R mutation, however, causes near total loss of Nramp2 function that cannot be fully explained by a decreased amount of protein, indicating that G185R disrupts iron transport through an alteration in the function of Nramp2, rather than degradation of the protein.

Authors
Su, MA; III, CCT; Fleming, JC; Fleming, MD; Andrews, NC
MLA Citation
Su, MA, III, CCT, Fleming, JC, Fleming, MD, and Andrews, NC. "The G185R mutation disrupts function of the iron transporter Nramp2." Blood 92.6 (1998): 2157-2163.
PMID
9731075
Source
scival
Published In
Blood
Volume
92
Issue
6
Publish Date
1998
Start Page
2157
End Page
2163

Mitogen-activated protein kinases enhance long-range activation by the β-globin locus control region

The human β-globin locus control region (LCR), which consists of four erythroid-specific DNase I hypersensitive sites (HS1-HS4), functions over a long distance to control the transcription, chromatin structure, and replication of the β-globin genes. We have used stable transfection assays to show that activation of the mitogen-activated protein (MAP) kinase pathway by low concentrations of the phorbol ester phorbol 12-tetradecanoate 13- acetate (TPA) induces enhancer activity of the LCR subregion HS2, but not HS3. Although HS2 enhancer activity is diminished with increasing distance from the promoter, the relative level of induction by TPA is independent of HS2-promoter distance. Mutation of cis-elements within HS2 reveals that the tandem-binding sites for the hematopoietic-specific transcription factor NF- E2 are required for induction by TPA, and induction is conferred by expressing NF-E2 in an NF-E2-null cell line. These results show that MAP kinases target factors functioning through the NF-E2 sites to enhance long- range transactivation by the LCR.

Authors
Versaw, WK; Blank, V; Andrews, NM; Bresnick, EH
MLA Citation
Versaw, WK, Blank, V, Andrews, NM, and Bresnick, EH. "Mitogen-activated protein kinases enhance long-range activation by the β-globin locus control region." Proceedings of the National Academy of Sciences of the United States of America 95.15 (1998): 8756-8760.
PMID
9671751
Source
scival
Published In
Proceedings of the National Academy of Sciences of USA
Volume
95
Issue
15
Publish Date
1998
Start Page
8756
End Page
8760
DOI
10.1073/pnas.95.15.8756

Nramp2 is mutated in the anemic Belgrade (b) rat: Evidence of a role for Nramp2 in endosomal iron transport

The Belgrade (b) rat has an autosomal recessively inherited, microcytic, hypochromic anemia associated with abnormal reticulocyte iron uptake and gastrointestinal iron absorption. The b reticulocyte defect appears to be failure of iron transport out of endosomes within the transferrin cycle. Aspects of this phenotype are similar to those reported for the microcytic anemia (mk) mutation in the mouse. Recently, mk has been attributed to a missense mutation in the gene encoding the putative iron transporter protein Nramp2. To investigate the possibility that Nramp2 was also mutated in the b rat, we established linkage of the phenotype to the centromeric portion of rat chromosome 7. This region exhibits synteny to the chromosomal location of Nramp2 in the mouse. A polymorphism within the rat Nramp2 gene cosegregated with the b phenotype. A glycine-to-arginine missense mutation (GI85R) was present in the b Nramp2 gene, but not in the normal allele. Strikingly, this amino acid alteration is the same as that seen in the mk mouse. Functional studies of the protein encoded by the b allele of rat Nramp2 demonstrated that the mutation disrupted iron transport. These results confirm the hypothesis that Nramp2 is the protein defective in the Belgrade rat and raise the possibility that the phenotype shared by mk and b animals is unique to the G185R mutation. Furthermore, the phenotypic characteristics of these animals indicate that Nramp2 is essential both for normal intestinal iron absorption and for transport of iron out of the transferrin cycle endosome.

Authors
Fleming, MD; Romano, MA; Maureen, ASU; Garrick, LM; Garrick, MD; Andrews, NC
MLA Citation
Fleming, MD, Romano, MA, Maureen, ASU, Garrick, LM, Garrick, MD, and Andrews, NC. "Nramp2 is mutated in the anemic Belgrade (b) rat: Evidence of a role for Nramp2 in endosomal iron transport." Proceedings of the National Academy of Sciences of the United States of America 95.3 (1998): 1148-1153.
PMID
9448300
Source
scival
Published In
Proceedings of the National Academy of Sciences of USA
Volume
95
Issue
3
Publish Date
1998
Start Page
1148
End Page
1153
DOI
10.1073/pnas.95.3.1148

Molecules in focus the NF-E2 transcription factor

NF-E2 belongs to the basic-leucine zipper family of dimeric transcription factors. It consists of a widely expressed 18 kDa subunit, related to chicken Maf proteins, and a tissue-restricted 45 kDa subunit, which contains a cnc domain. It is found almost exclusively in hematopoietic progenitors, and cells of the erythroid/mega/mast cell trilineage. NF-E2 is involved in regulation of globin gene transcription, acting through locus control regions (LCRs) upstream of the alpha and beta globin gene clusters. In addition, it is essential for normal platelet production. Targeted disruption of the gene encoding the 45 kDa subunit leads to severe thrombocytopenia but little if any defect in erythropoiesis, indicating that other molecules can substitute for p45 in red cell maturation in developing mice. However, retroviral integration within the p45 gene has been shown to disrupt erythroid differentiation in erythroleukemia cells; this suggests that p45 could, conceivably, be a target for pharmacologic interventions in patients with excess red cell production due to polycythemia vera.

Authors
Andrews, NC
MLA Citation
Andrews, NC. "Molecules in focus the NF-E2 transcription factor." International Journal of Biochemistry and Cell Biology 30.4 (1998): 429-432.
PMID
9675875
Source
scival
Published In
International Journal of Biochemistry and Cell Biology
Volume
30
Issue
4
Publish Date
1998
Start Page
429
End Page
432
DOI
10.1016/S1357-2725(97)00135-0

The Maf transcription factors: Regulators of differentiation

Since the identification of the v-Maf oncogene in an avian tumor virus, the Maf protein family has grown rapidly, forming a unique subclass of basic- leucine zipper transcription (bZIP) factors. Maf family members appear to play important roles in the regulation of differentiation.

