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Yao, Tso-Pang

Overview:



My laboratory studies the regulatory functions of protein acetylation in cell signaling and human disease. We focus on a class of protein deacetylases, HDACs, which we have discovered versatile functions beyond gene transcription. We wish to use knowledge of HDAC biology to develop smart and rational clinical strategies for HDAC inhibitors, a growing class of compounds that show potent anti-tumor and other clinically relevant activities. Currently, there two major research major areas in the laboratory: aging/age-related disease, and mitochondrial biology/cancer metabolism. 


(1) Quality control (QC) autophagy in aging and neurodegenerative disease. The accumulation of damaged proteins and mitochondria is prominently linked to aging and age-associated disease, including neurodegeneration, metabolic disorders and cancer. Autophagy has emerged as specialized degradation machinery for the disposal of damaged protein aggregates and mitochondria, two common denominators in neurodegenerative diseases. We have discovered that this form of quality control (QC) autophagy is controlled by a ubiquitin-binding deacetylase, HDAC6.  Using both mouse and cell models, we are investigating how HDAC6 enforces QC autophagy and its importance in neurodegenerative disease and metabolic disorders. The potential of HDAC6 as a therapeutic target is being actively pursued.


(2) HDAC in mitochondria function and quality control. Acetyl-CoA is the donor of acetyl group for protein acetylation and numerous metabolic reactions. Remarkably, many mitochondrial enzymes and proteins are subject to acetylation. We are interested in characterizing the roles of HDAC in mitochondrial adaptation to changing metabolic demands and elucidating the intimate relationship between metabolism and protein acetylation. 


(3) HDAC, skeletal muscle remodeling, regeneration and neuromuscular disease. Skeletal muscle undergoes active remodeling in response to change in neural inputs or damage. Loss in neural input causes dramatic muscle dysfunction and disease, such as ALS. We have discovered that neural activity controls muscle phenotype through HDAC4, whose activity becomes deregulated in ALS patients. We have characterized this novel HDAC4-dependent signaling pathway and are evaluating modulators of this pathway for potential clinical utility in motor neuron disease.

Positions:

Professor of Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Assistant Professor in Radiation Oncology

Radiation Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1994

Ph.D. — University of California at San Diego

News:

Ben Wang: A Student Researcher and Food Lover

January 29, 2015 — Duke Research Blog

Grants:

Duke University Program in Environmental Health

Administered By
Environmental Sciences and Policy
AwardedBy
National Institute of Environmental Health Sciences
Role
Mentor
Start Date
July 01, 2013
End Date
June 30, 2018

The role of MEST (mesoderm specific transcript) in rhabdomyosarcoma

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
St. Baldrick's Foundation
Role
Co Investigator
Start Date
July 01, 2015
End Date
December 31, 2016

Histone deacetylase 4 and neural activity-dependent muscle remodeling and atrophy

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 01, 2008
End Date
July 31, 2014

HDAC10, Mitochondria and autophagy-a novel network targeted by HDAC inhibitors

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 01, 2009
End Date
July 31, 2011

Multispectral Imaging Flow Cytometer Core

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Major User
Start Date
March 04, 2010
End Date
March 03, 2011

Control of p53 Tumor Supressor by CBP/p300

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
January 05, 2001
End Date
June 30, 2006
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Publications:

Dopaminergic abnormalities in Hdac6-deficient mice

Authors
Fukada, M; Nakayama, A; Mamiya, T; Yao, T-P; Kawaguchi, Y
MLA Citation
Fukada, M, Nakayama, A, Mamiya, T, Yao, T-P, and Kawaguchi, Y. "Dopaminergic abnormalities in Hdac6-deficient mice." Neuropharmacology 110 (November 2016): 470-479.
Source
crossref
Published In
Neuropharmacology
Volume
110
Publish Date
2016
Start Page
470
End Page
479
DOI
10.1016/j.neuropharm.2016.08.018

HDAC6 regulates the dynamics of lytic granules in cytotoxic T lymphocytes.

HDAC6 is a tubulin deacetylase involved in many cellular functions related to cytoskeleton dynamics, including cell migration and autophagy. In addition, HDAC6 affects antigen-dependent CD4(+)T cell activation. In this study, we show that HDAC6 contributes to the cytotoxic function of CD8(+)T cells. Immunization studies revealed defective cytotoxic activity in vivo in the absence of HDAC6. Adoptive transfer of wild-type or Hdac6(-/-)CD8(+)T cells to Rag1(-/-)mice demonstrated specific impairment in CD8(+)T cell responses against vaccinia infection. Mechanistically, HDAC6-deficient cytotoxic T lymphocytes (CTLs) showed defective in vitro cytolytic activity related to altered dynamics of lytic granules, inhibited kinesin-1-dynactin-mediated terminal transport of lytic granules to the immune synapse and deficient exocytosis, but not to target cell recognition, T cell receptor (TCR) activation or interferon (IFN)γ production. Our results establish HDAC6 as an effector of the immune cytotoxic response that acts by affecting the dynamics, transport and secretion of lytic granules by CTLs.

Authors
Núñez-Andrade, N; Iborra, S; Trullo, A; Moreno-Gonzalo, O; Calvo, E; Catalán, E; Menasche, G; Sancho, D; Vázquez, J; Yao, T-P; Martín-Cófreces, NB; Sánchez-Madrid, F
MLA Citation
Núñez-Andrade, N, Iborra, S, Trullo, A, Moreno-Gonzalo, O, Calvo, E, Catalán, E, Menasche, G, Sancho, D, Vázquez, J, Yao, T-P, Martín-Cófreces, NB, and Sánchez-Madrid, F. "HDAC6 regulates the dynamics of lytic granules in cytotoxic T lymphocytes." Journal of cell science 129.7 (April 2016): 1305-1311.
PMID
26869226
Source
epmc
Published In
Journal of cell science
Volume
129
Issue
7
Publish Date
2016
Start Page
1305
End Page
1311
DOI
10.1242/jcs.180885

HDAC6 regulates cellular viral RNA sensing by deacetylation of RIG-I.

RIG-I is a key cytosolic sensor that detects RNA viruses through its C-terminal region and activates the production of antiviral interferons (IFNs) and proinflammatory cytokines. While posttranslational modification has been demonstrated to regulate RIG-I signaling activity, its significance for the sensing of viral RNAs remains unclear. Here, we first show that the RIG-I C-terminal region undergoes deacetylation to regulate its viral RNA-sensing activity and that the HDAC6-mediated deacetylation of RIG-I is critical for viral RNA detection. HDAC6 transiently bound to RIG-I and removed the lysine 909 acetylation in the presence of viral RNAs, promoting RIG-I sensing of viral RNAs. Depletion of HDAC6 expression led to impaired antiviral responses against RNA viruses, but not against DNA viruses. Consequently, HDAC6 knockout mice were highly susceptible to RNA virus infections compared to wild-type mice. These findings underscore the critical role of HDAC6 in the modulation of the RIG-I-mediated antiviral sensing pathway.

Authors
Choi, SJ; Lee, H-C; Kim, J-H; Park, SY; Kim, T-H; Lee, W-K; Jang, D-J; Yoon, J-E; Choi, Y-I; Kim, S; Ma, J; Kim, C-J; Yao, T-P; Jung, JU; Lee, J-Y; Lee, J-S
MLA Citation
Choi, SJ, Lee, H-C, Kim, J-H, Park, SY, Kim, T-H, Lee, W-K, Jang, D-J, Yoon, J-E, Choi, Y-I, Kim, S, Ma, J, Kim, C-J, Yao, T-P, Jung, JU, Lee, J-Y, and Lee, J-S. "HDAC6 regulates cellular viral RNA sensing by deacetylation of RIG-I." The EMBO journal 35.4 (February 2016): 429-442.
PMID
26746851
Source
epmc
Published In
EMBO Journal
Volume
35
Issue
4
Publish Date
2016
Start Page
429
End Page
442
DOI
10.15252/embj.201592586

Parkin Regulation and Neurodegenerative Disorders

Authors
Zhang, C-W; Hang, L; Yao, T-P; Lim, K-L
MLA Citation
Zhang, C-W, Hang, L, Yao, T-P, and Lim, K-L. "Parkin Regulation and Neurodegenerative Disorders." Frontiers in Aging Neuroscience 7 (January 12, 2016).
Source
crossref
Published In
Frontiers in Aging Neuroscience
Volume
7
Publish Date
2016
DOI
10.3389/fnagi.2015.00248

HDAC6 maintains mitochondrial connectivity under hypoxic stress by suppressing MARCH5/MITOL dependent MFN2 degradation.

Mitochondria undergo fusion and fission in response to various metabolic stresses. Growing evidences have suggested that the morphological change of mitochondria by fusion and fission plays a critical role in protecting mitochondria from metabolic stresses. Here, we showed that hypoxia treatment could induce interaction between HDAC6 and MFN2, thus protecting mitochondrial connectivity. Mechanistically, we demonstrated that a mitochondrial ubiquitin ligase MARCH5/MITOL was responsible for hypoxia-induced MFN2 degradation in HDAC6 deficient cells. Notably, genetic abolition of HDAC6 in amyotrophic lateral sclerosis model mice showed MFN2 degradation with MARCH5 induction. Our results indicate that HDAC6 is a critical regulator of MFN2 degradation by MARCH5, thus protecting mitochondrial connectivity from hypoxic stress.

Authors
Kim, H-J; Nagano, Y; Choi, SJ; Park, SY; Kim, H; Yao, T-P; Lee, J-Y
MLA Citation
Kim, H-J, Nagano, Y, Choi, SJ, Park, SY, Kim, H, Yao, T-P, and Lee, J-Y. "HDAC6 maintains mitochondrial connectivity under hypoxic stress by suppressing MARCH5/MITOL dependent MFN2 degradation." Biochemical and biophysical research communications 464.4 (September 2015): 1235-1240.
PMID
26210454
Source
epmc
Published In
Biochemical and Biophysical Research Communications
Volume
464
Issue
4
Publish Date
2015
Start Page
1235
End Page
1240
DOI
10.1016/j.bbrc.2015.07.111

Convergence of Parkin, PINK1, and α-Synuclein on Stress-induced Mitochondrial Morphological Remodeling.

Mutations in PARKIN (PARK2), an ubiquitin ligase, cause early onset Parkinson disease. Parkin was shown to bind, ubiquitinate, and target depolarized mitochondria for destruction by autophagy. This process, mitophagy, is considered crucial for maintaining mitochondrial integrity and suppressing Parkinsonism. Here, we report that under moderate mitochondrial stress, parkin does not translocate to mitochondria to induce mitophagy; rather, it stimulates mitochondrial connectivity. Mitochondrial stress-induced fusion requires PINK1 (PARK6), mitofusins, and parkin ubiquitin ligase activity. Upon exposure to mitochondrial toxins, parkin binds α-synuclein (PARK1), and in conjunction with the ubiquitin-conjugating enzyme Ubc13, stimulates K63-linked ubiquitination. Importantly, α-synuclein inactivation phenocopies parkin overexpression and suppresses stress-induced mitochondria fission, whereas Ubc13 inactivation abrogates parkin-dependent mitochondrial fusion. The convergence of parkin, PINK1, and α-synuclein on mitochondrial dynamics uncovers a common function of these PARK genes in the mitochondrial stress response and provides a potential physiological basis for the prevalence of α-synuclein pathology in Parkinson disease.

Authors
Norris, KL; Hao, R; Chen, L-F; Lai, C-H; Kapur, M; Shaughnessy, PJ; Chou, D; Yan, J; Taylor, JP; Engelender, S; West, AE; Lim, K-L; Yao, T-P
MLA Citation
Norris, KL, Hao, R, Chen, L-F, Lai, C-H, Kapur, M, Shaughnessy, PJ, Chou, D, Yan, J, Taylor, JP, Engelender, S, West, AE, Lim, K-L, and Yao, T-P. "Convergence of Parkin, PINK1, and α-Synuclein on Stress-induced Mitochondrial Morphological Remodeling." The Journal of biological chemistry 290.22 (May 2015): 13862-13874.
PMID
25861987
Source
epmc
Published In
The Journal of biological chemistry
Volume
290
Issue
22
Publish Date
2015
Start Page
13862
End Page
13874
DOI
10.1074/jbc.m114.634063

Chaperone-mediated 26S proteasome remodeling facilitates free K63 ubiquitin chain production and aggresome clearance.

Efficient elimination of misfolded proteins by the proteasome system is critical for proteostasis. Inadequate proteasome capacity can lead to aberrant aggregation of misfolded proteins and inclusion body formation, a hallmark of neurodegenerative disease. The proteasome system cannot degrade aggregated proteins; however, it stimulates autophagy-dependent aggregate clearance by producing unanchored lysine (K)63-linked ubiquitin chains via the proteasomal deubiquitinating enzyme Poh1. The canonical function of Poh1, which removes ubiquitin chains en bloc from proteasomal substrates prior to their degradation, requires intact 26S proteasomes. Here we present evidence that during aggresome clearance, 20S proteasomes dissociate from protein aggregates, while Poh1 and selective subunits of 19S proteasomes are retained. The dissociation of 20S proteasome components requires the molecular chaperone Hsp90. Hsp90 inhibition suppresses 26S proteasome remodeling, unanchored ubiquitin chain production, and aggresome clearance. Our results suggest that 26S proteasomes undergo active remodeling to generate a Poh1-dependent K63-deubiquitinating enzyme to facilitate protein aggregate clearance.

Authors
Nanduri, P; Hao, R; Fitzpatrick, T; Yao, T-P
MLA Citation
Nanduri, P, Hao, R, Fitzpatrick, T, and Yao, T-P. "Chaperone-mediated 26S proteasome remodeling facilitates free K63 ubiquitin chain production and aggresome clearance." The Journal of biological chemistry 290.15 (April 2015): 9455-9464.
PMID
25713068
Source
epmc
Published In
The Journal of biological chemistry
Volume
290
Issue
15
Publish Date
2015
Start Page
9455
End Page
9464
DOI
10.1074/jbc.m114.627950

HDAC4 regulates muscle fiber type-specific gene expression programs.

Fiber type-specific programs controlled by the transcription factor MEF2 dictate muscle functionality. Here, we show that HDAC4, a potent MEF2 inhibitor, is predominantly localized to the nuclei in fast/glycolytic fibers in contrast to the sarcoplasm in slow/oxidative fibers. The cytoplasmic localization is associated with HDAC4 hyper-phosphorylation in slow/oxidative-fibers. Genetic reprogramming of fast/glycolytic fibers to oxidative fibers by active CaMKII or calcineurin leads to increased HDAC4 phosphorylation, HDAC4 nuclear export, and an increase in markers associated with oxidative fibers. Indeed, HDAC4 represses the MEF2-dependent, PGC-1α-mediated oxidative metabolic gene program. Thus differential phosphorylation and localization of HDAC4 contributes to establishing fiber type-specific transcriptional programs.

Authors
Cohen, TJ; Choi, M-C; Kapur, M; Lira, VA; Yan, Z; Yao, T-P
MLA Citation
Cohen, TJ, Choi, M-C, Kapur, M, Lira, VA, Yan, Z, and Yao, T-P. "HDAC4 regulates muscle fiber type-specific gene expression programs." Molecules and cells 38.4 (April 2015): 343-348.
PMID
25728750
Source
epmc
Published In
Molecules and Cells
Volume
38
Issue
4
Publish Date
2015
Start Page
343
End Page
348
DOI
10.14348/molcells.2015.2278

Proteomic identification and functional characterization of MYH9, Hsc70, and DNAJA1 as novel substrates of HDAC6 deacetylase activity.

Histone deacetylase 6 (HDAC6), a predominantly cytoplasmic protein deacetylase, participates in a wide range of cellular processes through its deacetylase activity. However, the diverse functions of HDAC6 cannot be fully elucidated with its known substrates. In an attempt to explore the substrate diversity of HDAC6, we performed quantitative proteomic analyses to monitor changes in the abundance of protein lysine acetylation in response to HDAC6 deficiency. We identified 107 proteins with elevated acetylation in the liver of HDAC6 knockout mice. Three cytoplasmic proteins, including myosin heavy chain 9 (MYH9), heat shock cognate protein 70 (Hsc70), and dnaJ homolog subfamily A member 1 (DNAJA1), were verified to interact with HDAC6. The acetylation levels of these proteins were negatively regulated by HDAC6 both in the mouse liver and in cultured cells. Functional studies reveal that HDAC6-mediated deacetylation modulates the actin-binding ability of MYH9 and the interaction between Hsc70 and DNAJA1. These findings consolidate the notion that HDAC6 serves as a critical regulator of protein acetylation with the capability of coordinating various cellular functions.