Authors
Blank, V; Andrews, NC
MLA Citation
Blank, V, and Andrews, NC. "The Maf transcription factors: Regulators of differentiation." Trends in Biochemical Sciences 22.11 (1997): 437-441.
PMID
9397686
Source
scival
Published In
Trends in Biochemical Sciences
Volume
22
Issue
11
Publish Date
1997
Start Page
437
End Page
441
DOI
10.1016/S0968-0004(97)01105-5

Molecular characterization and localization of the human MAFG gene

The human MAFG gene encodes a basic-leucine zipper (bZIP) protein that belongs to a family of transcription factors related to the v-mar oncogene. The ubiquitously expressed MAFG protein dimerizes with blood cell-specific bZIP factor p45 NF-E2, indicating that it may play a role in regulating hematopoietic gene expression. We have characterized the human MAFG gene and shown that it consists of at least three exons, which are separated by small introns. The first exon is not translated. The genomic structure of the MAFG locus is highly conserved between human and chicken. We have mapped the MAFG gene to human chromosome region 17q25 by fluorescence in situ hybridization. Several putative human disease loci have been mapped to this telomeric portion of chromosome 17.

Authors
Blank, V; Knoll, JHM; Andrews, NC
MLA Citation
Blank, V, Knoll, JHM, and Andrews, NC. "Molecular characterization and localization of the human MAFG gene." Genomics 44.1 (1997): 147-149.
PMID
9286713
Source
scival
Published In
Genomics
Volume
44
Issue
1
Publish Date
1997
Start Page
147
End Page
149
DOI
10.1006/geno.1997.4847

P45 NF-E2 regulates expression of thromboxane synthase in megakaryocytes

Transcription factor p45 NF-E2 is highly expressed in the erythroid and megakaryocytic lineages. Although p45 recognizes regulatory regions of several erythroid genes, mice deficient for this protein display only mild dyserythropoiesis but have abnormal megakaryocytes and lack circulating platelets. A number of megakaryocytic marker genes have been extensively studied, but none of them is regulated by NF-E2. To find target genes for p45 NF-E2 in megakaryopoiesis, we used an in vivo immunoselection assay: genomic fragments bound to p45 NF-E2 in the chromatin of a megakaryocytic cell line were immunoprecipitated with an anti-p45 antiserum and cloned. One of these fragments belongs to the second intron of the thromboxane synthase gene (TXS). We demonstrate that the TXS gene, which is mainly expressed in megakaryocytes, is indeed directly regulated by p45 NF-E2. First, its promoter contains a functional NF-E2 binding site; second, the intronic NF-E2 binding site is located within a chromatin-dependent enhancer element; third, p45-null murine megakaryocytes do not express detectable TXS mRNA, although TXS expression can be detected in other cells. These data, and the structure of the TXS promoter and enhancer, suggest that TXS belongs to a distinct subgroup of genes involved in platelet formation and function.

Authors
Deveaux, S; Cohen-Kaminsky, S; Shivdasani, RA; Andrews, NC; Filipe, A; Kuzniak, I; Orkin, SH; Roméo, P-H; Mignotte, V
MLA Citation
Deveaux, S, Cohen-Kaminsky, S, Shivdasani, RA, Andrews, NC, Filipe, A, Kuzniak, I, Orkin, SH, Roméo, P-H, and Mignotte, V. "P45 NF-E2 regulates expression of thromboxane synthase in megakaryocytes." EMBO Journal 16.18 (1997): 5654-5661.
PMID
9312024
Source
scival
Published In
EMBO Journal
Volume
16
Issue
18
Publish Date
1997
Start Page
5654
End Page
5661
DOI
10.1093/emboj/16.18.5654

Human MafG is a functional partner for p45 NF-E2 in activating globin gene expression

Mammalian globin gene expression is activated through NF-E2 elements recognized by basic-leucine zipper proteins of the AP-1 superfamily. The specificity of NF-E2 DNA binding is determined by several nucleotides adjacent to a core AP-1 motif, comprising a recognition site for transcription factors of the Maf subfamily. Earlier work proposed that p18(MafK) forms a heterodimer with hematopoietic-specific protein p45 NF-E2 to activate transcription through NF-E2 sites. However, there was no direct evidence that p18(MafK) serves this function in vivo; in fact, mice lacking p18(MafK) have no phenotype. Here we describe a novel cDNA clone that encodes the human homolog of chicken MafG. Human MafG heterodimerizes with p45 NF-E2 and binds DNA with specificity identical to that of purified NF-E2 DNA binding activity. A tethered heterodimer of p45 and MafG is fully functional in supporting expression of α- and β-globin, and in promoting erythroid differentiation in CB3, a p45-deficient mouse erythroleukemia cell line. These results indicate that human MafG can serve as a functional partner for p45 NF-E2, and suggest that the p45/MafG heterodimer plays a role in the regulation of erythropoiesis.

Authors
Blank, V; Kim, MJ; Andrews, NC
MLA Citation
Blank, V, Kim, MJ, and Andrews, NC. "Human MafG is a functional partner for p45 NF-E2 in activating globin gene expression." Blood 89.11 (1997): 3925-3935.
PMID
9166829
Source
scival
Published In
Blood
Volume
89
Issue
11
Publish Date
1997
Start Page
3925
End Page
3935

The transcriptional integrator CREB-binding protein mediates positive cross talk between nuclear hormone receptors and the hematopoietic bZip protein p45/NF-E2

Thyroid hormone (T3) and retinoic acid (RA) play important roles in erythropoiesis. We found that the hematopoietic cell-specific bZip protein p45/NF-E2 interacts with T3 receptor (TR) and RA receptor (RAR) but not retinoid X receptor. The interaction is between the DNA-binding domain of the nuclear receptor and the leucine zipper region of p45/NF-E2 but is markedly enhanced by cognate ligand. Remarkably, ligand-dependent transactivation by TR and RAR is markedly potentiated by p45/NF-E2. This effect of p45/NF-E2 is prevented by maf-like protein p18, which functions positively as a heterodimer with p45/NF-E2 on DNA. Potentiation of hormone action by p45/NF- E2 requires its activation domain, which interacts strongly with the multifaceted coactivator cyclic AMP response element protein-binding protein (CBP). The region of CBP which interacts with p45/NF-E2 is the same interaction domain that mediates inhibition of hormone-stimulated transcription by AP1 transcription factors. Overexpression of the bZip interaction domain of CBP specifically abolishes the positive cross talk between TR and p45/NF-E2. Thus, positive cross talk between p45/NF-E2 and nuclear hormone receptors requires direct protein-protein interactions between these factors and with CBP, whose integration of positive signals from two transactivation domains provides a novel mechanism for potentiation of hormone action in hematopoietic cells.

Authors
Cheng, X; Reginato, MJ; Andrews, NC; Lazar, MA
MLA Citation
Cheng, X, Reginato, MJ, Andrews, NC, and Lazar, MA. "The transcriptional integrator CREB-binding protein mediates positive cross talk between nuclear hormone receptors and the hematopoietic bZip protein p45/NF-E2." Molecular and Cellular Biology 17.3 (1997): 1407-1416.
PMID
9032267
Source
scival
Published In
Molecular and Cellular Biology
Volume
17
Issue
3
Publish Date
1997
Start Page
1407
End Page
1416

Iron deficiency: Lessons from anemic mice

Iron is an essential nutrient, and disorders of iron metabolism are common. Nonetheless, intestinal iron absorption and cellular iron transport are poorly understood. Biochemical approaches to elucidating these processes have yielded little in the past decade. As an alternative approach, we have begun to study spontaneous mouse mutants, that have inherited defects in key steps in iron transport. We have undertaken positional cloning of the gene responsible for microcytic anemia (gene symbol mk). This report describes the important characteristics of these mice, and our progress in studying them.

Authors
Andrews, NC
MLA Citation
Andrews, NC. "Iron deficiency: Lessons from anemic mice." Yale Journal of Biology and Medicine 70.3 (1997): 219-226.
PMID
9544492
Source
scival
Published In
The Yale journal of biology and medicine
Volume
70
Issue
3
Publish Date
1997
Start Page
219
End Page
226

Disorders of red cell iron during infancy and childhood

Authors
Andrews, NC; Bennett, CM
MLA Citation
Andrews, NC, and Bennett, CM. "Disorders of red cell iron during infancy and childhood." International Journal of Pediatric Hematology/Oncology 4.2 (1997): 171-180.
Source
scival
Published In
International Journal of Pediatric Hematology/Oncology
Volume
4
Issue
2
Publish Date
1997
Start Page
171
End Page
180

Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene

Although disorders of iron metabolism are prevalent, iron transport remains poorly understood. To address this problem, we undertook a positional cloning strategy to identify the causative mutation in mice with microcytic anaemia (mk). Homozygous mk/mk mice have microcytic, hypochromic anaemia due to severe defects in intestinal iron absorption and erythroid iron utilization. We report the identification of a strong candidate gene for mk, and suggest that the phenotype is a consequence of a missense mutation in Nramp2 (ref. 5), a previously identified gene of unknown function. Nramp2 is homologous to Nramp1, a gene active in host defense. If Nramp2 is mk, as the cumulative evidence suggests, our findings have broad implications for the understanding of iron transport and resistance to intracellular pathogens.

Authors
Fleming, MD; III, CCT; Su, MA; Foernzler, D; Beier, DR; Dietrich, WE; Andrews, NC
MLA Citation
Fleming, MD, III, CCT, Su, MA, Foernzler, D, Beier, DR, Dietrich, WE, and Andrews, NC. "Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene." Nature Genetics 16.4 (1997): 383-386.
PMID
9241278
Source
scival
Published In
Nature Genetics
Volume
16
Issue
4
Publish Date
1997
Start Page
383
End Page
386

Erythroid AP-1/NF-E2 elements vary in their response to NF-E2

AP-1/NF-E2 motifs found in erythroid transcriptional control elements are associated with powerful transcriptional activation and thought to be regulated by the erythroid transcription factor NF-E2. We have studied AP-1/NF-E2 motifs from three different erythroid control elements (5'HS2 of the human β-globin locus control region [LCR], the porphobilinogen deaminase [PBGD] promoter, and the mouse Band 3 promoter). We find that these AP-1/NF-E2 elements differ both in their ability to bind NF-E2 and their activity in transient assays. Each of the elements is bound by AP-1, but only the 5'HS2 and PBGD sites are bound by NF-E2. We examined the activity of these sites in minimal promoter constructs in transient assays. In erythroid cells, activity of duplicated NF-E2 motifs is positively correlated with binding by NF-E2; however, the Band 3 element not bound by NF-E2 is also active in some contexts. In HeLa cells, all sites were active and duplicated sites were most active. In F9 mouse teratocarcinoma cells, which express neither NF-E2 nor AP-1, the elements' activity parallels that in erythroid cells. While these findings are consistent with other evidence that NF-E2 is an important regulator of erythroid transcription, they suggest that some sites that resemble NF-E2 elements are actually regulated by other factors; we speculate that other tissue-specific and/or generally expressed factors may act on these sites.

Authors
Walters, M; Andrews, NC; Magis, W; Martin, DIK
MLA Citation
Walters, M, Andrews, NC, Magis, W, and Martin, DIK. "Erythroid AP-1/NF-E2 elements vary in their response to NF-E2." Experimental Hematology 24.3 (1996): 445-452.
PMID
8599974
Source
scival
Published In
Experimental Hematology
Volume
24
Issue
3
Publish Date
1996
Start Page
445
End Page
452

Iron deficiency anemia associated with an error of iron metabolism in two siblings: A thirty year follow up

For thirty years we have followed two siblings with apparent iron deficiency anemia in the setting of systemic iron overload. This report details their clinical courses, which have been surprisingly disparate. The female sibling has been more severely affected, requiring multiple transfusions. In contrast, the male sibling demonstrated apparent improvement at puberty. Although both have shown evidence of systemic iron overload for many years, neither has had significant end organ toxicity. We discuss the probable pathophysiology of their disorder, drawing from animal models with similar defects in iron uptake and utilization.

Authors
Parsons, SK; Fleming, MD; Phil, D; Nathan, DG; Andrews, NC
MLA Citation
Parsons, SK, Fleming, MD, Phil, D, Nathan, DG, and Andrews, NC. "Iron deficiency anemia associated with an error of iron metabolism in two siblings: A thirty year follow up." Hematology 1.1 (1996): 65-73.
Source
scival
Published In
Hematology
Volume
1
Issue
1
Publish Date
1996
Start Page
65
End Page
73

Multiple proteins interact with the nuclear inhibitory protein repressor element in the human interleukin-3 promoter.