Authors
Zhang, L; Liu, S; Liu, N; Zhang, Y; Liu, M; Li, D; Seto, E; Yao, T-P; Shui, W; Zhou, J
MLA Citation
Zhang, L, Liu, S, Liu, N, Zhang, Y, Liu, M, Li, D, Seto, E, Yao, T-P, Shui, W, and Zhou, J. "Proteomic identification and functional characterization of MYH9, Hsc70, and DNAJA1 as novel substrates of HDAC6 deacetylase activity." Protein & cell 6.1 (January 2015): 42-54.
PMID
25311840
Source
epmc
Published In
Protein & Cell
Volume
6
Issue
1
Publish Date
2015
Start Page
42
End Page
54
DOI
10.1007/s13238-014-0102-8

Uncoupling of Protein Aggregation and Neurodegeneration in a Mouse Amyotrophic Lateral Sclerosis Model.

Aberrant accumulation of protein aggregates is a pathological hallmark of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Although a buildup of protein aggregates frequently leads to cell death, whether it is the key pathogenic factor in driving neurodegenerative disease remains controversial. HDAC6, a cytosolic ubiquitin-binding deacetylase, has emerged as an important regulator of ubiquitin-dependent quality control autophagy, a lysosome-dependent degradative system responsible for the disposal of misfolded protein aggregates and damaged organelles. Here, we show that in cell models HDAC6 plays a protective role against multiple disease-associated and aggregation-prone cytosolic proteins by facilitating their degradation. We further show that HDAC6 is required for efficient localization of lysosomes to protein aggregates, indicating that lysosome targeting to autophagic substrates is regulated. Supporting a critical role of HDAC6 in protein aggregate disposal in vivo, genetic ablation of HDAC6 in a transgenic SOD1G93A mouse, a model of ALS, leads to dramatic accumulation of ubiquitinated SOD1G93A protein aggregates. Surprisingly, despite a robust buildup of SOD1G93A aggregates, deletion of HDAC6 only moderately modified the motor phenotypes. These findings indicate that SOD1G93A aggregation is not the only determining factor to drive neurodegeneration in ALS, and that HDAC6 likely modulates neurodegeneration through additional mechanisms beyond protein aggregate clearance.

Authors
Lee, J-Y; Kawaguchi, Y; Li, M; Kapur, M; Choi, SJ; Kim, H-J; Park, S-Y; Zhu, H; Yao, T-P
MLA Citation
Lee, J-Y, Kawaguchi, Y, Li, M, Kapur, M, Choi, SJ, Kim, H-J, Park, S-Y, Zhu, H, and Yao, T-P. "Uncoupling of Protein Aggregation and Neurodegeneration in a Mouse Amyotrophic Lateral Sclerosis Model." Neuro-degenerative diseases 15.6 (January 2015): 339-349.
PMID
26360702
Source
epmc
Published In
Neuro-degenerative diseases
Volume
15
Issue
6
Publish Date
2015
Start Page
339
End Page
349
DOI
10.1159/000437208

Glycolysis-dependent histone deacetylase 4 degradation regulates inflammatory cytokine production.

Activation of the inflammatory response is accompanied by a metabolic shift to aerobic glycolysis. Here we identify histone deacetylase 4 (HDAC4) as a new component of the immunometabolic program. We show that HDAC4 is required for efficient inflammatory cytokine production activated by lipopolysaccharide (LPS). Surprisingly, prolonged LPS treatment leads to HDAC4 degradation. LPS-induced HDAC4 degradation requires active glycolysis controlled by GSK3β and inducible nitric oxide synthase (iNOS). Inhibition of GSK3β or iNOS suppresses nitric oxide (NO) production, glycolysis, and HDAC4 degradation. We present evidence that sustained glycolysis induced by LPS treatment activates caspase-3, which cleaves HDAC4 and triggers its degradation. Of importance, a caspase-3-resistant mutant HDAC4 escapes LPS-induced degradation and prolongs inflammatory cytokine production. Our findings identify the GSK3β-iNOS-NO axis as a critical signaling cascade that couples inflammation to metabolic reprogramming and a glycolysis-driven negative feedback mechanism that limits inflammatory response by triggering HDAC4 degradation.

Authors
Wang, B; Liu, T-Y; Lai, C-H; Rao, Y-H; Choi, M-C; Chi, J-T; Dai, J-W; Rathmell, JC; Yao, T-P
MLA Citation
Wang, B, Liu, T-Y, Lai, C-H, Rao, Y-H, Choi, M-C, Chi, J-T, Dai, J-W, Rathmell, JC, and Yao, T-P. "Glycolysis-dependent histone deacetylase 4 degradation regulates inflammatory cytokine production." Molecular biology of the cell 25.21 (November 2014): 3300-3307.
PMID
25187650
Source
epmc
Published In
Molecular Biology of the Cell
Volume
25
Issue
21
Publish Date
2014
Start Page
3300
End Page
3307
DOI
10.1091/mbc.e13-12-0757

MFN1 deacetylation activates adaptive mitochondrial fusion and protects metabolically challenged mitochondria.

Fasting and glucose shortage activate a metabolic switch that shifts more energy production to mitochondria. This metabolic adaptation ensures energy supply, but also elevates the risk of mitochondrial oxidative damage. Here, we present evidence that metabolically challenged mitochondria undergo active fusion to suppress oxidative stress. In response to glucose starvation, mitofusin 1 (MFN1) becomes associated with the protein deacetylase HDAC6. This interaction leads to MFN1 deacetylation and activation, promoting mitochondrial fusion. Deficiency in HDAC6 or MFN1 prevents mitochondrial fusion induced by glucose deprivation. Unexpectedly, failure to undergo fusion does not acutely affect mitochondrial adaptive energy production; instead, it causes excessive production of mitochondrial reactive oxygen species and oxidative damage, a defect suppressed by an acetylation-resistant MFN1 mutant. In mice subjected to fasting, skeletal muscle mitochondria undergo dramatic fusion. Remarkably, fasting-induced mitochondrial fusion is abrogated in HDAC6-knockout mice, resulting in extensive mitochondrial degeneration. These findings show that adaptive mitochondrial fusion protects metabolically challenged mitochondria.

Authors
Lee, J-Y; Kapur, M; Li, M; Choi, M-C; Choi, S; Kim, H-J; Kim, I; Lee, E; Taylor, JP; Yao, T-P
MLA Citation
Lee, J-Y, Kapur, M, Li, M, Choi, M-C, Choi, S, Kim, H-J, Kim, I, Lee, E, Taylor, JP, and Yao, T-P. "MFN1 deacetylation activates adaptive mitochondrial fusion and protects metabolically challenged mitochondria." Journal of cell science 127.Pt 22 (November 2014): 4954-4963.
PMID
25271058
Source
epmc
Published In
Journal of cell science
Volume
127
Issue
Pt 22
Publish Date
2014
Start Page
4954
End Page
4963
DOI
10.1242/jcs.157321

HDAC4 promotes Pax7-dependent satellite cell activation and muscle regeneration.

During muscle regeneration, the transcription factor Pax7 stimulates the differentiation of satellite cells (SCs) toward the muscle lineage but restricts adipogenesis. Here, we identify HDAC4 as a regulator of Pax7-dependent muscle regeneration. In HDAC4-deficient SCs, the expression of Pax7 and its target genes is reduced. We identify HDAC4-regulated Lix1 as a Pax7 target gene required for SC proliferation. HDAC4 inactivation leads to defective SC proliferation, muscle regeneration, and aberrant lipid accumulation. Further, expression of the brown adipose master regulator Prdm16 and its inhibitory microRNA-133 are also deregulated. Thus, HDAC4 is a novel regulator of Pax7-dependent SC proliferation and potentially fate determination in regenerating muscle.

Authors
Choi, M-C; Ryu, S; Hao, R; Wang, B; Kapur, M; Fan, C-M; Yao, T-P
MLA Citation
Choi, M-C, Ryu, S, Hao, R, Wang, B, Kapur, M, Fan, C-M, and Yao, T-P. "HDAC4 promotes Pax7-dependent satellite cell activation and muscle regeneration." EMBO Reports 15.11 (November 2014): 1175-1183.
PMID
25205686
Source
epmc
Published In
EMBO Reports
Volume
15
Issue
11
Publish Date
2014
Start Page
1175
End Page
1183
DOI
10.15252/embr.201439195

PARK2 Induces Autophagy Removal of Impaired Mitochondria via Ubiquitination

© 2014 Elsevier Inc. All rights reserved. Mutations of PARK2, a gene encoding the ubiquitin ligase Parkin, are causative of autosomal recessive parkinsonism, a neurodegenerative disorder that is characterized by the relentless loss of dopaminergic neurons in the midbrain. The pivotal role that Parkin plays in maintaining dopaminergic neuronal survival is underscored by our current recognition that its dysfunction not only represents a prevalent cause of familial parkinsonism but also a formal risk factor for the more common, sporadic form of Parkinson's disease (PD). Accordingly, keen research on Parkin over the past decade or so has led to a significant advancement in our knowledge regarding its physiological roles and its relevance to PD. In particular, a recent seminal discovery that identified Parkin as a key regulator of mitochondrial quality control has provided an attractive mechanism that potentially underlies mitochondrial dysfunction commonly seen in the PD brain, which is thought to be a pathogenic driver of the disease. Indeed, the finding has led to a flurry of activity to elucidate the precise molecular events underlying Parkin-mediated mitophagy that ensues to this date. However, like all newly proposed models, the current model of Parkin-mediated mitophagy remains imperfect and is continually being debated and updated. In this chapter, we shall discuss the current knowledge and controversies surrounding this exciting topic.

Authors
Lim, KL; Chua, DSK; Palau, XG; Yao, TP
MLA Citation
Lim, KL, Chua, DSK, Palau, XG, and Yao, TP. "PARK2 Induces Autophagy Removal of Impaired Mitochondria via Ubiquitination." Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging. July 25, 2014. 175-188.
Source
scopus
Volume
4
Publish Date
2014
Start Page
175
End Page
188
DOI
10.1016/B978-0-12-405528-5.00011-0

Microtubule acetylation amplifies p38 kinase signalling and anti-inflammatory IL-10 production.

Reversible acetylation of α-tubulin is an evolutionarily conserved modification in microtubule networks. Despite its prevalence, the physiological function and regulation of microtubule acetylation remain poorly understood. Here we report that macrophages challenged by bacterial lipopolysaccharides (LPS) undergo extensive microtubule acetylation. Suppression of LPS-induced microtubule acetylation by inactivating the tubulin acetyltransferase, MEC17, profoundly inhibits the induction of anti-inflammatory interleukin-10 (IL-10), a phenotype effectively reversed by an acetylation-mimicking α-tubulin mutant. Conversely, elevating microtubule acetylation by inhibiting the tubulin deacetylase, HDAC6, or stabilizing microtubules via Taxol stimulates IL-10 hyper-induction. Supporting the anti-inflammatory function of microtubule acetylation, HDAC6 inhibition significantly protects mice from LPS toxicity. In HDAC6-deficient macrophages challenged by LPS, p38 kinase signalling becomes selectively amplified, leading to SP1-dependent IL-10 transcription. Remarkably, the augmented p38 signalling is suppressed by MEC17 inactivation. Our findings identify reversible microtubule acetylation as a kinase signalling modulator and a key component in the inflammatory response.

Authors
Wang, B; Rao, Y-H; Inoue, M; Hao, R; Lai, C-H; Chen, D; McDonald, SL; Choi, M-C; Wang, Q; Shinohara, ML; Yao, T-P
MLA Citation
Wang, B, Rao, Y-H, Inoue, M, Hao, R, Lai, C-H, Chen, D, McDonald, SL, Choi, M-C, Wang, Q, Shinohara, ML, and Yao, T-P. "Microtubule acetylation amplifies p38 kinase signalling and anti-inflammatory IL-10 production." Nature communications 5 (March 17, 2014): 3479-.
PMID
24632940
Source
epmc
Published In
Nature Communications
Volume
5
Publish Date
2014
Start Page
3479
DOI
10.1038/ncomms4479

Proteomic identification and functional characterization of MYH9, Hsc70, and DNAJA1 as novel substrates of HDAC6 deacetylase activity

© 2014, The Author(s). ABSTRACT: Histone deacetylase 6 (HDAC6), a predominantly cytoplasmic protein deacetylase, participates in a wide range of cellular processes through its deacetylase activity. However, the diverse functions of HDAC6 cannot be fully elucidated with its known substrates. In an attempt to explore the substrate diversity of HDAC6, we performed quantitative proteomic analyses to monitor changes in the abundance of protein lysine acetylation in response to HDAC6 deficiency. We identified 107 proteins with elevated acetylation in the liver of HDAC6 knockout mice. Three cytoplasmic proteins, including myosin heavy chain 9 (MYH9), heat shock cognate protein 70 (Hsc70), and dnaJ homolog subfamily A member 1 (DNAJA1), were verified to interact with HDAC6. The acetylation levels of these proteins were negatively regulated by HDAC6 both in the mouse liver and in cultured cells. Functional studies reveal that HDAC6-mediated deacetylation modulates the actin-binding ability of MYH9 and the interaction between Hsc70 and DNAJA1. These findings consolidate the notion that HDAC6 serves as a critical regulator of protein acetylation with the capability of coordinating various cellular functions.

Authors
Zhang, L; Liu, S; Liu, N; Zhang, Y; Liu, M; Li, D; Seto, E; Yao, TP; Shui, W; Zhou, J
MLA Citation
Zhang, L, Liu, S, Liu, N, Zhang, Y, Liu, M, Li, D, Seto, E, Yao, TP, Shui, W, and Zhou, J. "Proteomic identification and functional characterization of MYH9, Hsc70, and DNAJA1 as novel substrates of HDAC6 deacetylase activity." Protein and Cell 6.1 (January 1, 2014): 42-54.
Source
scopus
Published In
Protein & Cell
Volume
6
Issue
1
Publish Date
2014
Start Page
42
End Page
54
DOI
10.1007/s13238-014-0102-8

A Mec17-Myosin II Effector Axis Coordinates Microtubule Acetylation and Actin Dynamics to Control Primary Cilium Biogenesis.

Primary cilia are specialized, acetylated microtubule-based signaling processes. Cilium assembly is activated by cellular quiescence and requires reconfiguration of microtubules, the actin cytoskeleton, and vesicular trafficking machinery. How these components are coordinated to activate ciliogenesis remains unknown. Here we identify the microtubule acetyltransferase Mec-17 and myosin II motors as the key effectors in primary cilium biogenesis. We found that myosin IIB (Myh10) is required for cilium formation; however, myosin IIA (Myh9) suppresses it. Myh10 binds and antagonizes Myh9 to increase actin dynamics, which facilitates the assembly of the pericentrosomal preciliary complex (PPC) that supplies materials for cilium growth. Importantly, Myh10 expression is upregulated by serum-starvation and this induction requires Mec-17, which is itself accumulated upon cellular quiescence. Pharmacological stimulation of microtubule acetylation also induces Myh10 expression and cilium formation. Thus cellular quiescence induces Mec17 to couple the production of acetylated microtubules and Myh10, whose accumulation overcomes the inhibitory role of Myh9 and initiates ciliogenesis.