T cell expression of interleukin 3 (IL-3) is directed by positive and negative cis-acting DNA elements clustered within 300 base pairs of the transcriptional start site. A strong repressor element, termed nuclear inhibitory protein (NIP), was previously mapped to a segment of the IL-3 promoter between nucleotides -271 and -250. Functional characterization of this element demonstrates that it can mediate repression when linked in cis to a heterologous promoter. DNA binding experiments were carried out to characterize the repressor activity. Using varying conditions, three distinct complexes were shown to interact specifically with the NIP region, although only one correlates with repressor activity. Complex 1 results from binding of a ubiquitous polypeptide that recognizes the 3' portion of this sequence and is not required for repression. Complex 2 corresponds to binding of transcription factor (upstream stimulatory factor) to an E-box motif in the 5' portion of the NIP region. DNA binding specificity of complex 3 overlaps with that of upstream stimulatory factor but is clearly distinct. To determine which of the latter two complexes represents NIP activity, we incorporated small alterations into the NIP site of an IL-3 promoter-linked reporter construct and examined their effects on NIP-mediated repression. Functional specificity for repression matches the DNA binding specificity of complex 3; both repressor activity and complex 3 binding require the consensus sequence CTCACNTNC.

Authors
Engeland, K; Andrews, NC; Mathey-Prevot, B
MLA Citation
Engeland, K, Andrews, NC, and Mathey-Prevot, B. "Multiple proteins interact with the nuclear inhibitory protein repressor element in the human interleukin-3 promoter." J Biol Chem 270.41 (October 13, 1995): 24572-24579.
PMID
7592676
Source
pubmed
Published In
The Journal of biological chemistry
Volume
270
Issue
41
Publish Date
1995
Start Page
24572
End Page
24579

cAMP-dependent protein kinase is necessary for increased NF-E2·DNA complex formation during erythroleukemia cell differentiation

When murine erythroleukemia (MEL) cells are induced to differentiate by hexamethylene bisacetamide (HMBA), erythroid-specific genes are transcriptionally activated; however, transcriptional activation of these genes is severely impaired in cAMP-dependent protein kinase (protein kinase A)-deficient MEL cells. The transcription factor NF-E2, composed of a 45-kDa (p45) and an 18-kDa (p18) subunit, is essential for enhancer activity of the globin locus control regions (LCRs). DNA binding of NF-E2 and α-globin LCR enhancer activity was significantly less in HMBA-treated protein kinase A-deficient cells compared to cells containing normal protein kinase A activity; DNA binding of several other transcription factors was the same in both cell types. In parental cells, HMBA treatment and/or prolonged activation of protein kinase A increased the amount of NF-E2 · DNA complexes without change in DNA binding affinity; the expression of p45 and p18 was the same under all conditions. p45 and p18 were phosphorylated by protein kinase A in vitro, but the phosphorylation did not affect NF-E2 · DNA complexes, suggesting that protein kinase A regulates NF-E2 · DNA complex formation indirectly, e.g. by altering expression of a regulatory factor(s). Thus, protein kinase A appears to be necessary for increased NF-E2 · DNA complex formation during differentiation of MEL cells and may influence erythroid-specific gene expression through this mechanism.

Authors
Garingo, AD; Suhasini, M; Andrews, NC; Pilz, RB
MLA Citation
Garingo, AD, Suhasini, M, Andrews, NC, and Pilz, RB. "cAMP-dependent protein kinase is necessary for increased NF-E2·DNA complex formation during erythroleukemia cell differentiation." Journal of Biological Chemistry 270.16 (1995): 9169-9177.
PMID
7721832
Source
scival
Published In
Journal of Biological Chemistry
Volume
270
Issue
16
Publish Date
1995
Start Page
9169
End Page
9177
DOI
10.1074/jbc.270.16.9169

Microcytic anemia in mk/mk mice is not corrected by retroviral-mediated gene transfer of wild-type p45 NF-E2

Mice homozygous for the mk mutation have a severe hypochromic, microcytic anemia that is characterized by a decreased mean-corpuscular hemoglobin concentration and balanced α- and β-globin-chain synthesis. Transplantation studies have shown that the defect in homozygous mk/mk mice is intrinsic to both the hematopoietic system and the gut. The gene for the hematopoietic-specific transcription factor, p45 NF-E2, has been found to cosegregate with the mk phenotype and contain a point mutation in mk/mk mice that results in an amino acid substitution (173V→A). In order to test the hypothesis that this amino acid substitution is responsible for the mk phenotype, we have used recombinant retroviruses to introduce wild-type p45 NF-E2 into the bone marrow of mk/mk mice. Despite gene transfer and expression of p45 NF-E2 in erythroid cells, we found no evidence for correction of the phenotype in mk/mk mice. These results indicate that the mk mutation cannot be corrected by enforced expression of wild-type p45 NF-E2 and suggest that the 173V→A mutation of the p45 NF-E2 gene is not the cause of anemia in mk/mk mice.

Authors
Ney, PA; Farina, SF; Bodine, DM; Andrews, NC; Orkin, SH; Nienhuis, AW
MLA Citation
Ney, PA, Farina, SF, Bodine, DM, Andrews, NC, Orkin, SH, and Nienhuis, AW. "Microcytic anemia in mk/mk mice is not corrected by retroviral-mediated gene transfer of wild-type p45 NF-E2." Experimental Hematology 23.1 (1995): 74-80.
PMID
7995373
Source
scival
Published In
Experimental Hematology
Volume
23
Issue
1
Publish Date
1995
Start Page
74
End Page
80

Mouse microcytic anaemia caused by a defect in the gene encoding the globin enhancer-binding protein NF-E2 [8]

Authors
Peters, LL; Andrews, NC; Eicher, EM; Davidson, MB; Orkin, SH; Lux, SE
MLA Citation
Peters, LL, Andrews, NC, Eicher, EM, Davidson, MB, Orkin, SH, and Lux, SE. "Mouse microcytic anaemia caused by a defect in the gene encoding the globin enhancer-binding protein NF-E2 [8]." Nature 371.6495 (December 1, 1994): 358-. (Letter)
Source
scopus
Published In
Nature
Volume
371
Issue
6495
Publish Date
1994
Start Page
358

Structure and regulation of the chicken erythroid δ-aminolevulinate synthase gene

Erythroid cells regulate heme biosynthesis in a manner that is distinct from all other cell types. While heme negatively regulates the synthesis of the housekeeping δ-aminolevulinate synthase (ALAS-N) in all non-erythroid cells, the expression of an erythroid-specific isozyme (ALAS-E) is developmentally regulated in red blood cells. As a first step towards understanding the molecular basis for the transcriptional regulation of ALAS-E during erythropoiesis, we cloned and characterized the chicken ALAS-E locus. This gene spans 18 kbp and is composed of eleven exons. The intron/exon structure of erythroid ALAS was found to be conserved among several vertebrate species. Direct RNA sequencing identified a 5' untranslated region that is derived from two contiguous exons and is predicted to form a very stable stem-loop structure that bears resemblance to the ferritin iron-responsive element. Tissue-specific expression of the ALAS-E gene was analyzed by transient transfection assays in hematopoietic cells of both erythroid and non-erythroid origins. These experiments identified distal (-784 to -505 bp) and proximal (-155 to +21 bp) promoter elements which are required for high level, erythroid-specific transcription.

Authors
Lim, K-C; Ishihara, H; Riddle, RD; Yang, Z; Andrews, N; Yamamoto, M; Engel, JD
MLA Citation
Lim, K-C, Ishihara, H, Riddle, RD, Yang, Z, Andrews, N, Yamamoto, M, and Engel, JD. "Structure and regulation of the chicken erythroid δ-aminolevulinate synthase gene." Nucleic Acids Research 22.7 (1994): 1226-1233.
PMID
8165137
Source
scival
Published In
Nucleic Acids Research
Volume
22
Issue
7
Publish Date
1994
Start Page
1226
End Page
1233

Transcriptional control of erythropoiesis.

Over the past year, substantial progress was made toward understanding transcriptional control of red cell differentiation. Complementary DNAs encoding two novel erythroid-restricted transcription factors--globin locus control region regulatory factor NF-E2 and CACC-binding protein EKLF--were cloned and characterized. Other DNA-binding activities have been implicated in developmental regulation of hemoglobin expression; these are postulated to mediate competitive interactions between globin gene promoters. As individual transcriptional regulatory factors are better understood, attention must turn to how they interact among themselves and with other proteins to initiate and maintain the erythroid program.

Authors
Andrews, NC; Orkin, SH
MLA Citation
Andrews, NC, and Orkin, SH. "Transcriptional control of erythropoiesis." Current opinion in hematology 1.2 (1994): 119-124.
PMID
9371270
Source
scival
Published In
Current Opinion in Hematology
Volume
1
Issue
2
Publish Date
1994
Start Page
119
End Page
124

Erythroid transcription factor NF-E2 coordinates hemoglobin synthesis

Authors
Andrews, NC
MLA Citation
Andrews, NC. "Erythroid transcription factor NF-E2 coordinates hemoglobin synthesis." Pediatric Research 36.4 (1994): 419-423.
PMID
7816514
Source
scival
Published In
Pediatric Research
Volume
36
Issue
4
Publish Date
1994
Start Page
419
End Page
423

Novel bacterial P-type ATPases with histidine-rich-heavy-metal-associated sequences

Menkes disease and Wilson disease are human disorders of copper metabolism. It has recently been shown that both are due to mutations in P-type ATPase copper transport molecules. Related heavy metal transporting ATPases have been described in several strains of bacteria. In an effort to isolate other mammalian metal transporters, we screened a human small intestine library with probes homologous to conserved sequences in the known proteins. Two novel cDNAs were isolated, which encode new members of this family. Surprisingly, they were both of bacterial origin, most likely derived from E. coli sequences transduced during library construction.

Authors
III, CT; Lin, W; Andrews, NC
MLA Citation
III, CT, Lin, W, and Andrews, NC. "Novel bacterial P-type ATPases with histidine-rich-heavy-metal-associated sequences." Biochemical and Biophysical Research Communications 205.3 (1994): 1644-1650.
PMID
7811248
Source
scival
Published In
Biochemical and Biophysical Research Communications
Volume
205
Issue
3
Publish Date
1994
Start Page
1644
End Page
1650
DOI
10.1006/bbrc.1994.2856

Erratum: Mouse microcytic anaemia caused by a defect in the gene encoding the globin enhancer-binding protein NF-E2 (Nature 362, 768-770 (1992))

Authors
Peters, LL; Andrews, NC; Eicher, EM; Davidson, MB; Orkin, SH; Lux, SE
MLA Citation
Peters, LL, Andrews, NC, Eicher, EM, Davidson, MB, Orkin, SH, and Lux, SE. "Erratum: Mouse microcytic anaemia caused by a defect in the gene encoding the globin enhancer-binding protein NF-E2 (Nature 362, 768-770 (1992))." Nature 371.6495 (1994): 358--.
Source
scival
Published In
Nature
Volume
371
Issue
6495
Publish Date
1994
Start Page
358-

Purification of the human NF-E2 complex: cDNA cloning of the hematopoietic cell-specific subunit and evidence for an associated partner

The human globin locus control region-binding protein, NF-E2, was purified by DNA affinity chromatography. Its tissue-specific component, p45 NF-E2, was cloned by use of a low-stringency library screen with murine p45 NF-E2 cDNA (N. C. Andrews, H. Erdjument-Bromage, M. B. Davidson, P. Tempst, and S. H. Orkin, Nature [London] 362:722-728,1993). The human p45 NF-E2 gene was localized to chromosome 12q13 by fluorescent in situ hybridization. Human p45 NF-E2 and murine p45 NF-E2 are highly homologous basic region-leucine zipper (bZIP) proteins with identical DNA-binding domains. Immunoprecipitation experiments demonstrated that p45 NF-E2 is associated in vivo with an 18-kDa protein (p18). Because bZIP proteins bind DNA as dimers, we infer that native NF-E2 must be a heterodimer of 45- and 18-kDa subunits. Although AP-1 and CREB copurified with NF-E2, no evidence was found for heterodimer formation between p45 NF-E2 and proteins other than p18. Thus, p18 appears to be the sole specific partner of p45 NF-E2 in erythroid cells. Cloning of human p45 NF-E2 should permit studies of the role of NF-E2 in globin gene regulation and erythroid differentiation.