Authors
Rao, Y; Hao, R; Wang, B; Yao, T-P
MLA Citation
Rao, Y, Hao, R, Wang, B, and Yao, T-P. "A Mec17-Myosin II Effector Axis Coordinates Microtubule Acetylation and Actin Dynamics to Control Primary Cilium Biogenesis." PloS one 9.12 (January 2014): e114087-.
PMID
25494100
Source
epmc
Published In
PloS one
Volume
9
Issue
12
Publish Date
2014
Start Page
e114087
DOI
10.1371/journal.pone.0114087

VCP Is Essential for Mitochondrial Quality Control by PINK1/Parkin and this Function Is Impaired by VCP Mutations

Authors
Kim, NC; Tresse, E; Kolaitis, R-M; Molliex, A; Thomas, RE; Alami, NH; Wang, B; Joshi, A; Smith, RB; Ritson, GP; Winborn, BJ; Moore, J; Lee, J-Y; Yao, T-P; Pallanck, L; Kundu, M; Taylor, JP
MLA Citation
Kim, NC, Tresse, E, Kolaitis, R-M, Molliex, A, Thomas, RE, Alami, NH, Wang, B, Joshi, A, Smith, RB, Ritson, GP, Winborn, BJ, Moore, J, Lee, J-Y, Yao, T-P, Pallanck, L, Kundu, M, and Taylor, JP. "VCP Is Essential for Mitochondrial Quality Control by PINK1/Parkin and this Function Is Impaired by VCP Mutations." NEURON 78.1 (April 10, 2013): 65-80.
PMID
23498974
Source
wos-lite
Published In
Neuron
Volume
78
Issue
1
Publish Date
2013
Start Page
65
End Page
80
DOI
10.1016/j.neuron.2013.02.029

Erratum to: VCP Is Essential for Mitochondrial Quality Control by PINK1/Parkin and this Function Is Impaired by VCP Mutations

Authors
Kim, N; Tresse, E; Kolaitis, R-M; Molliex, A; Thomas, R; Alami, N; Wang, B; Joshi, A; Smith, R; Ritson, G; Winborn, B; Moore, J; Lee, J-Y; Yao, T-P; Pallanck, L; Kundu, M; Taylor, JP
MLA Citation
Kim, N, Tresse, E, Kolaitis, R-M, Molliex, A, Thomas, R, Alami, N, Wang, B, Joshi, A, Smith, R, Ritson, G, Winborn, B, Moore, J, Lee, J-Y, Yao, T-P, Pallanck, L, Kundu, M, and Taylor, JP. "Erratum to: VCP Is Essential for Mitochondrial Quality Control by PINK1/Parkin and this Function Is Impaired by VCP Mutations." Neuron 78.2 (2013): 403--.
Source
scival
Published In
Neuron
Volume
78
Issue
2
Publish Date
2013
Start Page
403-
DOI
10.1016/j.neuron.2013.04.020

Proteasomes Activate Aggresome Disassembly and Clearance by Producing Unanchored Ubiquitin Chains

Aberrant protein aggregation is a dominant pathological feature in neurodegenerative diseases. Protein aggregates cannot be processed by the proteasome; instead, they are frequently concentrated to the aggresome, a perinuclear inclusion body, and subsequently removed by autophagy. Paradoxically, proteasomes are also concentrated at aggresomes and other related inclusion bodies prevalent in neurodegenerative disease. Here, we show that proteasomes are crucial components in aggresome clearance. The disassembly and disposal of aggresomes requires Poh1, a proteasomal deubiquitinating enzyme that cleaves ubiquitinated proteins and releases ubiquitin chains. In Poh1-deficient cells, aggresome clearance is blocked. Remarkably, microinjection of free lysine (K) 63-linked ubiquitin chains restores aggresome degradation. We present evidence that free ubiquitin chains produced by Poh1 bind and activate the deacetylase HDAC6, which, in turn, stimulates actinomyosin- and autophagy-dependent aggresome processing. Thus, unanchored ubiquitin chains are key signaling molecules that connect and coordinate the proteasome and autophagy to eliminate toxic protein aggregates. © 2013 Elsevier Inc.

Authors
Hao, R; Nanduri, P; Rao, Y; Panichelli, RS; Ito, A; Yoshida, M; Yao, T-P
MLA Citation
Hao, R, Nanduri, P, Rao, Y, Panichelli, RS, Ito, A, Yoshida, M, and Yao, T-P. "Proteasomes Activate Aggresome Disassembly and Clearance by Producing Unanchored Ubiquitin Chains." Molecular Cell 51.6 (2013): 819-828.
PMID
24035499
Source
scival
Published In
Molecular Cell
Volume
51
Issue
6
Publish Date
2013
Start Page
819
End Page
828
DOI
10.1016/j.molcel.2013.08.016

Guidelines for the use and interpretation of assays for monitoring autophagy.

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.

Authors
Klionsky, DJ; Abdalla, FC; Abeliovich, H; Abraham, RT; Acevedo-Arozena, A; Adeli, K; Agholme, L; Agnello, M; Agostinis, P; Aguirre-Ghiso, JA; Ahn, HJ; Ait-Mohamed, O; Ait-Si-Ali, S; Akematsu, T; Akira, S; Al-Younes, HM; Al-Zeer, MA; Albert, ML; Albin, RL; Alegre-Abarrategui, J; Aleo, MF; Alirezaei, M; Almasan, A; Almonte-Becerril, M; Amano, A; Amaravadi, R; Amarnath, S; Amer, AO; Andrieu-Abadie, N; Anantharam, V; Ann, DK; Anoopkumar-Dukie, S; Aoki, H; Apostolova, N; Arancia, G; Aris, JP et al.
MLA Citation
Klionsky, DJ, Abdalla, FC, Abeliovich, H, Abraham, RT, Acevedo-Arozena, A, Adeli, K, Agholme, L, Agnello, M, Agostinis, P, Aguirre-Ghiso, JA, Ahn, HJ, Ait-Mohamed, O, Ait-Si-Ali, S, Akematsu, T, Akira, S, Al-Younes, HM, Al-Zeer, MA, Albert, ML, Albin, RL, Alegre-Abarrategui, J, Aleo, MF, Alirezaei, M, Almasan, A, Almonte-Becerril, M, Amano, A, Amaravadi, R, Amarnath, S, Amer, AO, Andrieu-Abadie, N, Anantharam, V, Ann, DK, Anoopkumar-Dukie, S, Aoki, H, Apostolova, N, Arancia, G, and Aris, JP et al. "Guidelines for the use and interpretation of assays for monitoring autophagy." Autophagy 8.4 (April 2012): 445-544.
PMID
22966490
Source
pubmed
Published In
Autophagy
Volume
8
Issue
4
Publish Date
2012
Start Page
445
End Page
544

Loss of deacetylation activity of Hdac6 affects emotional behavior in mice.

Acetylation is mediated by acetyltransferases and deacetylases, and occurs not only on histones but also on diverse proteins. Although histone acetylation in chromatin structure and transcription has been well studied, the biological roles of non-histone acetylation remain elusive. Histone deacetylase 6 (Hdac6), a member of the histone deacetylase (HDAC) family, is a unique deacetylase that localizes to cytoplasm and functions in many cellular events by deacetylating non-histone proteins including α-tubulin, Hsp90, and cortactin. Since robust expression of Hdac6 is observed in brain, it would be expected that Hdac6-mediated reversible acetylation plays essential roles in CNS. Here we demonstrate the crucial roles of Hdac6 deacetylase activity in the expression of emotional behavior in mice. We found that Hdac6-deficient mice exhibit hyperactivity, less anxiety, and antidepressant-like behavior in behavioral tests. Moreover, administration of Hdac6-specific inhibitor replicated antidepressant-like behavior in mice. In good agreement with behavioral phenotypes of Hdac6-deficient mice, Hdac6 dominantly localizes to the dorsal and median raphe nuclei, which are involved in emotional behaviors. These findings suggest that HDAC6-mediated reversible acetylation might contribute to maintain proper neuronal activity in serotonergic neurons, and also provide a new therapeutic target for depression.

Authors
Fukada, M; Hanai, A; Nakayama, A; Suzuki, T; Miyata, N; Rodriguiz, RM; Wetsel, WC; Yao, T-P; Kawaguchi, Y
MLA Citation
Fukada, M, Hanai, A, Nakayama, A, Suzuki, T, Miyata, N, Rodriguiz, RM, Wetsel, WC, Yao, T-P, and Kawaguchi, Y. "Loss of deacetylation activity of Hdac6 affects emotional behavior in mice." PLoS One 7.2 (2012): e30924-.
PMID
22328923
Source
pubmed
Published In
PloS one
Volume
7
Issue
2
Publish Date
2012
Start Page
e30924
DOI
10.1371/journal.pone.0030924

A Direct HDAC4-MAP Kinase Crosstalk Activates Muscle Atrophy Program

Prolonged deficits in neural input activate pathological muscle remodeling, leading to atrophy. In denervated muscle, activation of the atrophy program requires HDAC4, a potent repressor of the master muscle transcription factor MEF2. However, the signaling mechanism that connects HDAC4, a protein deacetylase, to the atrophy machinery remains unknown. Here, we identify the AP1 transcription factor as a critical target of HDAC4 in neurogenic muscle atrophy. In denervated muscle, HDAC4 activates AP1-dependent transcription, whereas AP1 inactivation recapitulates HDAC4 deficiency and blunts the muscle atrophy program. We show that HDAC4 activates AP1 independently of its canonical transcriptional repressor activity. Surprisingly, HDAC4 stimulates AP1 activity by activating the MAP kinase cascade. We present evidence that HDAC4 binds and promotes the deacetylation and activation of a key MAP3 kinase, MEKK2. Our findings establish an HDAC4-MAPK-AP1 signaling axis essential for neurogenic muscle atrophy and uncover a direct crosstalk between acetylation- and phosphorylation-dependent signaling cascades. © 2012 Elsevier Inc.

Authors
Choi, M-C; Cohen, TJ; Barrientos, T; Wang, B; Li, M; Simmons, BJ; Yang, JS; Cox, GA; Zhao, Y; Yao, T-P
MLA Citation
Choi, M-C, Cohen, TJ, Barrientos, T, Wang, B, Li, M, Simmons, BJ, Yang, JS, Cox, GA, Zhao, Y, and Yao, T-P. "A Direct HDAC4-MAP Kinase Crosstalk Activates Muscle Atrophy Program." Molecular Cell 47.1 (2012): 122-132.
PMID
22658415
Source
scival
Published In
Molecular Cell
Volume
47
Issue
1
Publish Date
2012
Start Page
122
End Page
132
DOI
10.1016/j.molcel.2012.04.025

Mitochondrial dynamics and Parkinson's disease: Focus on parkin

Significance: Parkinson's disease (PD) is a prevalent neurodegenerative disease affecting millions of individuals worldwide. Despite intensive efforts devoted to drug discovery, the disease remains incurable. To provide more effective medical therapy for PD, better understanding of the underlying causes of the disease is clearly necessary. Recent Advances: A broad range of studies conducted over the past few decades have collectively implicated aberrant mitochondrial homeostasis as a key contributor to the development of PD. Supporting this, mutations in several PD-linked genes are directly or indirectly linked to mitochondrial dysfunction. In particular, recent discoveries have identified parkin, whose mutations are causative of recessive parkinsonism, as a key regulator of mitochondrial homeostasis. Critical Issues: Parkin appears to be involved in the entire spectrum of mitochondrial dynamics, including organelle biogenesis, fusion/fission, and clearance via mitophagy. How a single protein can regulate such diverse mitochondrial events is as intriguing as it is amazing; the mechanism underlying this is currently under intense research. Here, we provide an overview of mitochondrial dynamics and its relationship with neurodegenerative diseases and discuss current evidence and controversies surrounding the role of parkin in mitochondrial quality control and its relevance to PD pathogenesis. Future Directions: Although the emerging field of parkin-mediated mitochondrial quality control has proven to be exciting, it is important to recognize that PD pathogenesis is likely to involve an intricate network of interacting pathways. Elucidating the reciprocity of pathways, particularly how other PD-related pathways potentially influence mitochondrial homeostasis, may hold the key to therapeutic development. © 2012, Mary Ann Liebert, Inc.

Authors
Lim, K-L; Ng, X-H; Grace, LG-Y; Yao, T-P
MLA Citation
Lim, K-L, Ng, X-H, Grace, LG-Y, and Yao, T-P. "Mitochondrial dynamics and Parkinson's disease: Focus on parkin." Antioxidants and Redox Signaling 16.9 (2012): 935-949.
PMID
21668405
Source
scival
Published In
Antioxidants & Redox Signaling
Volume
16
Issue
9
Publish Date
2012
Start Page
935
End Page
949
DOI
10.1089/ars.2011.4105

Lysine modifications and autophagy

Nutrient deprivation or cellular stress leads to the activation of a catabolic pathway that is conserved across species, known as autophagy. This process is considered to be adaptive and plays an important role in a number of cellular processes, including metabolism, immunity and development. Autophagy has also been linked to diseases, such as cancer and neurodegeneration, highlighting the importance of a better insight into its regulation. In the present chapter, we discuss how PTMs (post-translational modifications) of lysine residues by acetylation and ubiquitination alter the function of key proteins involved in the activation, maturation and substrate selectivity of autophagy. We also discuss the clinical potential of targeting these modifications to modulate autophagic activities. © 2012 Biochemical Society.

Authors
Norris, KL; Yao, T-P
MLA Citation
Norris, KL, and Yao, T-P. "Lysine modifications and autophagy." Essays in Biochemistry 52.1 (2012): 65-77.
PMID
22708564
Source
scival
Published In
Essays in biochemistry
Volume
52
Issue
1
Publish Date
2012
Start Page
65
End Page
77
DOI
10.1042/BSE0520065

HDACs in skeletal muscle remodeling and neuromuscular disease

Skeletal muscle is made of heterogeneous myofibers with different contractile and metabolic properties. The diverse functionality of myofibers enables skeletal muscle to carry out different tasks from maintaining body posture to performing active movements. In addition to motility, skeletal muscle, which constitutes 40% of body mass, is also a key target of insulin action and performs an essential function in glucose metabolism. Adult skeletal muscle is a highly adaptive organ system and can undergo specific changes in contractile and metabolic properties to meet different functional demands. This plasticity of myofibers reflects a highly coordinated change in gene expression program that is controlled by neural activity. The capacity for on-demand remodeling confers skeletal muscle the remarkable adaptability important for animal survival; its dysregulation, however, could contribute to muscle and metabolic diseases. How neural activity dictates transcriptional programming to modify muscle functionality and diversity is a fundamental issue. Recent studies have identified members of class IIa HDACs as important effectors in both physiological and pathological muscle remodeling. By way of modifying myofiber properties, pharmacological manipulation of IIa HDACs activity could have potential therapeutic utility in the treatment of muscle disorders. © 2011 Springer-Verlag Berlin Heidelberg.

Authors
Simmons, BJ; Cohen, TJ; Bedlack, R; Yao, T-P
MLA Citation
Simmons, BJ, Cohen, TJ, Bedlack, R, and Yao, T-P. "HDACs in skeletal muscle remodeling and neuromuscular disease." Handbook of Experimental Pharmacology 206 (2011): 79-101.
PMID
21879447
Source
scival
Published In
Handbook of experimental pharmacology
Volume
206
Publish Date
2011
Start Page
79
End Page
101
DOI
10.1007/978-3-642-21631-2_5

The discovery of histone deacetylase.

Authors
Yao, T-P; Seto, E
MLA Citation
Yao, T-P, and Seto, E. "The discovery of histone deacetylase." Handbook of experimental pharmacology 206 (2011): v-.
PMID
22046630
Source
scival
Published In
Handbook of experimental pharmacology
Volume
206
Publish Date
2011
Start Page
v

Class IIb HDAC6 regulates endothelial cell migration and angiogenesis by deacetylation of cortactin

Histone deacetylases (HDACs) deacetylate histones and non-histone proteins, thereby affecting protein activity and gene expression. The regulation and function of the cytoplasmic class IIb HDAC6 in endothelial cells (ECs) is largely unexplored. Here, we demonstrate that HDAC6 is upregulated by hypoxia and is essential for angiogenesis. Silencing of HDAC6 in ECs decreases sprouting and migration in vitro and formation of functional vascular networks in matrigel plugs in vivo. HDAC6 regulates zebrafish vessel formation, and HDAC6-deficient mice showed a reduced formation of perfused vessels in matrigel plugs. Consistently, overexpression of wild-type HDAC6 increases sprouting from spheroids. HDAC6 function requires the catalytic activity but is independent of ubiquitin binding and deacetylation of α-tubulin. Instead, we found that HDAC6 interacts with and deacetylates the actin-remodelling protein cortactin in ECs, which is essential for zebrafish vessel formation and which mediates the angiogenic effect of HDAC6. In summary, we show that HDAC6 is necessary for angiogenesis in vivo and in vitro, involving the interaction and deacetylation of cortactin that regulates EC migration and sprouting. © 2011 European Molecular Biology Organization | All Rights Reserved.

Authors
Kaluza, D; Kroll, J; Gesierich, S; Yao, T-P; Boon, RA; Hergenreider, E; Tjwa, M; Rössig, L; Seto, E; Augustin, HG; Zeiher, AM; Dimmeler, S; Urbich, C
MLA Citation
Kaluza, D, Kroll, J, Gesierich, S, Yao, T-P, Boon, RA, Hergenreider, E, Tjwa, M, Rössig, L, Seto, E, Augustin, HG, Zeiher, AM, Dimmeler, S, and Urbich, C. "Class IIb HDAC6 regulates endothelial cell migration and angiogenesis by deacetylation of cortactin." EMBO Journal 30.20 (2011): 4142-4156.
PMID
21847094
Source
scival
Published In
EMBO Journal
Volume
30
Issue
20
Publish Date
2011
Start Page
4142
End Page
4156
DOI
10.1038/emboj.2011.298

Preface

Authors
Yao, T-P; Seto, E
MLA Citation
Yao, T-P, and Seto, E. "Preface." Handbook of Experimental Pharmacology 206 (2011): v-.
Source
scival
Published In
Handbook of experimental pharmacology
Volume
206
Publish Date
2011
Start Page
v

Disease-causing mutations in parkin impair mitochondrial ubiquitination, aggregation, and HDAC6-dependent mitophagy.