Authors
Ney, PA; Andrews, NC; Jane, SM; Safer, B; Purucker, ME; Weremowicz, S; Morton, CC; Goff, SC; Orkin, SH; Nienhuis, AW
MLA Citation
Ney, PA, Andrews, NC, Jane, SM, Safer, B, Purucker, ME, Weremowicz, S, Morton, CC, Goff, SC, Orkin, SH, and Nienhuis, AW. "Purification of the human NF-E2 complex: cDNA cloning of the hematopoietic cell-specific subunit and evidence for an associated partner." Molecular and Cellular Biology 13.9 (1993): 5604-5612.
PMID
8355703
Source
scival
Published In
Molecular and Cellular Biology
Volume
13
Issue
9
Publish Date
1993
Start Page
5604
End Page
5612

Erythroid transcription factor NF-E2 is a haematopoietic-specific basic-leucine zipper protein

Expression of globin genes in developing erythroid cells is controlled by upstream locus control regions. Activity of these regions in vivo requires an erythroid-speciflc nuclear factor (NF-E2) that binds AP-1-like recognition sites. Its tissue-specific component (p45 NF-E2) has been characterized by complementary DNA cloning as a new basic region-leucine zipper protein which dimerizes with a ubiquitous partner to form native NF-E2.

Authors
Andrews, NC; Erdjument-Bromage, H; Davidson, MB; Tempst, P; Orkin, SH
MLA Citation
Andrews, NC, Erdjument-Bromage, H, Davidson, MB, Tempst, P, and Orkin, SH. "Erythroid transcription factor NF-E2 is a haematopoietic-specific basic-leucine zipper protein." Nature 362.6422 (1993): 722-728.
PMID
8469283
Source
scival
Published In
Nature
Volume
362
Issue
6422
Publish Date
1993
Start Page
722
End Page
728
DOI
10.1038/362722a0

Mouse microcytic anaemia caused by a defect in the gene encoding the globin enhancer-binding protein NF-E2

The nuclear DNA-binding protein NF-E2 is thought to mediate the powerful erythroid enhancer activity of the α- and β-globin locus control regions1-4 and participates in the control of genes encoding two enzymes of haem biosynthesis (porphobilinogen deaminase and ferrochelatase)1,5. The major component of NF-E2 is a 45K polypeptide (designated p45 NF-E2) that belongs to the basic region-leucine zipper family of transcription factors6. This subunit of NF-E2 is specifically expressed in haematopoietic progenitor cells and differentiated cells of the erythroid, megakaryocyte and mast cell lineages6. The gene encoding p45 NF-E2 (murine gene Nfe2) has been mapped to mouse chromosome 15 near the mutation microcytosis (mk). Homozygous mk mice have severe hypochromic microcytic anaemia as a result of decreased globin synthesis and defects in intestinal and erythroid iron absorption. Here we investigate whether the mk mutation lies within Nfe2 by characterizing the p45 NF-E2 gene and determining its DNA sequence in wild-type and mk alleles. The mk allele carries a missense mutation that causes substitution of valine by alanine at amino acid 173 of the p45 NF-E2 protein. Expression of p45 NF-E2 messenger RNA was detected in erythroid tissues of normal mice and in the duodenum of normal and severely anaemic β-thalassaemic (Hbbd-th3/Hbbd-th3) mice. We propose that the mk mutation results in an impaired form of NF-E2 which fails to regulate both globin production and iron metabolism properly.

Authors
Peters, LL; Andrews, NC; Eicher, EM; Davidson, MB; Orkin, SH; Lux, SE
MLA Citation
Peters, LL, Andrews, NC, Eicher, EM, Davidson, MB, Orkin, SH, and Lux, SE. "Mouse microcytic anaemia caused by a defect in the gene encoding the globin enhancer-binding protein NF-E2." Nature 362.6422 (1993): 768-770.
PMID
8469289
Source
scival
Published In
Nature
Volume
362
Issue
6422
Publish Date
1993
Start Page
768
End Page
770
DOI
10.1038/362768a0

The ubiquitous subunit of erythroid transcription factor NF-E2 is a small basic-leucine zipper protein related to the v-maf oncogene

Erythroid transcription factor NF-E2 is a tissue-restricted heterodimeric protein which recognizes an extended AP-1 motif [(T/C)TGCTGA(C/G)TCA(T/C)] found in the upstream locus control regions of the α- and β-globin gene clusters. A cDNA clone encoding a cell-type-specific subunit of NF-E2, designated p45 NF-E2, has previously been characterized and shown to encode a basic-leucine zipper DNA-binding protein. Here we describe protein purification and cloning of cDNA that encodes the second basic-leucine zipper subunit of the native NF-E2 heterodimer. This polypeptide, designated p18, is widely expressed. It displays extensive homology to the v-maf oncogene product and a human retinal-specific protein, NRL. Unusual features in the basic region shared by v-Maf, NRL, and p18 place them in a distinct subfamily of AP-1-like proteins.

Authors
Andrews, NC; Kotkow, KJ; Ney, PA; Erdjument-Bromage, H; Tempst, P; Orkin, SH
MLA Citation
Andrews, NC, Kotkow, KJ, Ney, PA, Erdjument-Bromage, H, Tempst, P, and Orkin, SH. "The ubiquitous subunit of erythroid transcription factor NF-E2 is a small basic-leucine zipper protein related to the v-maf oncogene." Proceedings of the National Academy of Sciences of the United States of America 90.24 (1993): 11488-11492.
PMID
8265578
Source
scival
Published In
Proceedings of the National Academy of Sciences of the United States of America
Volume
90
Issue
24
Publish Date
1993
Start Page
11488
End Page
11492
DOI
10.1073/pnas.90.24.11488

Enhanced expression of interleukin-3 and granulocyte-macrophage colony-stimulating factor receptor subunits in murine hematopoietic cells stimulated with hematopoietic growth factors.