Mutations in parkin, a ubiquitin ligase, cause early-onset familial Parkinson's disease (AR-JP). How parkin suppresses parkinsonism remains unknown. Parkin was recently shown to promote the clearance of impaired mitochondria by autophagy, termed mitophagy. Here, we show that parkin promotes mitophagy by catalyzing mitochondrial ubiquitination, which in turn recruits ubiquitin-binding autophagic components, HDAC6 and p62, leading to mitochondrial clearance. During the process, juxtanuclear mitochondrial aggregates resembling a protein aggregate-induced aggresome are formed. The formation of these "mito-aggresome" structures requires microtubule motor-dependent transport and is essential for efficient mitophagy. Importantly, we show that AR-JP-causing parkin mutations are defective in supporting mitophagy due to distinct defects at recognition, transportation, or ubiquitination of impaired mitochondria, thereby implicating mitophagy defects in the development of parkinsonism. Our results show that impaired mitochondria and protein aggregates are processed by common ubiquitin-selective autophagy machinery connected to the aggresomal pathway, thus identifying a mechanistic basis for the prevalence of these toxic entities in Parkinson's disease.

Authors
Lee, J-Y; Nagano, Y; Taylor, JP; Lim, KL; Yao, T-P
MLA Citation
Lee, J-Y, Nagano, Y, Taylor, JP, Lim, KL, and Yao, T-P. "Disease-causing mutations in parkin impair mitochondrial ubiquitination, aggregation, and HDAC6-dependent mitophagy." J Cell Biol 189.4 (May 17, 2010): 671-679.
PMID
20457763
Source
pubmed
Published In
The Journal of Cell Biology
Volume
189
Issue
4
Publish Date
2010
Start Page
671
End Page
679
DOI
10.1083/jcb.201001039

Quality control autophagy: a joint effort of ubiquitin, protein deacetylase and actin cytoskeleton.

Autophagy has been predominantly studied as a nonselective self-digestion process that recycles macromolecules and produces energy in response to starvation. However, autophagy independent of nutrient status has long been known to exist. Recent evidence suggests that this form of autophagy enforces intracellular quality control by selectively disposing of aberrant protein aggregates and damaged organelles--common denominators in various forms of neurodegenerative diseases. By definition, this form of autophagy, termed quality-control (QC) autophagy, must be different from nutrient-regulated autophagy in substrate selectivity, regulation and function. We have recently identified the ubiquitin-binding deacetylase, HDAC6, as a key component that establishes QC. HDAC6 is not required for autophagy activation per se; rather, it is recruited to ubiquitinated autophagic substrates where it stimulates autophagosome-lysosome fusion by promoting F-actin remodeling in a cortactin-dependent manner. Remarkably, HDAC6 and cortactin are dispensable for starvation-induced autophagy. These findings reveal that autophagosomes associated with QC are molecularly and biochemically distinct from those associated with starvation autophagy, thereby providing a new molecular framework to understand the emerging complexity of autophagy and therapeutic potential of this unique machinery.

Authors
Lee, J-Y; Yao, T-P
MLA Citation
Lee, J-Y, and Yao, T-P. "Quality control autophagy: a joint effort of ubiquitin, protein deacetylase and actin cytoskeleton." Autophagy 6.4 (May 2010): 555-557.
Website
http://hdl.handle.net/10161/3964
PMID
20404488
Source
pubmed
Published In
Autophagy
Volume
6
Issue
4
Publish Date
2010
Start Page
555
End Page
557
DOI
10.4161/auto.6.4.11812

HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy.

Autophagy is primarily considered a non-selective degradation process induced by starvation. Nutrient-independent basal autophagy, in contrast, imposes intracellular QC by selective disposal of aberrant protein aggregates and damaged organelles, a process critical for suppressing neurodegenerative diseases. The molecular mechanism that distinguishes these two fundamental autophagic responses, however, remains mysterious. Here, we identify the ubiquitin-binding deacetylase, histone deacetylase-6 (HDAC6), as a central component of basal autophagy that targets protein aggregates and damaged mitochondria. Surprisingly, HDAC6 is not required for autophagy activation; rather, it controls the fusion of autophagosomes to lysosomes. HDAC6 promotes autophagy by recruiting a cortactin-dependent, actin-remodelling machinery, which in turn assembles an F-actin network that stimulates autophagosome-lysosome fusion and substrate degradation. Indeed, HDAC6 deficiency leads to autophagosome maturation failure, protein aggregate build-up, and neurodegeneration. Remarkably, HDAC6 and F-actin assembly are completely dispensable for starvation-induced autophagy, uncovering the fundamental difference of these autophagic modes. Our study identifies HDAC6 and the actin cytoskeleton as critical components that define QC autophagy and uncovers a novel regulation of autophagy at the level of autophagosome-lysosome fusion.

Authors
Lee, J-Y; Koga, H; Kawaguchi, Y; Tang, W; Wong, E; Gao, Y-S; Pandey, UB; Kaushik, S; Tresse, E; Lu, J; Taylor, JP; Cuervo, AM; Yao, T-P
MLA Citation
Lee, J-Y, Koga, H, Kawaguchi, Y, Tang, W, Wong, E, Gao, Y-S, Pandey, UB, Kaushik, S, Tresse, E, Lu, J, Taylor, JP, Cuervo, AM, and Yao, T-P. "HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy." EMBO J 29.5 (March 3, 2010): 969-980.
PMID
20075865
Source
pubmed
Published In
EMBO Journal
Volume
29
Issue
5
Publish Date
2010
Start Page
969
End Page
980
DOI
10.1038/emboj.2009.405

The microtubule-associated histone deacetylase 6 (HDAC6) regulates epidermal growth factor receptor (EGFR) endocytic trafficking and degradation

Histone deacetylase 6 (HDAC6) is a microtubule-associated deacetylase with tubulin deacetylase activity, and it binds dynein motors. Recent studies revealed that microtubule acetylation affects the affinity and processivity of microtubule motors. These unique properties implicate a role for HDAC6 in intracellular organelle transport. Here, we show that HDAC6 associates with the endosomal compartments and controls epidermal growth factor receptor (EGFR) trafficking and degradation. We found that loss of HDAC6 promoted EGFR degradation. Mechanistically,HDAC6deficiency did not cause aberrant EGFR internalization and recycling. Rather, it resulted in accelerated segregation of EGFR from early endosomes and premature delivery of EGFR to the late endosomal and lysosomal compartments. The deregulated EGFR endocytic trafficking was accompanied by an increase in microtubule-dependent movement of EGFR-bearing vesicles, revealing a novel regulation of EGFR vesicular trafficking and degradation by the microtubule deacetylase HDAC6. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

Authors
Gao, Y-S; Hubbert, CC; Yao, T-P
MLA Citation
Gao, Y-S, Hubbert, CC, and Yao, T-P. "The microtubule-associated histone deacetylase 6 (HDAC6) regulates epidermal growth factor receptor (EGFR) endocytic trafficking and degradation." Journal of Biological Chemistry 285.15 (2010): 11219-11226.
PMID
20133936
Source
scival
Published In
The Journal of biological chemistry
Volume
285
Issue
15
Publish Date
2010
Start Page
11219
End Page
11226
DOI
10.1074/jbc.M109.042754

VCP/p97 is essential for maturation of ubiquitin-containing autophagosomes and this function is impaired by mutations that cause IBMPFD

VCP (VCP/p97) is a ubiquitously expressed member of the AAA +-ATPase family of chaperone-like proteins that regulates numerous cellular processes including chromatin decondensation, homotypic membrane fusion and ubiquitin-dependent protein degradation by the proteasome. Mutations in VCP cause a multisystem degenerative disease consisting of inclusion body myopathy, Paget disease of bone, and frontotemporal dementia (IBMPFD). Here we show that VCP is essential for autophagosome maturation. We generated cells stably expressing dual-tagged LC3 (mCherry-EGFPLC3) which permit monitoring of autophagosome maturation. We determined that VCP deficiency by RNAi-mediated knockdown or overexpression of dominant-negative VCP results in significant accumulation of immature autophagic vesicles, some of which are abnormally large, acidified and exhibit cathepsin B activity. Furthermore, expression of disease-associated VCP mutants (R155H and A232E) also causes this autophagy defect. VCP was found to be essential to autophagosome maturation under basal conditions and in cells challenged by proteasome inhibition, but not in cells challenged by starvation, suggesting that VCP might be selectively required for autophagic degradation of ubiquitinated substrates. Indeed, a high percentage of the accumulated autophagic vesicles contain ubiquitin-positive contents, a feature that is not observed in autophagic vesicles that accumulate following starvation or treatment with Bafilomycin A. Finally, we show accumulation of numerous, large LAMP-1 and LAMP-2-positive vacuoles and accumulation of LC3-II in myoblasts derived from patients with IBMPFD. We conclude that VCP is essential for maturation of ubiquitin-containing autophagosomes and that defect in this function may contribute to IBMPFD pathogenesis. © 2010 Landes Bioscience.

Authors
Tresse, E; Salomons, FA; Vesa, J; Bott, LC; Kimonis, V; Yao, T-P; Dantuma, NP; Taylor, JP
MLA Citation
Tresse, E, Salomons, FA, Vesa, J, Bott, LC, Kimonis, V, Yao, T-P, Dantuma, NP, and Taylor, JP. "VCP/p97 is essential for maturation of ubiquitin-containing autophagosomes and this function is impaired by mutations that cause IBMPFD." Autophagy 6.2 (2010): 217-227.
Website
http://hdl.handle.net/10161/3965
PMID
20104022
Source
scival
Published In
Autophagy
Volume
6
Issue
2
Publish Date
2010
Start Page
217
End Page
227
DOI
10.4161/auto.6.2.11014

The role of ubiquitin in autophagy-dependent protein aggregate processing

The efficient management of misfolded protein aggregates is essential for cell viability and requires 3 interconnected pathways: the molecular chaperone machinery that assists protein folding, the proteasome pathway that degrades misfolded proteins, and the aggresomal pathway that sequesters and delivers toxic protein aggregates to autophagy for clearance. Although autophagy is generally considered as nonselective degradative machinery, growing evidence supports the existence of a selective autophagy that specifically targets protein aggregates for clearance. This "quality control autophagy" is established by specific ubiquitin E3 ligases, autophagic substrate ubiquitination, and specific ubiquitin-binding proteins p62 and HDAC6. In this context, quality control autophagy is similar to the proteasome system and utilizes ubiquitin tags for substrate recognition and processing. Here, I will discuss the recent progress toward understanding the molecular basis of this unique form of ubiquitin-dependent autophagy in protein aggregate clearance and its relevance to disease. © The Author(s) 2010.

Authors
Yao, T-P
MLA Citation
Yao, T-P. "The role of ubiquitin in autophagy-dependent protein aggregate processing." Genes and Cancer 1.7 (2010): 779-786.
Source
scival
Published In
Genes and Cancer
Volume
1
Issue
7
Publish Date
2010
Start Page
779
End Page
786
DOI
10.1177/1947601910383277

Acetylation goes global: the emergence of acetylation biology.

For the first 30 years since its discovery, reversible protein acetylation has been studied and understood almost exclusively in the context of histone modification and gene transcription. With the discovery of non-histone acetylated proteins and acetylation-modifying enzymes in cellular compartments outside the nucleus, the regulatory potential of reversible acetylation has slowly been recognized in the last decade. However, the scope of protein acetylation involvement in complex biological processes remains uncertain. The recent development of new technology has enabled, for the first time, the identification and quantification of the acetylome, acetylation events at the whole-proteome level. These efforts have uncovered a stunning complexity of the acetylome that potentially rivals that of the phosphoproteome. The remarkably ubiquitous and conserved nature of protein acetylation revealed by these new studies suggests the regulatory power of this dynamic modification. The establishment of comprehensive acetylomes will change the landscape of protein acetylation, where an exciting research frontier awaits.

Authors
Norris, KL; Lee, J-Y; Yao, T-P
MLA Citation
Norris, KL, Lee, J-Y, and Yao, T-P. "Acetylation goes global: the emergence of acetylation biology. (Published online)" Sci Signal 2.97 (November 17, 2009): pe76-.
PMID
19920250
Source
pubmed
Published In
Science Signaling
Volume
2
Issue
97
Publish Date
2009
Start Page
pe76
DOI
10.1126/scisignal.297pe76

The deacetylase HDAC4 controls myocyte enhancing factor-2-dependent structural gene expression in response to neural activity.

Histone deacetylase 4 (HDAC4) binds and inhibits activation of the critical muscle transcription factor myocyte enhancer factor-2 (MEF2). However, the physiological significance of the HDAC4-MEF2 complex in skeletal muscle has not been established. Here we show that in skeletal muscle, HDAC4 is a critical modulator of MEF2-dependent structural and contractile gene expression in response to neural activity. We present evidence that loss of neural input leads to concomitant nuclear accumulation of HDAC4 and transcriptional reduction of MEF2-regulated gene expression. Cell-based assays show that HDAC4 represses structural gene expression via direct binding to AT-rich MEF2 response elements. Notably, using both surgical denervation and the neuromuscular disease amyotrophic lateral sclerosis (ALS) model, we found that elevated levels of HDAC4 are required for efficient repression of MEF2-dependent structural gene expression, indicating a link between the pathological induction of HDAC4 and subsequent MEF2 target gene suppression. Supporting this supposition, we show that ectopic expression of HDAC4 in muscle fibers is sufficient to induce muscle damage in mice. Our study identifies HDAC4 as an activity-dependent regulator of MEF2 function and suggests that activation of HDAC4 in response to chronically reduced neural activity suppresses MEF2-dependent gene expression and contributes to progressive muscle dysfunction observed in neuromuscular diseases.

Authors
Cohen, TJ; Barrientos, T; Hartman, ZC; Garvey, SM; Cox, GA; Yao, T-P
MLA Citation
Cohen, TJ, Barrientos, T, Hartman, ZC, Garvey, SM, Cox, GA, and Yao, T-P. "The deacetylase HDAC4 controls myocyte enhancing factor-2-dependent structural gene expression in response to neural activity." FASEB J 23.1 (January 2009): 99-106.
PMID
18780762
Source
pubmed
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
23
Issue
1
Publish Date
2009
Start Page
99
End Page
106
DOI
10.1096/fj.08-115931

Parathyroid hormone-related peptide represses chondrocyte hypertrophy through a protein phosphatase 2A/histone deacetylase 4/MEF2 pathway

The maturation of immature chondrocytes to hypertrophic chondrocytes is regulated by parathyroid hormone-related peptide (PTHrP). We demonstrate that PTHrP or forskolin administration can block induction of collagen X-luciferase by exogenous Runx2, MEF2, and Smad1 in transfected chondrocytes. We have found that PTHrP/forskolin administration represses the transcriptional activity of MEF2 and that forced expression of MEF2-VP16 can restore expression of the collagen X reporter in chondrocytes treated with these agents. PTHrP/forskolin induces dephosphorylation of histone deacetylase 4 (HDAC4) phospho-S246, which decreases interaction of HDAC4 with cytoplasmic 14-3-3 proteins and promotes nuclear translocation of HDAC4 and repression of MEF2 transcriptional activity. We have found that forskolin increases the activity of an HDAC4 phospho-S246 phosphatase and that forskolin-induced nuclear translocation of HDAC4 was reversed by the protein phosphatase 2A (PP2A) antagonist, okadaic acid. Finally, we demonstrate that knockdown of PP2A inhibits forskolin-induced nuclear translocation of HDAC4 and attenuates the ability of this signaling molecule to repress collagen X expression in chondrocytes, indicating that PP2A is critical for PTHrP-mediated regulation of chondrocyte hypertrophy. Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Authors
Kozhemyakina, E; Cohen, T; Yao, T-P; Lassar, AB
MLA Citation
Kozhemyakina, E, Cohen, T, Yao, T-P, and Lassar, AB. "Parathyroid hormone-related peptide represses chondrocyte hypertrophy through a protein phosphatase 2A/histone deacetylase 4/MEF2 pathway." Molecular and Cellular Biology 29.21 (2009): 5751-5762.
PMID
19704004
Source
scival
Published In
Molecular and Cellular Biology
Volume
29
Issue
21
Publish Date
2009
Start Page
5751
End Page
5762
DOI
10.1128/MCB.00415-09

The cytoplasmic deacetylase HDAC6 is required for efficient oncogenic tumorigenesis.

Histone deacetylase inhibitors (HDACI) are promising antitumor agents. Although transcriptional deregulation is thought to be the main mechanism underlying their therapeutic effects, the exact mechanism and targets by which HDACIs achieve their antitumor effects remain poorly understood. It is not known whether any of the HDAC members support robust tumor growth. In this report, we show that HDAC6, a cytoplasmic-localized and cytoskeleton-associated deacetylase, is required for efficient oncogenic transformation and tumor formation. We found that HDAC6 expression is induced upon oncogenic Ras transformation. Fibroblasts deficient in HDAC6 are more resistant to both oncogenic Ras and ErbB2-dependent transformation, indicating a critical role for HDAC6 in oncogene-induced transformation. Supporting this hypothesis, inactivation of HDAC6 in several cancer cell lines reduces anchorage-independent growth and the ability to form tumors in mice. The loss of anchorage-independent growth is associated with increased anoikis and defects in AKT and extracellular signal-regulated kinase activation upon loss of adhesion. Lastly, HDAC6-null mice are more resistant to chemical carcinogen-induced skin tumors. Our results provide the first experimental evidence that a specific HDAC member is required for efficient oncogenic transformation and indicate that HDAC6 is an important component underlying the antitumor effects of HDACIs.

Authors
Lee, Y-S; Lim, K-H; Guo, X; Kawaguchi, Y; Gao, Y; Barrientos, T; Ordentlich, P; Wang, X-F; Counter, CM; Yao, T-P
MLA Citation
Lee, Y-S, Lim, K-H, Guo, X, Kawaguchi, Y, Gao, Y, Barrientos, T, Ordentlich, P, Wang, X-F, Counter, CM, and Yao, T-P. "The cytoplasmic deacetylase HDAC6 is required for efficient oncogenic tumorigenesis." Cancer Res 68.18 (September 15, 2008): 7561-7569.
PMID
18794144
Source
pubmed
Published In
Cancer Research
Volume
68
Issue
18
Publish Date
2008
Start Page
7561
End Page
7569
DOI
10.1158/0008-5472.CAN-08-0188

Requirement of HDAC6 for transforming growth factor-β1-induced epithelial-mesenchymal transition

The aberrant expression of transforming growth factor (TGF)-β1 in the tumor microenvironment and fibrotic lesions plays a critical role in tumor progression and tissue fibrosis by inducing epithelial-mesenchymal transition (EMT). EMT promotes tumor cell motility and invasiveness. How EMT affects motility and invasion is not well understood. Here we report that HDAC6 is a novel modulator of TGF-β1-induced EMT. HDAC6 is a microtubule-associated deacetylase that predominantly deacetylates nonhistone proteins, including α-tubulin, and regulates cell motility. We showed that TGF-β1-induced EMT is accompanied by HDAC6-dependent deacetylation of α-tubulin. Importantly, inhibition of HDAC6 by small interfering RNA or the small molecule inhibitor tubacin attenuated the TGF-β1-induced EMT markers, such as the aberrant expression of epithelial and mesenchymal peptides, as well as the formation of stress fibers. Reduced expression of HDAC6 also impaired the activation of SMAD3 in response to TGF-β1. Conversely, inhibition of SMAD3 activation substantially impaired HDAC6-dependent deacetylation of α-tubulin as well as the expression of EMT markers. These findings reveal a novel function of HDAC6 in EMT by intercepting the TGF-β-SMAD3 signaling cascade. Our results identify HDAC6 as a critical regulator of EMT and a potential therapeutic target against pathological EMT, a key event for tumor progression and fibrogenesis. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc.

Authors
Shan, B; Yao, T-P; Nguyen, HT; Zhuo, Y; Levy, DR; Klingsberg, RC; Tao, H; Palmer, ML; Holder, KN; Lasky, JA
MLA Citation
Shan, B, Yao, T-P, Nguyen, HT, Zhuo, Y, Levy, DR, Klingsberg, RC, Tao, H, Palmer, ML, Holder, KN, and Lasky, JA. "Requirement of HDAC6 for transforming growth factor-β1-induced epithelial-mesenchymal transition." Journal of Biological Chemistry 283.30 (2008): 21065-21073.
PMID
18499657
Source
scival
Published In
The Journal of biological chemistry
Volume
283
Issue
30
Publish Date
2008
Start Page
21065
End Page
21073
DOI
10.1074/jbc.M802786200

Effects of downregulated HDAC6 expression on the proliferation of lung cancer cells

Histone deacetylase 6 (HDAC6) is a multifunctional, cytosolic protein deacetylase that primarily acts on α-tubulin. Here we report that stable knockdown of HDAC6 expression causes a decrease in the steady-state level of receptor tyrosine kinases, such as epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor α, in A549 lung cancer cells. The decreased levels of in EGFR in HDAC6-knockdown cells, which correlated with increased acetylation of microtubules, were due to increased turnover of EGFR protein. Despite the decrease in EGFR levels, A549 cells lacking functional HDAC6 appeared to grow normally, probably due to increased expression of extracellular signal-regulated kinases 1 and 2. Indeed, HDAC6-knockdown cells were more sensitive than control cells to the MEK inhibitor U0126. These results suggest that HDAC6 inhibitors combined with inhibitors of growth factor signaling may be useful as cancer therapy. © 2008 Elsevier Inc. All rights reserved.

Authors
Kamemura, K; Ito, A; Shimazu, T; Matsuyama, A; Maeda, S; Yao, T-P; Horinouchi, S; Khochbin, S; Yoshida, M
MLA Citation
Kamemura, K, Ito, A, Shimazu, T, Matsuyama, A, Maeda, S, Yao, T-P, Horinouchi, S, Khochbin, S, and Yoshida, M. "Effects of downregulated HDAC6 expression on the proliferation of lung cancer cells." Biochemical and Biophysical Research Communications 374.1 (2008): 84-89.
PMID
18602369
Source
scival
Published In
Biochemical and Biophysical Research Communications
Volume
374
Issue
1
Publish Date
2008
Start Page
84
End Page
89
DOI
10.1016/j.bbrc.2008.06.092

Hos2p/Set3p deacetylase complex signals secretory stress through the Mpk1p cell integrity pathway

Perturbations in secretory function activate stress response pathways critical for yeast survival. Here we report the identification of the Hos2p/Set3p deacetylase complex (SET3C) as an essential component of the secretory stress response. Strains lacking core components of the Hos2p/Set3p complex exhibit hypersensitivity to secretory stress. Although not required for the unfolded protein response (UPR) and ribosomal gene repression, the Hos2p complex is required for proper activation of the Mpk1p/Slt2p cell integrity kinase cascade. Disruption of the Hos2p complex results in abrogated Mpk1p phosphorylation, whereas constitutive activation of the Mpk1p pathway rescues the hos2Δ mutant growth defect in response to secretory stress. Furthermore, Hos2p activity is required for the Mpk1p-mediated activation of stress-responsive transcription factor Rlm1p, but not for the stress-induced degradation of the C-type cyclin Ssn8p. Our results identify the Hos2p complex as a critical component of the secretory stress response and support the existence a coordinated stress response consisting of the UPR, ribosomal gene repression, and mitogen-activated protein kinase signaling in response to defects in secretory function. Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Authors
Cohen, TJ; Mallory, MJ; Strich, R; Yao, T-P
MLA Citation
Cohen, TJ, Mallory, MJ, Strich, R, and Yao, T-P. "Hos2p/Set3p deacetylase complex signals secretory stress through the Mpk1p cell integrity pathway." Eukaryotic Cell 7.7 (2008): 1191-1199.
PMID
18487345
Source
scival
Published In
Eukaryotic cell
Volume
7
Issue
7
Publish Date
2008
Start Page
1191
End Page
1199
DOI
10.1128/EC.00059-08

HDAC6 is required for epidermal growth factor-induced β-catenin nuclear localization

Nuclear translocation of β-catenin is a hallmark of Wnt signaling and is associated with various cancers. In addition to the canonical Wnt pathway activated by Wnt ligands, growth factors such as epidermal growth factor (EGF) also induce β-catenin dissociation from the adherens junction complex, translocation into the nucleus, and activation of target genes such as c-myc. Here we report that EGF-induced β-catenin nuclear localization and activation of c-myc are dependent on the deacetylase HDAC6. We show that EGF induces HDAC6 translocation to the caveolae membrane and association with β-catenin. HDAC6 deacetylates β-catenin at lysine 49, a site frequently mutated in anaplastic thyroid cancer, and inhibits β-catenin phosphorylation at serine 45. HDAC6 inactivation blocks EGF-induced β-catenin nuclear localization and decreases c-Myc expression, leading to inhibition of tumor cell proliferation. These results suggest that EGF-induced nuclear localization of β-catenin is regulated by HDAC6-dependent deacetylation and provide a new mechanism by which HDAC inhibitors prevent tumor growth. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc.

Authors
Li, Y; Zhang, X; Polakiewicz, RD; Yao, T-P; Comb, MJ
MLA Citation
Li, Y, Zhang, X, Polakiewicz, RD, Yao, T-P, and Comb, MJ. "HDAC6 is required for epidermal growth factor-induced β-catenin nuclear localization." Journal of Biological Chemistry 283.19 (2008): 12686-12690.
PMID
18356165
Source
scival
Published In
The Journal of biological chemistry
Volume
283
Issue
19
Publish Date
2008
Start Page
12686
End Page
12690
DOI
10.1074/jbc.C700185200

Histone deacetylase 6 regulates growth factor-induced actin remodeling and endocytosis.

Histone deacetylase 6 (HDAC6) is a cytoplasmic deacetylase that uniquely catalyzes alpha-tubulin deacetylation and promotes cell motility. However, the mechanism underlying HDAC6-dependent cell migration and the role for microtubule acetylation in motility are not known. Here we show that HDAC6-induced global microtubule deacetylation was not sufficient to stimulate cell migration. Unexpectedly, in response to growth factor stimulation, HDAC6 underwent rapid translocation to actin-enriched membrane ruffles and subsequently became associated with macropinosomes, the vesicles for fluid-phase endocytosis. Supporting the importance of these associations, membrane ruffle formation, macropinocytosis, and cell migration were all impaired in HDAC6-deficient cells. Conversely, elevated HDAC6 levels promoted membrane ruffle formation with a concomitant increase in macropinocytosis and motility. In search for an HDAC6 target, we found that heat shock protein 90 (Hsp90), another prominent substrate of HDAC6, was also recruited to membrane ruffles and macropinosomes. Significantly, inhibition of Hsp90 activity suppressed membrane ruffling and cell migration, while expression of an acetylation-resistant Hsp90 mutant promoted ruffle formation. Our results uncover a surprising role for HDAC6 in actin remodeling-dependent processes and identify the actin cytoskeleton as an important target of HDAC6-regulated protein deacetylation.

Authors
Gao, Y-S; Hubbert, CC; Lu, J; Lee, Y-S; Lee, J-Y; Yao, T-P
MLA Citation
Gao, Y-S, Hubbert, CC, Lu, J, Lee, Y-S, Lee, J-Y, and Yao, T-P. "Histone deacetylase 6 regulates growth factor-induced actin remodeling and endocytosis." Mol Cell Biol 27.24 (December 2007): 8637-8647.
PMID
17938201
Source
pubmed
Published In
Molecular and Cellular Biology
Volume
27
Issue
24
Publish Date
2007
Start Page
8637
End Page
8647
DOI
10.1128/MCB.00393-07

The histone deacetylase HDAC4 connects neural activity to muscle transcriptional reprogramming.

Neural activity actively regulates muscle gene expression. This regulation is crucial for specifying muscle functionality and synaptic protein expression. How neural activity is relayed into nuclei and connected to the muscle transcriptional machinery, however, is not known. Here we identify the histone deacetylase HDAC4 as the critical linker connecting neural activity to muscle transcription. We found that HDAC4 is normally concentrated at the neuromuscular junction (NMJ), where nerve innervates muscle. Remarkably, reduced neural input by surgical denervation or neuromuscular diseases dissociates HDAC4 from the NMJ and dramatically induces its expression, leading to robust HDAC4 nuclear accumulation. We present evidence that nuclear accumulated HDAC4 is responsible for the coordinated induction of synaptic genes upon denervation. Inactivation of HDAC4 prevents denervation-induced synaptic acetyl-choline receptor (nAChR) and MUSK transcription whereas forced expression of HDAC4 mimics denervation and activates ectopic nAChR transcription throughout myofibers. We determined that HDAC4 executes activity-dependent transcription by regulating the Dach2-myogenin transcriptional cascade where inhibition of the repressor Dach2 by HDAC4 permits the induction of the transcription factor myogenin, which in turn activates synaptic gene expression. Our findings establish HDAC4 as a neural activity-regulated deacetylase and a key signaling component that relays neural activity to the muscle transcriptional machinery.

Authors
Cohen, TJ; Waddell, DS; Barrientos, T; Lu, Z; Feng, G; Cox, GA; Bodine, SC; Yao, T-P
MLA Citation
Cohen, TJ, Waddell, DS, Barrientos, T, Lu, Z, Feng, G, Cox, GA, Bodine, SC, and Yao, T-P. "The histone deacetylase HDAC4 connects neural activity to muscle transcriptional reprogramming." J Biol Chem 282.46 (November 16, 2007): 33752-33759.
PMID
17873280
Source
pubmed
Published In
The Journal of biological chemistry
Volume
282
Issue
46
Publish Date
2007
Start Page
33752
End Page
33759
DOI
10.1074/jbc.M706268200

The neurodegenerative disease protein ataxin-1 antagonizes the neuronal survival function of myocyte enhancer factor-2.

Ataxin-1 is a neurodegenerative disorder protein whose mutant form causes spinocerebellar ataxia type-1 (SCA1). Evidence suggests that ataxin-1 may function as a transcription repressor. However, neither the importance of this putative transcriptional repression activity in neural cytotoxicity nor the transcriptional targets of ataxin-1 are known. Here we identify the MEF2-HDAC4 transcriptional complex involved in neuron survival as a target of ataxin-1. We show that ataxin-1 binds specifically to histone deacetylase-4 (HDAC4) and MEF2 and colocalizes with them in nuclear inclusion bodies. Significantly, these interactions are greatly reduced by the S776A mutation, which largely abrogates the cytotoxicity of ataxin-1. Supporting the importance of these interactions, we show that wild type ataxin-1 represses MEF2-dependent transcription, whereas the S776A mutant is less potent. Furthermore, overexpression of MEF2 can partially reverse cytotoxicity caused by ataxin-1. Our results identify the MEF2-HDAC4 complex as a target for ataxin-1 transcriptional repression activity and suggest a novel pathogenic mechanism whereby ataxin-1 sequesters and inhibits the neuronal survival factor MEF2.

Authors
Bolger, TA; Zhao, X; Cohen, TJ; Tsai, C-C; Yao, T-P
MLA Citation
Bolger, TA, Zhao, X, Cohen, TJ, Tsai, C-C, and Yao, T-P. "The neurodegenerative disease protein ataxin-1 antagonizes the neuronal survival function of myocyte enhancer factor-2." J Biol Chem 282.40 (October 5, 2007): 29186-29192.
PMID
17646162
Source
pubmed
Published In
The Journal of biological chemistry
Volume
282
Issue
40
Publish Date
2007
Start Page
29186
End Page
29192
DOI
10.1074/jbc.M704182200

Solution structure of the Ubp-M BUZ domain, a highly specific protein module that recognizes the C-terminal tail of free ubiquitin.

The BUZ/Znf-UBP domain is a distinct ubiquitin-binding module found in the cytoplasmic deacetylase HDAC6, the E3 ubiquitin ligase BRAP2/IMP, and a subfamily of deubiquitinating enzymes. Here, we report the solution structure of the BUZ domain of Ubp-M, a ubiquitin-specific protease, and its interaction with ubiquitin. Unlike the BUZ domain from isopeptidase T (isoT) that contains a single zinc finger, the Ubp-M BUZ domain features three zinc-binding sites consisting of 12 residues. These zinc ligands form a pair of cross-braced ring fingers encapsulated within a third zinc finger in the primary structure. In contrast to isoT, which can form an N-terminal loop swapped dimer in the crystal state, the formation of additional zinc fingers in the Ubp-M BUZ domain restricts its N-terminal loop to intra-domain interactions. The ubiquitin-binding site of the Ubp-M BUZ domain is mapped to the highly conserved, concave surface formed by the alpha 3 helix and the central beta-sheet. We further show that this site binds to the C-terminal tail of free ubiquitin, and corresponding peptides display essentially the same binding affinities as full-length ubiquitin does for the Ubp-M BUZ domain. However, modification of the G76(Ub) carboxylate group either by a peptide or isopeptide bond abolishes BUZ-domain interaction. The unique ubiquitin-recognition mode of the BUZ domain family suggests that they may function as "sensors" of free ubiquitin in cells to achieve regulatory roles in many aspects of ubiquitin-dependent processes.