AIC2A and AIC2B are closely related genes encoding components of the receptors for murine interleukin-3 (IL-3) (AIC2A) and granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-5 (AIC2B). We have studied the parallel regulation of expression of these genes in erythroid and myeloid progenitor cell lines. AIC2A and AIC2B transcription was transiently induced in these cells in response to a variety of hematopoietic growth factors, including erythropoietin (EPO), monocyte-CSF, IL-3, GM-CSF, and stem cell factor (SCF or kit ligand). Run-on assays established that the increase occurred mainly at the transcriptional level. Immunoprecipitation experiments confirmed that the increase in messenger RNA expression resulted in augmented synthesis of both AIC2A and AIC2B proteins, and binding studies further showed these proteins to be functional. We observed a fourfold increase in low-affinity IL-3 sites in an erythroid precursor cell line stimulated with EPO, and a threefold increase in GM-CSF high-affinity sites in a myeloid cell line stimulated with IL-3. In addition, we showed that the increase in the IL-3 receptor chain AIC2A in the erythroid precursor cell line correlated with the ability of IL-3 to exert a cooperative effect with EPO in the induction of beta-globin in these cells.

Authors
Liboi, E; Jubinsky, P; Andrews, NC; Nathan, DG; Mathey-Prevot, B
MLA Citation
Liboi, E, Jubinsky, P, Andrews, NC, Nathan, DG, and Mathey-Prevot, B. "Enhanced expression of interleukin-3 and granulocyte-macrophage colony-stimulating factor receptor subunits in murine hematopoietic cells stimulated with hematopoietic growth factors." Blood 80.5 (September 1, 1992): 1183-1189.
PMID
1387562
Source
pubmed
Published In
Blood
Volume
80
Issue
5
Publish Date
1992
Start Page
1183
End Page
1189

In vivo footprinting of the human α-globin locus upstream regulatory element by guanine and adenine ligation-mediated polymerase chain reaction

A major regulatory element required for expression of the human α-globin genes is located 40 kb upstream of the embryonic ζ-globin gene. To understand how this and other locus control region (LCR) elements contribute to high-level expression in erythroid cells, we have performed high-resolution, in vivo dimethyl sulfate footprinting. In addition, we have modified the dimethyl sulfate-based ligation-mediated polymerase chain reaction in vivo footprinting procedure to permit the assessment of interactions at guanine and adenine residues, rather than guanines alone. In vivo footprinting of the human α-LCR element carried on chromosome 16 in a mouse erythroleukemia cell environment revealed protein occupancy at GATA-1, AP-1/NF-E2, and CACC/GGTGG motifs, specific differences compared with in vitro protein binding, and distinct changes in one region upon dimethyl sulfoxide-induced cellular maturation. No protein contacts were detected in nonexpressing hepatoma cells. In addition, we have demonstrated that two AP-1 motifs in the α-LCR element which are occupied in vivo bind purified mouse NF-E2 protein in vitro. Our data suggest that three proteins, GATA-1, NF-E2, and unknown CACC/GGTGG factors, are minimally required as DNA-binding proteins for the function of LCR-like elements. The juxtaposition and interaction of these factors with each other, and with accessory proteins not directly in contact with DNA, are likely to account for the relative position independence of the upstream globin regulatory elements.

Authors
Strauss, EC; Andrews, NC; Higgs, DR; Orkin, SH
MLA Citation
Strauss, EC, Andrews, NC, Higgs, DR, and Orkin, SH. "In vivo footprinting of the human α-globin locus upstream regulatory element by guanine and adenine ligation-mediated polymerase chain reaction." Molecular and Cellular Biology 12.5 (1992): 2135-2142.
PMID
1569944
Source
scival
Published In
Molecular and Cellular Biology
Volume
12
Issue
5
Publish Date
1992
Start Page
2135
End Page
2142

A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells

Authors
Andrews, NC; Faller, DV
MLA Citation
Andrews, NC, and Faller, DV. "A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells." Nucleic Acids Research 19.9 (1991): 2499--.
PMID
2041787
Source
scival
Published In
Nucleic Acids Research
Volume
19
Issue
9
Publish Date
1991
Start Page
2499-

Positive and negative elements regulate human interleukin 3 expression.

The human interleukin 3 (IL-3) promoter is comprised of several cis-acting DNA sequences that modulate T-cell expression of IL-3. These are located within 315 nucleotides upstream of the mRNA start site. Transient expression of reporter genes linked to serially deleted sequences of the IL-3 promoter has allowed mapping of two activator sequences and an interposed repressor sequence. The proximal regulatory region is specific to IL-3 and prerequisite for efficient transcription. Its effect is enhanced by a second, more distal activating sequence consisting of an AP-1 binding site. Between the two activators lies a transcriptional silencer, which is a potent repressor in the absence of the AP-1 site. DNA-nuclear protein binding experiments demonstrate specific complex formation within each of these functional regions. Thus, both positive and negative regulatory elements appear to control expression of the human IL-3 gene in activated T cells.

Authors
Mathey-Prevot, B; Andrews, NC; Murphy, HS; Kreissman, SG; Nathan, DG
MLA Citation
Mathey-Prevot, B, Andrews, NC, Murphy, HS, Kreissman, SG, and Nathan, DG. "Positive and negative elements regulate human interleukin 3 expression." Proc Natl Acad Sci U S A 87.13 (July 1990): 5046-5050.
PMID
1695008
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
87
Issue
13
Publish Date
1990
Start Page
5046
End Page
5050

Regulation of the human interleukin-3 gene.

Authors
Andrews, NC; Mathey-Prevot, B; Murphy, H; Nathan, DG
MLA Citation
Andrews, NC, Mathey-Prevot, B, Murphy, H, and Nathan, DG. "Regulation of the human interleukin-3 gene." Trans Assoc Am Physicians 102 (1989): 240-251.
PMID
2638528
Source
pubmed
Published In
Transactions of the Association of American Physicians
Volume
102
Publish Date
1989
Start Page
240
End Page
251

Lack of evidence for VPg priming of poliovirus RNA synthesis in the host factor-dependent in vitro replicase reaction

Anti-VPg immunoprecipitable RNA labeled in vitro during a poliovirus RNA polymerase reaction was formed by the elongation of VPg-containing template fragments rather than by initiation with VPg. The reaction was dependent on a host factor (terminal uridylyl transferase). The incorporation of labeled UTP could be detected with only the host factor present.