Authors
Pai, M-T; Tzeng, S-R; Kovacs, JJ; Keaton, MA; Li, SS-C; Yao, T-P; Zhou, P
MLA Citation
Pai, M-T, Tzeng, S-R, Kovacs, JJ, Keaton, MA, Li, SS-C, Yao, T-P, and Zhou, P. "Solution structure of the Ubp-M BUZ domain, a highly specific protein module that recognizes the C-terminal tail of free ubiquitin." J Mol Biol 370.2 (July 6, 2007): 290-302.
PMID
17512543
Source
pubmed
Published In
Journal of Molecular Biology
Volume
370
Issue
2
Publish Date
2007
Start Page
290
End Page
302
DOI
10.1016/j.jmb.2007.04.015

HDAC6 controls major cell response pathways to cytotoxic accumulation of protein aggregates

A cellular defense mechanism counteracts the deleterious effects of misfolded protein accumulation by eliciting a stress response. The cytoplasmic deacetylase HDAC6 (histone deacetylase 6) was previously shown to be a key element in this response by coordinating the clearance of protein aggregates through aggresome formation and their autophagic degradation. Here, for the first time, we demonstrate that HDAC6 is involved in another crucial cell response to the accumulation of ubiquitinated protein aggregates, and unravel its molecular basis. Indeed, our data show that HDAC6 senses ubiquitinated cellular aggregates and consequently induces the expression of major cellular chaperones by triggering the dissociation of a repressive HDAC6/HSF1 (heat-shock factor 1)/HSP90 (heat-shock protein 90) complex and a subsequent HSF1 activation. HDAC6 therefore appears as a master regulator of the cell protective response to cytotoxic protein aggregate formation. © 2007 by Cold Spring Harbor Laboratory Press.

Authors
Boyault, C; Zhang, Y; Fritah, S; Caron, C; Gilquin, B; So, HK; Garrido, C; Yao, T-P; Vourc'h, C; Matthias, P; Khochbin, S
MLA Citation
Boyault, C, Zhang, Y, Fritah, S, Caron, C, Gilquin, B, So, HK, Garrido, C, Yao, T-P, Vourc'h, C, Matthias, P, and Khochbin, S. "HDAC6 controls major cell response pathways to cytotoxic accumulation of protein aggregates." Genes and Development 21.17 (2007): 2172-2181.
PMID
17785525
Source
scival
Published In
Genes & development
Volume
21
Issue
17
Publish Date
2007
Start Page
2172
End Page
2181
DOI
10.1101/gad.436407

HDAC6 Modulates Cell Motility by Altering the Acetylation Level of Cortactin

Histone deacetylase 6 (HDAC6) is a tubulin-specific deacetylase that regulates microtubule-dependent cell movement. In this study, we identify the F-actin-binding protein cortactin as a HDAC6 substrate. We demonstrate that HDAC6 binds cortactin and that overexpression of HDAC6 leads to hypoacetylation of cortactin, whereas inhibition of HDAC6 activity leads to cortactin hyperacetylation. HDAC6 alters the ability of cortactin to bind F-actin by modulating a "charge patch" in its repeat region. Introduction of charge-preserving or charge-neutralizing mutations in this cortactin repeat region correlates with the gain or loss of F-actin binding ability, respectively. Cells expressing a charge-neutralizing cortactin mutant were less motile than control cells or cells expressing a charge-preserving mutant. These findings suggest that, in addition to its role in microtubule-dependent cell motility, HDAC6 influences actin-dependent cell motility by altering the acetylation status of cortactin, which, in turn, changes the F-actin binding activity of cortactin. © 2007 Elsevier Inc. All rights reserved.

Authors
Zhang, X; Yuan, Z; Zhang, Y; Yong, S; Salas-Burgos, A; Koomen, J; Olashaw, N; Parsons, JT; Yang, X-J; Dent, SR; Yao, T-P; Lane, WS; Seto, E
MLA Citation
Zhang, X, Yuan, Z, Zhang, Y, Yong, S, Salas-Burgos, A, Koomen, J, Olashaw, N, Parsons, JT, Yang, X-J, Dent, SR, Yao, T-P, Lane, WS, and Seto, E. "HDAC6 Modulates Cell Motility by Altering the Acetylation Level of Cortactin." Molecular Cell 27.2 (2007): 197-213.
PMID
17643370
Source
scival
Published In
Molecular Cell
Volume
27
Issue
2
Publish Date
2007
Start Page
197
End Page
213
DOI
10.1016/j.molcel.2007.05.033

HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS

A prominent feature of late-onset neurodegenerative diseases is accumulation of misfolded protein in vulnerable neurons. When levels of misfolded protein overwhelm degradative pathways, the result is cellular toxicity and neurodegeneration. Cellular mechanisms for degrading misfolded protein include the ubiquitin-proteasome system (UPS), the main non-lysosomal degradative pathway for ubiquitinated proteins, and autophagy, a lysosome-mediated degradative pathway. The UPS and autophagy have long been viewed as complementary degradation systems with no point of intersection. This view has been challenged by two observations suggesting an apparent interaction: impairment of the UPS induces autophagy in vitro, and conditional knockout of autophagy in the mouse brain leads to neurodegeneration with ubiquitin-positive pathology. It is not known whether autophagy is strictly a parallel degradation system, or whether it is a compensatory degradation system when the UPS is impaired; furthermore, if there is a compensatory interaction between these systems, the molecular link is not known. Here we show that autophagy acts as a compensatory degradation system when the UPS is impaired in Drosophila melanogaster, and that histone deacetylase 6 (HDAC6), a microtubule-associated deacetylase that interacts with polyubiquitinated proteins, is an essential mechanistic link in this compensatory interaction. We found that compensatory autophagy was induced in response to mutations affecting the proteasome and in response to UPS impairment in a fly model of the neurodegenerative disease spinobulbar muscular atrophy. Autophagy compensated for impaired UPS function in an HDAC6-dependent manner. Furthermore, expression of HDAC6 was sufficient to rescue degeneration associated with UPS dysfunction in vivo in an autophagy-dependent manner. This study suggests that impairment of autophagy (for example, associated with ageing or genetic variation) might predispose to neurodegeneration. Morover, these findings suggest that it may be possible to intervene in neurodegeneration by augmenting HDAC6 to enhance autophagy. ©2007 Nature Publishing Group.

Authors
Pandey, UB; Nie, Z; Batlevi, Y; McCray, BA; Ritson, GP; Nedelsky, NB; Schwartz, SL; Diprospero, NA; Knight, MA; Schuldiner, O; Padmanabhan, R; Hild, M; Berry, DL; Garza, D; Hubbert, CC; Yao, T-P; Baehrecke, EH; Taylor, JP
MLA Citation
Pandey, UB, Nie, Z, Batlevi, Y, McCray, BA, Ritson, GP, Nedelsky, NB, Schwartz, SL, Diprospero, NA, Knight, MA, Schuldiner, O, Padmanabhan, R, Hild, M, Berry, DL, Garza, D, Hubbert, CC, Yao, T-P, Baehrecke, EH, and Taylor, JP. "HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS." Nature 447.7146 (2007): 859-863.
PMID
17568747
Source
scival
Published In
Nature
Volume
447
Issue
7146
Publish Date
2007
Start Page
859
End Page
863
DOI
10.1038/nature05853

HDAC6 deacetylation of tubulin modulates dynamics of cellular adhesions

Genetic or pharmacological alteration of the activity of the histone deacetylase 6 (HDAC6) induces a parallel alteration in cell migration. Using tubacin to block deacetylation of α-tubulin, and not other HDAC6 substrates, yielded a motility reduction equivalent to agents that block all NAD-independent HDACs. Accordingly, we investigated how the failure to deacetylate tubulin contributes to decreased motility in HDAC6-inhibited cells. Testing the hypothesis that motility is reduced because cellular adhesion is altered, we found that inhibiting HDAC6 activity towards tubulin rapidly increased total adhesion area. Next, we investigated the mechanism of the adhesion area increase. Formation of adhesions proceeded normally and cell spreading was more rapid in the absence of active HDAC6; however, photobleaching assays and adhesion breakdown showed that adhesion turnover was slower. To test the role of hyperacetylated tubulin in altering adhesion turnover, we measured microtubule dynamics in HDAC6-inhibited cells because dynamic microtubules are required to target adhesions for turnover. HDAC6 inhibition yielded a decrease in microtubule, dynamics that was sufficient to decrease focal adhesion turnover. Thus, our results suggest a scenario in which the decreased dynamics of hyperacetylated microtubules in HDAC6-inhibited cells compromises their capacity to mediate the focal adhesion dynamics required for rapid cell migration.

Authors
Tran, AD-A; Marmo, TP; Salam, AA; Che, S; Finkelstein, E; Kabarriti, R; Xenias, HS; Mazitschek, R; Hubbert, C; Kawaguchi, Y; Sheetz, MP; Yao, T-P; Bulinski, C
MLA Citation
Tran, AD-A, Marmo, TP, Salam, AA, Che, S, Finkelstein, E, Kabarriti, R, Xenias, HS, Mazitschek, R, Hubbert, C, Kawaguchi, Y, Sheetz, MP, Yao, T-P, and Bulinski, C. "HDAC6 deacetylation of tubulin modulates dynamics of cellular adhesions." Journal of Cell Science 120.8 (2007): 1469-1479.
PMID
17389687
Source
scival
Published In
Journal of cell science
Volume
120
Issue
8
Publish Date
2007
Start Page
1469
End Page
1479
DOI
10.1242/jcs.03431

Charge modification at multiple c-terminal lysine residues regulates p53 oligomerization and its nucleus-cytoplasm trafficking

The basal level of the tumor suppressor p53 is regulated by MDM2-mediated ubiquitination at specific lysines, which leads to p53 nuclear export and degradation. Upon p53 activation, however, these lysines become acetylated by p300/CREB-binding protein. Here we have reported an unexpected finding that p300-mediated acetylation also regulates p53 subcellular localization and can promote cytoplasmic localization of p53. This activity is independent of MDM2 but requires a p53 nuclear export signal and acetylation of multiple lysines by p300. Mechanistically, we showed that conversion of a minimal four of these lysines to alanines but not arginines mimics p300-mediated p53 nuclear export, and these lysine-neutralizing mutations effectively prevent p53 tetramerization, thus exposing the oligomerization-regulated nuclear export signal. Our study suggested a threshold mechanism whereby the degree of acetylation regulates p53 nucleus-cytoplasm trafficking by neutralizing a lysine-dependent charge patch, which in turn, controls oligomerization-dependent p53 nuclear export.

Authors
Kawaguchi, Y; Ito, A; Appella, E; Yao, T-P
MLA Citation
Kawaguchi, Y, Ito, A, Appella, E, and Yao, T-P. "Charge modification at multiple c-terminal lysine residues regulates p53 oligomerization and its nucleus-cytoplasm trafficking." Journal of Biological Chemistry 281.3 (2006): 1394-1400.
PMID
16291740
Source
scival
Published In
The Journal of biological chemistry
Volume
281
Issue
3
Publish Date
2006
Start Page
1394
End Page
1400
DOI
10.1074/jbc.M505772200

Merlin facilitates ubiquitination and degradation of transactivation- responsive RNA-binding protein

The Nf2 tumor suppressor codes for merlin, a protein whose function is largely unknown. We have previously demonstrated a novel interaction between merlin and TRBP, which inhibits the oncogenic activity of TRBP. In spite of the significance of their functional interaction, its molecular mechanism still remains to be elucidated. In this report, we investigated how merlin inhibits the oncogenic activity of TRBP in association with cell growth conditions. In the human embryonic kidney 293 cell line, the level of endogenous merlin increased, whereas that of endogenous TRBP significantly decreased along with the increase in cell confluence. We demonstrated that the carboxyl-terminal region of TRBP was responsible for this phenomenon using stable cell lines expressing deletion mutants of TRBP. The overexpression of merlin decreased the protein level of TRBP, and the ubiquitin-like subdomain of merlin's FERM domain was important for this activity. We also demonstrated that TRBP is ubiquitinylated and the ubiquitinylated forms of TRBP are accumulated by ectopically expressed merlin or cell confluence in the presence of MG132, a proteasome inhibitor. Furthermore, we showed that the regulation of TRBP in response to cell confluence was abolished upon knockdown of merlin expression by specific small interfering RNA. Finally, we showed that ectopically expressed merlin restored cell-cell contact inhibition in cells stably expressing TRBP but not in TRBPΔc. These results suggest that merlin is involved in the regulation of TRBP protein level by facilitating its ubiquitination in response to such cues as cell-cell contacts. © 2006 Nature Publishing Group All rights reserved.

Authors
Lee, JY; Moon, HJ; Lee, WK; Chun, HJ; Han, CW; Jeon, Y-W; Lim, Y; Kim, YH; Yao, T-P; Lee, K-H; Jun, T-Y; Rha, HK; Kang, J-K
MLA Citation
Lee, JY, Moon, HJ, Lee, WK, Chun, HJ, Han, CW, Jeon, Y-W, Lim, Y, Kim, YH, Yao, T-P, Lee, K-H, Jun, T-Y, Rha, HK, and Kang, J-K. "Merlin facilitates ubiquitination and degradation of transactivation- responsive RNA-binding protein." Oncogene 25.8 (2006): 1143-1152.
PMID
16247459
Source
scival
Published In
Oncogene
Volume
25
Issue
8
Publish Date
2006
Start Page
1143
End Page
1152
DOI
10.1038/sj.onc.1209150

Histone deacetylase 3 binds to and regulates the GCMa transcription factor

Human GCMa transcription factor regulates expression of syncytin, a placental fusogenic protein mediating trophoblastic fusion. Recently, we have demonstrated that CBP-mediated GCMa acetylation underlies the activated cAMP/PKA signaling pathway that stimulates trophoblastic fusion. Because protein acetylation is a reversible modification governed by histone acetyltransferases (HATs) and histone deacetylase (HDACs), in this study we investigated the key HDACs responsible for deacetylation of GCMa and thus the reduction in GCMa activity to avoid unwanted fusion events that may have adverse effects on placental morphogenesis. We herein demonstrate that the HDAC inhibitor, trichostatin A (TSA), increases the level of acetylated GCMa and that HDAC1, 3, 4 and 5 interact with and deacetylate GCMa. Glutathione S -transferase (GST) pull-down assays further verified direct interaction between GCMa and HDAC3 or CBP and HDAC3. HDAC3 counteracts the transcriptional coactivator activity of CBP and the enhancement effect of CBP on GCMa-mediated transcriptional activation. Correlatively, we found in placental cells that HDAC3 associates with the proximal GCMa-binding site (pGBS) in the syncytin promoter and dissociates from pGBS in the presence of forskolin, which stimulates the association of CBP and GCMa with pGBS. Our studies support that trophoblastic fusion in placental morphogenesis depends on the regulation of GCMa activity by HAT and HDAC. © 2006 Oxford University Press.

Authors
Chuang, H-C; Chang, C-W; Chang, G-D; Yao, T-P; Chen, H
MLA Citation
Chuang, H-C, Chang, C-W, Chang, G-D, Yao, T-P, and Chen, H. "Histone deacetylase 3 binds to and regulates the GCMa transcription factor." Nucleic Acids Research 34.5 (2006): 1459-1469.
PMID
16528103
Source
scival
Published In
Nucleic Acids Research
Volume
34
Issue
5
Publish Date
2006
Start Page
1459
End Page
1469
DOI
10.1093/nar/gkl048

A mechanism of COOH-terminal binding protein-mediated repression.

The E2F4 and E2F5 proteins specifically associate with the Rb-related p130 protein in quiescent cells to repress transcription of various genes encoding proteins important for cell growth. A series of reports has provided evidence that Rb-mediated repression involves both histone deacetylase (HDAC)-dependent and HDAC-independent events. Our previous results suggest that one such mechanism for Rb-mediated repression, independent of recruitment of HDAC, involves the recruitment of the COOH-terminal binding protein (CtBP) corepressor, a protein now recognized to play a widespread role in transcriptional repression. We now find that CtBP can interact with the histone acetyltransferase, cyclic AMP--responsive element--binding protein (CREB) binding protein, and inhibit its ability to acetylate histone. This inhibition is dependent on a NH2-terminal region of CtBP that is also required for transcription repression. These results thus suggest two complementary mechanisms for E2F/p130-mediated repression that have in common the control of histone acetylation at target promoters.

Authors
Meloni, AR; Lai, C-H; Yao, T-P; Nevins, JR
MLA Citation
Meloni, AR, Lai, C-H, Yao, T-P, and Nevins, JR. "A mechanism of COOH-terminal binding protein-mediated repression." Mol Cancer Res 3.10 (October 2005): 575-583.
PMID
16254191
Source
pubmed
Published In
Molecular cancer research : MCR
Volume
3
Issue
10
Publish Date
2005
Start Page
575
End Page
583
DOI
10.1158/1541-7786.MCR-05-0088

Regulation of MEF2 by histone deacetylase 4- and SIRT1 deacetylase-mediated lysine modifications.

The class II deacetylase histone deacetylase 4 (HDAC4) negatively regulates the transcription factor MEF2. HDAC4 is believed to repress MEF2 transcriptional activity by binding to MEF2 and catalyzing local histone deacetylation. Here we report that HDAC4 also controls MEF2 by a novel SUMO E3 ligase activity. We show that HDAC4 interacts with the SUMO E2 conjugating enzyme Ubc9 and is itself sumoylated. The overexpression of HDAC4 leads to prominent MEF2 sumoylation in vivo, whereas recombinant HDAC4 stimulates MEF2 sumoylation in a reconstituted system in vitro. Importantly, HDAC4 promotes sumoylation on a lysine residue that is also subject to acetylation by a MEF2 coactivator, the acetyltransferase CBP, suggesting a possible interplay between acetylation and sumoylation in regulating MEF2 activity. Indeed, MEF2 acetylation is correlated with MEF2 activation and dynamically induced upon muscle cell differentiation, while sumoylation inhibits MEF2 transcriptional activity. Unexpectedly, we found that HDAC4 does not function as a MEF2 deacetylase. Instead, the NAD+-dependent deacetylase SIRT1 can potently induce MEF2 deacetylation. Our studies reveal a novel regulation of MEF2 transcriptional activity by two distinct classes of deacetylases that affect MEF2 sumoylation and acetylation.

Authors
Zhao, X; Sternsdorf, T; Bolger, TA; Evans, RM; Yao, T-P
MLA Citation
Zhao, X, Sternsdorf, T, Bolger, TA, Evans, RM, and Yao, T-P. "Regulation of MEF2 by histone deacetylase 4- and SIRT1 deacetylase-mediated lysine modifications." Mol Cell Biol 25.19 (October 2005): 8456-8464.
PMID
16166628
Source
pubmed
Published In
Molecular and Cellular Biology
Volume
25
Issue
19
Publish Date
2005
Start Page
8456
End Page
8464
DOI
10.1128/MCB.25.19.8456-8464.2005

HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor.

The molecular chaperone heat shock protein 90 (Hsp90) and its accessory cochaperones function by facilitating the structural maturation and complex assembly of client proteins, including steroid hormone receptors and selected kinases. By promoting the activity and stability of these signaling proteins, Hsp90 has emerged as a critical modulator in cell signaling. Here, we present evidence that Hsp90 chaperone activity is regulated by reversible acetylation and controlled by the deacetylase HDAC6. We show that HDAC6 functions as an Hsp90 deacetylase. Inactivation of HDAC6 leads to Hsp90 hyperacetylation, its dissociation from an essential cochaperone, p23, and a loss of chaperone activity. In HDAC6-deficient cells, Hsp90-dependent maturation of the glucocorticoid receptor (GR) is compromised, resulting in GR defective in ligand binding, nuclear translocation, and transcriptional activation. Our results identify Hsp90 as a target of HDAC6 and suggest reversible acetylation as a unique mechanism that regulates Hsp90 chaperone complex activity.

Authors
Kovacs, JJ; Murphy, PJM; Gaillard, S; Zhao, X; Wu, J-T; Nicchitta, CV; Yoshida, M; Toft, DO; Pratt, WB; Yao, T-P
MLA Citation
Kovacs, JJ, Murphy, PJM, Gaillard, S, Zhao, X, Wu, J-T, Nicchitta, CV, Yoshida, M, Toft, DO, Pratt, WB, and Yao, T-P. "HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor." Mol Cell 18.5 (May 27, 2005): 601-607.
PMID
15916966
Source
pubmed
Published In
Molecular Cell
Volume
18
Issue
5
Publish Date
2005
Start Page
601
End Page
607
DOI
10.1016/j.molcel.2005.04.021

Intracellular trafficking of histone deacetylase 4 regulates neuronal cell death

Histone deacetylase 4 (HDAC4) undergoes signal-dependent shuttling between the cytoplasm and nucleus, which is regulated in part by calcium/calmodulin- dependent kinase (CaMK)-mediated phosphorylation. Here, we report that HDAC4 intracellular trafficking is important in regulating neuronal cell death. HDAC4 is normally localized to the cytoplasm in brain tissue and cultured cerebellar granule neurons (CGNs). However, in response to low-potassium or excitotoxic glutamate conditions that induce neuronal cell death, HDAC4 rapidly translocates into the nucleus of cultured CGNs. Treatment with the neuronal survival factor BDNF suppresses HDAC4 nuclear translocation, whereas a proapoptotic CaMK inhibitor stimulates HDAC4 nuclear accumulation. Moreover, ectopic expression of nuclear-localized HDAC4 promotes neuronal apoptosis and represses the transcriptional activities of myocyte enhancer factor 2 and cAMP response element-binding protein, survival factors in neurons. In contrast, inactivation of HDAC4 by small interfering RNA or HDAC inhibitors suppresses neuronal cell death. Finally, an increase of nuclear HDAC4 in granule neurons is also observed in weaver mice, which harbor a mutation that promotes CGN apoptosis. Our data identify HDAC4 and its intracellular trafficking as key effectors of multiple pathways that regulate neuronal cell death. Copyright © 2005 Society for Neuroscience.

Authors
Bolger, TA; Yao, T-P
MLA Citation
Bolger, TA, and Yao, T-P. "Intracellular trafficking of histone deacetylase 4 regulates neuronal cell death." Journal of Neuroscience 25.41 (2005): 9544-9553.
PMID
16221865
Source
scival
Published In
The Journal of neuroscience : the official journal of the Society for Neuroscience
Volume
25
Issue
41
Publish Date
2005
Start Page
9544
End Page
9553
DOI
10.1523/JNEUROSCI.1826-05.2005

Regulation of the dynamics of hsp90 action on the glucocorticoid receptor by acetylation/deacetylation of the chaperone

It is known that inhibition of histone deacetylases (HDACs) leads to acetylation of the abundant protein chaperone hsp90. In a recent study, we have shown that knockdown of HDAC6 by a specific small interfering RNA leads to hyperacetylation of hsp90 and that the glucocorticoid receptor (GR), an established hsp90 "client" protein, is defective in ligand binding, nuclear translocation, and gene activation in HDAC6-deficient cells (Kovacs, J. J., Murphy, P. J. M., Gaillard, S., Zhao, X., Wu, J-T., Nicchitta, C. V., Yoshida, M., Toft, D. O., Pratt, W. B., and Yao, T-P. (2005) Mol. Cell 18, 601-607). Using human embryonic kidney wild-type and HDAC6 (small interfering RNA) knockdown cells transiently expressing the mouse GR, we show here that the intrinsic properties of the receptor protein itself are not affected by HDAC6 knockdown, but the knockdown cytosol has a markedly decreased ability to assemble stable GR·hsp90 heterocomplexes and generate stable steroid binding activity under cell-free conditions. HDAC6 knockdown cytosol has the same ability to carry out dynamic GR·hsp90 heterocomplex assembly as wild-type cytosol. Addition of purified hsp90 to HDAC6 knockdown cytosol restores stable GR·hsp90 heterocomplex assembly to the level of wild-type cytosol. hsp90 from HDAC6 knockdown cytosol has decreased ATP-binding affinity, and it does not assemble stable GR·hsp90 heterocomplexes when it is a component of a purified five-protein assembly system. Incubation of knockdown cell hsp90 with purified HDAC6 converts the hsp90 to wild-type behavior. Thus, acetylation of hsp90 results in dynamic GR·hsp90 heterocomplex assembly/disassembly, and this is manifest in the cell as a ∼100-fold shift to the right in the steroid dose response for gene activation. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.

Authors
Murphy, PJM; Morishima, Y; Kovacs, JJ; Yao, T-P; Pratt, WB
MLA Citation
Murphy, PJM, Morishima, Y, Kovacs, JJ, Yao, T-P, and Pratt, WB. "Regulation of the dynamics of hsp90 action on the glucocorticoid receptor by acetylation/deacetylation of the chaperone." Journal of Biological Chemistry 280.40 (2005): 33792-33799.
PMID
16087666
Source
scival
Published In
The Journal of biological chemistry
Volume
280
Issue
40
Publish Date
2005
Start Page
33792
End Page
33799
DOI
10.1074/jbc.M506997200

Stimulation of GCMa transcriptional activity by cyclic AMP/protein kinase A signaling is attributed to CBP-mediated acetylation of GCMa

Human GCMa is a zinc-containing transcription factor primarily expressed in placenta. GCMa regulates expression of syncytin gene, which encodes for a placenta-specific membrane protein that mediates trophoblastic fusion and the formation of syncytiotrophoblast layer required for efficient fetal-maternal exchange of nutrients and oxygen. The aelenylate cyclase activator, forskolin, stimulates syncytin gene expression and cell fusion in cultured placental cells. Here we present evidence that cyclic AMP (cAMP) signaling pathway activates the syncytin gene expression by regulating GCMa activity. We found that forskolin and protein kinase A (PKA) enhances GCMa-mediated transcriptional activation. Furthermore, PKA treatment stimulates the association of GCMa with CBP and increases GCMa acetylation. CBP primarily acetylates GCMa at lysine 367, lysine406, and lysine409 in the transactivation domain (TAD). We found that acetylation of these residues is required to protect GCMa from ubiquitination and increases the TAD stability with a concomitant increase in transcriptional activity, supporting the importance of acetylation in PKA-dependent GCMa activation. Our results reveal a novel regulation of GCMa activity by cAMP-dependent protein acetylation and provide a molecular mechanism by which cAMP signaling regelates trophoblastic fusion. Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Authors
Chang, C-W; Chuang, H-C; Yu, C; Yao, T-P; Chen, H
MLA Citation
Chang, C-W, Chuang, H-C, Yu, C, Yao, T-P, and Chen, H. "Stimulation of GCMa transcriptional activity by cyclic AMP/protein kinase A signaling is attributed to CBP-mediated acetylation of GCMa." Molecular and Cellular Biology 25.19 (2005): 8401-8414.
PMID
16166624
Source
scival
Published In
Molecular and Cellular Biology
Volume
25
Issue
19
Publish Date
2005
Start Page
8401
End Page
8414
DOI
10.1128/MCB.25.19.8401-8414.2005

Cyclin D1 inhibits peroxisome proliferator-activated receptor γ-mediated adipogenesis through histone deacetylase recruitment

The cyclin D1 gene encodes the labile serum-inducible regulatory subunit of a holoenzyme that phosphorylates and inactivates the retinoblastoma protein. Overexpression of cyclin D1 promotes cellular proliferation and normal physiological levels of cyclin D1 function to inhibit adipocyte differentiation in vivo. We have previously shown that cyclin D1 inhibits peroxisome proliferator-activated receptor (PPAR)γ-dependent activity through a cyclin-dependent kinase- and retinoblastoma protein-binding-independent mechanism. In this study, we determined the molecular mechanism by which cyclin D1 regulated PPARγ function. Herein, murine embryonic fibroblast (MEF) differentiation by PPARγ ligand was associated with a reduction in histone deacetylase (HDAC1) activity. Cyclin D1-/- MEFs showed an increased propensity to undergo differentiation into adipocytes. Genetic deletion of cyclin D1 reduced HDAC1 activity. Reconstitution of cyclin D1 into the cyclin D1-/- MEFs increased HDAC1 activity and blocked PPARγ-mediated adipogenesis. PPARγ activity was enhanced in cyclin D1-/- cells. Reintroduction of cyclin D1 inhibited basal and ligand-induced PPARγ activity and enhanced HDAC repression of PPARγ activity. Cyclin D1 bound HDAC in vivo and preferentially physically associated with HDAC1, HDAC2, HDAC3, and HDAC5. Chromatin immunoprecipitation assay demonstrated that cyclin D1 enhanced recruitment of HDAC1 and HDAC3 and histone methyltransferase SUV39H1 to the PPAR response element of the lipoprotein lipase promoter and decreased acetylation of total histone H3 and histone H3 lysine 9. Collectively, these studies suggest an important role of cyclin D1 in regulation of PPARγ-mediated adipocyte differentiation through recruitment of HDACs to regulate PPAR response element local chromatin structure and PPARγ function. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.

Authors
Fu, M; Rao, M; Bouras, T; Wang, C; Wu, K; Zhang, X; Li, Z; Yao, T-P; Pestell, RG
MLA Citation
Fu, M, Rao, M, Bouras, T, Wang, C, Wu, K, Zhang, X, Li, Z, Yao, T-P, and Pestell, RG. "Cyclin D1 inhibits peroxisome proliferator-activated receptor γ-mediated adipogenesis through histone deacetylase recruitment." Journal of Biological Chemistry 280.17 (2005): 16934-16941.
PMID
15713663
Source
scival
Published In
Journal of Biological Chemistry
Volume
280
Issue
17
Publish Date
2005
Start Page
16934
End Page
16941
DOI
10.1074/jbc.M500403200

The synergistic combination of the farnesyl transferase inhibitor lonafarnib and paclitaxel enhances tubulin acetylation and requires a functional tubulin deacetylase

Farnesyl transferase (FT) inhibitors (FTI) are anticancer agents developed to target encogenic Ras proteins by inhibiting Ras farnesylation. FTIs potently synergize with paclitaxel and other microtubule-stabilizing drugs; however, the mechanistic basis underlying this synergistic interaction remains elusive. Here we show that the FTI lonafarnib affects the microtubule cytoskeleton resulting in microtubule bundle formation, increased microtubule stabilization and acetylation, and suppression of microtubule dynamics. Notably, treatment with the combination of low doses of lonafarnib with paclitaxel markedly enhanced tubulin acetylation (a marker of microtubule stability) as compared with either drug alone. This synergistic effect correlated with FT inhibition and was accompanied by a synergistic increase in mitotic arrest and cell death. Mechanistically, we show that the combination of lonafarnib and paclitaxel inhibits the in vitro deacetylating activity of the only known tubulin deacetylase, histone deacetylase 6 (HDAC6). In addition, the lonafarnib/taxane combination is synergistic only in cells lines expressing the wild-type HDAC6, but not a catalytic-mutant HDAC6, revealing that functional HDAC6 is required for the synergy of lonafarnib with taxanes. Furthermore, tubacin, a specific HDAC6 inhibitor, synergistically enhanced tubulin acetylation in combination with paclitaxel, similar to the combination of lonafarnib and paclitaxel. Taken together, these data suggest a relationship between FT inhibition, HDAC6 function, and cell death, providing insight into the putative molecular basis of the lonafarnib/texane synergistic antiproliferative combination. ©2005 American Association for Cancer Research.

Authors
Marcus, AI; Zhou, J; O'Brate, A; Hamel, E; Wong, J; Nivens, M; El-Naggar, A; Yao, T-P; Khuri, FR; Giannakakou, P
MLA Citation
Marcus, AI, Zhou, J, O'Brate, A, Hamel, E, Wong, J, Nivens, M, El-Naggar, A, Yao, T-P, Khuri, FR, and Giannakakou, P. "The synergistic combination of the farnesyl transferase inhibitor lonafarnib and paclitaxel enhances tubulin acetylation and requires a functional tubulin deacetylase." Cancer Research 65.9 (2005): 3883-3893.
PMID
15867388
Source
scival
Published In
Cancer Research
Volume
65
Issue
9
Publish Date
2005
Start Page
3883
End Page
3893
DOI
10.1158/0008-5472.CAN-04-3757

FBW2 targets GCMa to the ubiquitin-proteasome degradation system

The GCM proteins GCMa/1 and GCMb/2 are novel zinc-containing transcription factors critical for glial cell differentiation in fly and for placental as well as parathyroid gland development in mouse. Previous pulse-chase experiments have demonstrated differential protein stabilities of GCM proteins with half-lives from ∼30 min to 2 h (Tuerk, E. E., Schreiber, J., and Wegner, M. (2000) J. Biol. Chem. 275, 4774-4782). However, little is known about the machinery that controls GCM protein degradation. Here, we report the identification of an SCF complex as the GCM ubiquitin-protein isopeptide ligase (E3) that regulates human GCMa (hGCMa) degradation. We found that SKP1 and CUL1, two key components of the SCF complex, associate with hGCMa in vivo. We further identify the human F-box protein FBW2 (hFBW2) as the substrate recognition subunit in the SCF E3 complex for hGCMa. We show that hFBW2 interacts with hGCMa in a phosphorylation-dependent manner and promotes hGCMa ubiquitination. Supporting a critical role for hFBW2 in hGCMa degradation, knockdown of hFBW2 expression by RNA interference leads to a reduction in hGCMa ubiquitination and a concomitant increase in hGCMa protein stability. Our study identifies the SCFhFBW2 E3 complex as the key machinery that targets hGCMa to the ubiquitin-proteasome degradation system. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.