Authors
Andrews, NC; Baltimore, D
MLA Citation
Andrews, NC, and Baltimore, D. "Lack of evidence for VPg priming of poliovirus RNA synthesis in the host factor-dependent in vitro replicase reaction." Journal of Virology 58.1 (1986): 212-215.
PMID
3005650
Source
scival
Published In
Journal of Virology
Volume
58
Issue
1
Publish Date
1986
Start Page
212
End Page
215

Purification of a terminal uridylyltransferase that acts as host factor in the in vitro poliovirus replicase reaction

Poliovirus RNA polymerase requires a host factor to initiate RNA synthesis in vitro. The host factor was previously purified to near homogeneity from HeLa cells but was not assigned an enzymatic activity. This report describes the purification of a terminal uridylyltransferase that can act as host factor. By all criteria examined it is identical to the factor purified previously. It has the same molecular weight (68,000), chromatographic properties, and cellular localization. We present evidence that terminal uridylyltransferase can add uridine residues to the 3' poly(A) end of virion RNA and that these anneal back to the poly(A) and form a hairpin primer for polymerase.

Authors
Andrews, NC; Baltimore, D
MLA Citation
Andrews, NC, and Baltimore, D. "Purification of a terminal uridylyltransferase that acts as host factor in the in vitro poliovirus replicase reaction." Proceedings of the National Academy of Sciences of the United States of America 83.2 (1986): 221-225.
PMID
2417240
Source
scival
Published In
Proceedings of the National Academy of Sciences of the United States of America
Volume
83
Issue
2
Publish Date
1986
Start Page
221
End Page
225

Poliovirus replicase stimulation by terminal uridylyl transferase

In an in vitro poliovirus replication system, purified viral polymerase, plus sense virion RNA, and a host factor have been previously shown to be necessary for the transcription of minus strands. We have found that a partially purified eukaryotic initiation factor-2 (eIF-2) fraction from rabbit reticulocytes can replace HeLa host factor in the replicase reaction. This enzyme preparation contains eIF-2 and two other major proteins. In addition to eIF-2 activity, which does not appear to play a role in the replicase reaction, we find that the fraction contains terminal uridylyl transferase activity. The enzyme adds UMP moieties to the 3' end of primer RNA molecules. The number of UMP residues added depends on the primer. Although long tails of heterogeneous lengths (50 to 100 nucleotides) can be polymerized on the 3' end of oligo(U), a poly(A) primer accepts only four U's. The terminal uridylyl transferase activity requires only UTP, Mg2+, a sulfhydryl reagent, and an RNA primer for activity. It is partially associated with ribosomes. We provide preliminary evidence that it may be responsible for host factor-like activity. We present a model for minus strand synthesis by poliovirus replicase, based on the hypothesis that a terminal uridylyl transferase can participate in initiation.

Authors
Andrews, NC; Levin, D; Baltimore, D
MLA Citation
Andrews, NC, Levin, D, and Baltimore, D. "Poliovirus replicase stimulation by terminal uridylyl transferase." Journal of Biological Chemistry 260.12 (1985): 7628-7635.
PMID
2987262
Source
scival
Published In
Journal of Biological Chemistry
Volume
260
Issue
12
Publish Date
1985
Start Page
7628
End Page
7635

Phage T3 DNA contains an exact copy of the 23 base-pair phage T7 RNA polymerase promoter sequence

The RNA polymerase encoded by bacteriophage T7 recognizes and transcribes from a single promoter in the late region of bacteriophage T3 DNA. This promoter is not utilized by T3 RNA polymerase. The DNA nucleotide sequence of this T7 RNA polymerase promoter, which is located at 85.4% on the T3 genome, has been determined; it contains the 23 base-pair sequence 5′ pT-A-A-T-A-C-G-A-C-T-C-A-C-T-A-T-A-G-G-G-A-G-AOH previously found to be conserved among five late promoters on T7 DNA. The RNA initiation site was identified by 5′-terminal RNA sequence analysis of the transcript made in vitro. Restriction endonuclease mapping and additional DNA sequence analysis indicate that this promoter is part of an extensive region in T3 DNA that is nearly identical to the corresponding 87% promoter region in T7. The probable protein synthesis termination codon for gene 16 of both phages has been located at the left-hand end of the promoter sequence. The likely phage gene 17 protein synthesis initiator region has been located within the 5′-terminal 60 nucleotides of the transcript synthesized from this promoter. © 1981.

Authors
Rosa, MD; Andrews, NC
MLA Citation
Rosa, MD, and Andrews, NC. "Phage T3 DNA contains an exact copy of the 23 base-pair phage T7 RNA polymerase promoter sequence." Journal of Molecular Biology 147.1 (1981): 41-53.
PMID
7265239
Source
scival
Published In
Journal of Molecular Biology
Volume
147
Issue
1
Publish Date
1981
Start Page
41
End Page
53

Two small RNAs encoded by Epstein-Barr virus and complexed with protein are precipitated by antibodies from patients with systemic lupus erythematosus

Primate cells harboring the Epstein-Barr virus (EBV) genome synthesize large amounts of two small RNAs:EBER 1 and EBER 2 (EBV-encoded RNA). These RNAs are approximately 180 nucleotides long, possess 5' pppA termini, and lack poly(A). They have different T1 and pancreatic RNase digestion fingerprints. They are not found in normal B lymphocytes, in transformed B lymphocytes that lack EBV DNA, in T lymphocytes transformed by Herpescirus ateles, or in a variety of other nonlymphoid mammalian cells. Hybridization analyses indicate that EBER 1 and EBER 2 are encoded by the EcoRI-J fragment of EBV(B95-8)DNA. In vivo both RNAs are associated with protein(s), allowing their specific precipitation by the systemic lupus erythematosus-associated antibody anti-La. The La antigen in uninfected mammalian cells consists of a heterogeneous class of small ribonucleoprotein particles, some of whose RNA components exhibit sequence homology with a highly repetitive, interspersed class of human DNA designated the Alu family. Possible functions for EBER 1 and EBER 2 in infection and cell transformation by EBV and their potential relationship to the pathogenesis of systemic lupus erythematosus are discussed.

Authors
Lerner, MR; Andrews, NC; Miller, G; Steitz, JA
MLA Citation
Lerner, MR, Andrews, NC, Miller, G, and Steitz, JA. "Two small RNAs encoded by Epstein-Barr virus and complexed with protein are precipitated by antibodies from patients with systemic lupus erythematosus." Proceedings of the National Academy of Sciences of the United States of America 78.2 II (1981): 805-809.
PMID
6262773
Source
scival
Published In
Proceedings of the National Academy of Sciences of the United States of America
Volume
78
Issue
2 II
Publish Date
1981
Start Page
805
End Page
809
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