Authors
Yang, C-S; Yu, C; Chuang, H-C; Chang, C-W; Chang, G-D; Yao, T-P; Chen, H
MLA Citation
Yang, C-S, Yu, C, Chuang, H-C, Chang, C-W, Chang, G-D, Yao, T-P, and Chen, H. "FBW2 targets GCMa to the ubiquitin-proteasome degradation system." Journal of Biological Chemistry 280.11 (2005): 10083-10090.
PMID
15640526
Source
scival
Published In
Journal of Biological Chemistry
Volume
280
Issue
11
Publish Date
2005
Start Page
10083
End Page
10090
DOI
10.1074/jbc.M413986200

Deactylase inhibitors disrupt cellular complexes containing protein phosphatases and deacetylases.

Affinity isolation of protein serine/threonine phosphatases on the immobilized phosphatase inhibitor microcystin-LR identified histone deacetylase 1(HDAC1), HDAC6, and HDAC10 as novel components of cellular phosphatase complexes. Other HDACs, specifically HDAC2, -3, -4, and -5, were excluded from such complexes. In vitro biochemical studies showed that recombinant HDAC6, but not HDAC4, bound directly to the protein phosphatase (PP)1 catalytic subunit. No association was observed between HDAC6 and PP2A, another major protein phosphatase. PP1 binding was mapped to the second catalytic domain and adjacent C-terminal sequences in HDAC6, and treatment of cells with trichostatin A (TSA) disrupted endogenous HDAC6.PP1 complexes. Consistent with the inhibition of tubulin deactylase activity of HDAC6, TSA enhanced cellular tubulin acetylation, and acetylated tubulin was present in the PP1 complexes from TSA-treated cells. Trapoxin B, a weak HDAC6 inhibitor, and calyculin A, a cell-permeable phosphatase inhibitor, had no effect on the stability of the HDAC6.PP1 complexes or on tubulin acetylation. Mutations that inactivated HDAC6 prevented its incorporation into cellular PP1 complexes and suggested that when bound together both enzymes were active. Interestingly, TSA disrupted all the cellular HDAC.phosphatase complexes analyzed. This study provided new insight into the mechanism by which HDAC inhibitors elicited coordinate changes in cellular protein phosphorylation and acetylation and suggested that changes in these protein modifications at multiple subcellular sites may contribute to the known ability of HDAC inhibitors to suppress cell growth and transformation.

Authors
Brush, MH; Guardiola, A; Connor, JH; Yao, T-P; Shenolikar, S
MLA Citation
Brush, MH, Guardiola, A, Connor, JH, Yao, T-P, and Shenolikar, S. "Deactylase inhibitors disrupt cellular complexes containing protein phosphatases and deacetylases." J Biol Chem 279.9 (February 27, 2004): 7685-7691.
PMID
14670976
Source
pubmed
Published In
The Journal of biological chemistry
Volume
279
Issue
9
Publish Date
2004
Start Page
7685
End Page
7691
DOI
10.1074/jbc.M310997200

AcK-knowledge reversible acetylation.

In 1966, the histone was identified as the first protein subject to reversible acetylation. The ensuing 30 years of research on histone acetylation has been critical for elucidating how gene transcription and chromatin remodeling are regulated at the molecular level. This central focus on histones, however, has also restricted our understanding of reversible acetylation, and therefore the enzymes that catalyze this reaction, to cellular processes predominantly associated with chromatin. The study of reversible acetylation has become more or less synonymous with histone acetylation. Recent developments-including increased ability to detect acetylated proteins, the characterization of novel acetyltransferases and deacetylases, and the identification of specific inhibitors for these enzymes-have revealed that this histone-central paradigm probably reflects only a fraction of the cellular processes regulated by reversible acetylation. New studies have uncovered unexpected roles for reversible acetylation in many diverse areas, thereby establishing protein acetylation as a highly versatile signaling modification that has functions beyond gene transcription and chromatin remodeling.

Authors
Cohen, T; Yao, T-P
MLA Citation
Cohen, T, and Yao, T-P. "AcK-knowledge reversible acetylation." Science's STKE : signal transduction knowledge environment 2004.245 (2004): pe42-.
PMID
15304664
Source
scival
Published In
Sciences STKE [electronic resource] : signal transduction knowledge environment
Volume
2004
Issue
245
Publish Date
2004
Start Page
pe42

The HDAC complex and cytoskeleton.

HDAC6 is a cytoplasmic deacetylase that dynamically associates with the microtubule and actin cytoskeletons. HDAC6 regulates growth factor-induced chemotaxis by its unique deacetylase activity towards microtubules or other substrates. Here we describe a non-catalytic structural domain that is essential for HDAC6 function and places HDAC6 as a critical mediator linking the acetylation and ubiquitination network. This evolutionarily conserved motif, termed the BUZ domain, has features of a zinc finger and binds both mono- and polyubiquitinated proteins. Furthermore, the BUZ domain promotes HDAC6 mono-ubiquitination. These results establish the BUZ domain, in addition to the UIM and CUE domains, as a novel motif that both binds ubiquitin and mediates mono-ubiquitination. Importantly, the BUZ domain is essential for HDAC6 to promote chemotaxis, indicating that communication with the ubiquitin network is critical for proper HDAC6 function. The unique presence of the UIM and CUE domains in proteins involved in endocytic trafficking suggests that HDAC6 might also regulate vesicle transport and protein degradation. Indeed, we have found that HDAC6 is actively transported and concentrated in vesicular compartments. We propose that an integration of reversible acetylation and ubiquitination by HDAC6 may be a novel component in regulating the cytoskeleton, vesicle transport and protein degradation.

Authors
Kovacs, JJ; Hubbert, C; Yao, T-P
MLA Citation
Kovacs, JJ, Hubbert, C, and Yao, T-P. "The HDAC complex and cytoskeleton." Novartis Found Symp 259 (2004): 170-177.
PMID
15171253
Source
pubmed
Published In
Novartis Foundation Symposium
Volume
259
Publish Date
2004
Start Page
170
End Page
177

The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress.

The efficient clearance of cytotoxic misfolded protein aggregates is critical for cell survival. Misfolded protein aggregates are transported and removed from the cytoplasm by dynein motors via the microtubule network to a novel organelle termed the aggresome where they are processed. However, the means by which dynein motors recognize misfolded protein cargo, and the cellular factors that regulate aggresome formation, remain unknown. We have discovered that HDAC6, a microtubule-associated deacetylase, is a component of the aggresome. We demonstrate that HDAC6 has the capacity to bind both polyubiquitinated misfolded proteins and dynein motors, thereby acting to recruit misfolded protein cargo to dynein motors for transport to aggresomes. Indeed, cells deficient in HDAC6 fail to clear misfolded protein aggregates from the cytoplasm, cannot form aggresomes properly, and are hypersensitive to the accumulation of misfolded proteins. These findings identify HDAC6 as a crucial player in the cellular management of misfolded protein-induced stress.

Authors
Kawaguchi, Y; Kovacs, JJ; McLaurin, A; Vance, JM; Ito, A; Yao, TP
MLA Citation
Kawaguchi, Y, Kovacs, JJ, McLaurin, A, Vance, JM, Ito, A, and Yao, TP. "The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress." Cell 115.6 (December 12, 2003): 727-738.
PMID
14675537
Source
pubmed
Published In
Cell
Volume
115
Issue
6
Publish Date
2003
Start Page
727
End Page
738

Regulation of E2A activities by histone acetyltransferases in B lymphocyte development.

Genetic studies have demonstrated that the basic helix-loop-helix protein E2A is an essential transcription factor in B lymphocyte lineage commitment and differentiation. However, the mechanism underlying E2A-mediated transcription regulation is not fully understood. Here, we investigated the physical and genetic interactions between E2A and co-activators histone acetyltransferases (HATs) in B cells. Gel filtration analysis of human pre-B cell nuclear extract showed that E2A co-elutes with the HATs p300, CBP, and PCAF. A co-immunoprecipitation assay further demonstrated that a fraction of endogenous E2A proteins is associated with each of the three HATs. We show that these HATs acetylate E2A in vitro, enhance E2A-mediated transcription activity, and promote nuclear retention of E2A proteins. A catalytic mutation of p300 completely abrogates the ability of p300 to acetylate E2A and to promote E2A nuclear retention in 293T cells. A breeding test between E2A heterozygous mice and p300 heterozygous mice demonstrated that these two genes interact for proper B cell development. Collectively, these results suggest that E2A and HATs collaboratively regulate B cell development.

Authors
Bradney, C; Hjelmeland, M; Komatsu, Y; Yoshida, M; Yao, T-P; Zhuang, Y
MLA Citation
Bradney, C, Hjelmeland, M, Komatsu, Y, Yoshida, M, Yao, T-P, and Zhuang, Y. "Regulation of E2A activities by histone acetyltransferases in B lymphocyte development." J Biol Chem 278.4 (January 24, 2003): 2370-2376.
PMID
12435739
Source
pubmed
Published In
The Journal of biological chemistry
Volume
278
Issue
4
Publish Date
2003
Start Page
2370
End Page
2376
DOI
10.1074/jbc.M211464200

MDM2-HDAC1-mediated deacetylation of p53 is required for its degradation.

The tumor suppressor p53 is stabilized and activated in response to cellular stress through post-translational modifications including acetylation. p300/CBP-mediated acetylation of p53 is negatively regulated by MDM2. Here we show that MDM2 can promote p53 deacetylation by recruiting a complex containing HDAC1. The HDAC1 complex binds MDM2 in a p53-independent manner and deacetylates p53 at all known acetylated lysines in vivo. Ectopic expression of a dominant-negative HDAC1 mutant restores p53 acetylation in the presence of MDM2, whereas wild-type HDAC1 and MDM2 deacetylate p53 synergistically. Fibroblasts overexpressing a dominant negative HDAC1 mutant display enhanced DNA damage-induced p53 acetylation, increased levels of p53 and a more pronounced induction of p21 and MDM2. These results indicate that acetylation promotes p53 stability and function. As the acetylated p53 lysine residues overlap with those that are ubiquitylated, our results suggest that one major function of p53 acetylation is to promote p53 stability by preventing MDM2-dependent ubiquitylation, while recruitment of HDAC1 by MDM2 promotes p53 degradation by removing these acetyl groups.

Authors
Ito, A; Kawaguchi, Y; Lai, C-H; Kovacs, JJ; Higashimoto, Y; Appella, E; Yao, T-P
MLA Citation
Ito, A, Kawaguchi, Y, Lai, C-H, Kovacs, JJ, Higashimoto, Y, Appella, E, and Yao, T-P. "MDM2-HDAC1-mediated deacetylation of p53 is required for its degradation." EMBO J 21.22 (November 15, 2002): 6236-6245.
PMID
12426395
Source
pubmed
Published In
EMBO Journal
Volume
21
Issue
22
Publish Date
2002
Start Page
6236
End Page
6245

HDAC6 is a microtubule-associated deacetylase

Reversible acetylation of α-tubulin has been implicated in regulating microtubule stability and function. The distribution of acetylated α-tubulin is tightly controlled and stereotypic. Acetylated α-tubulin is most abundant in stable microtubules but is absent from dynamic cellular structures such as neuronal growth cones and the leading edges of fibroblasts. However, the enzymes responsible for regulating tubulin acetylation and deacetylation are not known. Here we report that a member of the histone deacetylase family, HDAC6, functions as a tubulin deacetylase. HDAC6 is localized exclusively in the cytoplasm, where it associates with microtubules and localizes with the microtubule motor complex containing p150glued (ref. 3). In vivo, the overexpression of HDAC6 leads to a global deacetylation of α-tubulin, whereas a decrease in HDAC6 increases α-tubulin acetylation. In vitro, purified HDAC6 potently deacetylates α-tubulin in assembled microtubules. Furthermore, overexpression of HDAC6 promotes chemotactic cell movement, supporting the idea that HDAC6-mediated deacetylation regulates microtubule-dependent cell motility. Our results show that HDAC6 is the tubulin deacetylase, and provide evidence that reversible acetylation regulates important biological processes beyond histone metabolism and gene transcription.

Authors
Hubbert, C; Guardiola, A; Shao, R; Kawaguchi, Y; Ito, A; Nixon, A; Yoshida, M; Wang, X-F; Yao, T-P
MLA Citation
Hubbert, C, Guardiola, A, Shao, R, Kawaguchi, Y, Ito, A, Nixon, A, Yoshida, M, Wang, X-F, and Yao, T-P. "HDAC6 is a microtubule-associated deacetylase." Nature 417.6887 (2002): 455-458.
PMID
12024216
Source
scival
Published In
Nature
Volume
417
Issue
6887
Publish Date
2002
Start Page
455
End Page
458
DOI
10.1038/417455a

Molecular cloning and characterization of a novel histone deacetylase HDAC10

The growing number of proteins controlled by reversible acetylation suggests the existence of a large number of acetyltransferases and deacetylases. Here, we report the identification of a novel class II histone deacetylase, HDAC10. Homology comparison indicates that HDAC10 is most similar to HDAC6. Both contain a unique, putative second catalytic domain not found in other HDACs. In HDAC10, however, this domain is not functional. This tandem organization of two catalytic domains confers resistance to the inhibitors trapoxin B and sodium butyrate, which potently inhibit the deacetylase activity of all other HDAC members. Thus, HDAC10 and HDAC6 share unusual structural and pharmacological characteristics. However, unlike HDAC6, which is normally a cytoplasmic deacetylase, HDAC10 resides in both the nucleus and cytoplasm. In the nucleus, when tethered to a promoter, HDAC10 represses transcription independent of its deacetylase activity, indicating that HDAC10 contains a distinct transcriptional repressor domain. These observations suggest that HDAC10 might uniquely play roles both in the nucleus, as a transcriptional modulator, and in the cytoplasm in an unidentified role. Together, our results identify HDAC10 as a novel deacetylase with distinct structure, pharmacology and localization and further expand the complexity of the HDAC family.

Authors
Guardiola, AR; Yao, T-P
MLA Citation
Guardiola, AR, and Yao, T-P. "Molecular cloning and characterization of a novel histone deacetylase HDAC10." Journal of Biological Chemistry 277.5 (2002): 3350-3356.
PMID
11726666
Source
scival
Published In
The Journal of biological chemistry
Volume
277
Issue
5
Publish Date
2002
Start Page
3350
End Page
3356
DOI
10.1074/jbc.M109861200

The modular nature of histone deacetylase HDAC4 confers phosphorylation-dependent intracellular trafficking.

In C2C12 myoblasts, endogenous histone deacetylase HDAC4 shuttles between cytoplasmic and nuclear compartments, supporting the hypothesis that its subcellular localization is dynamically regulated. However, upon differentiation, this dynamic equilibrium is disturbed and we find that HDAC4 accumulates in the nuclei of myotubes, suggesting a positive role of nuclear HDAC4 in muscle differentiation. Consistent with the notion of regulation of HDAC4 intracellular trafficking, we reveal that HDAC4 contains a modular structure consisting of a C-terminal autonomous nuclear export domain, which, in conjunction with an internal regulatory domain responsive to calcium/calmodulin-dependent protein kinase IV (CaMKIV), determines its subcellular localization. CaMKIV phosphorylates HDAC4 in vitro and promotes its nuclear-cytoplasmic shuttling in vivo. However, although 14-3-3 binding of HDAC4 has been proposed to be important for its cytoplasmic retention, we find this interaction to be independent of CaMKIV. Rather, the HDAC4.14-3-3 complex exists in the nucleus and is required to confer CaMKIV responsiveness. Our results suggest that the subcellular localization of HDAC4 is regulated by sequential phosphorylation events. The first event is catalyzed by a yet to be identified protein kinase that promotes 14-3-3 binding, and the second event, involving protein kinases such as CaMKIV, leads to efficient nuclear export of the HDAC4.14-3-3 complex.

Authors
Zhao, X; Ito, A; Kane, CD; Liao, TS; Bolger, TA; Lemrow, SM; Means, AR; Yao, TP
MLA Citation
Zhao, X, Ito, A, Kane, CD, Liao, TS, Bolger, TA, Lemrow, SM, Means, AR, and Yao, TP. "The modular nature of histone deacetylase HDAC4 confers phosphorylation-dependent intracellular trafficking." J Biol Chem 276.37 (September 14, 2001): 35042-35048.
PMID
11470791
Source
pubmed
Published In
The Journal of biological chemistry
Volume
276
Issue
37
Publish Date
2001
Start Page
35042
End Page
35048
DOI
10.1074/jbc.M105086200

p300/CBP-mediated p53 acetylation is commonly induced by p53-activating agents and inhibited by MDM2.

The tumor suppressor p53 is activated in response to many types of cellular and environmental insults via mechanisms involving post-translational modification. Here we demonstrate that, unlike phosphorylation, p53 invariably undergoes acetylation in cells exposed to a variety of stress-inducing agents including hypoxia, anti-metabolites, nuclear export inhibitor and actinomycin D treatment. In vivo, p53 acetylation is mediated by the p300 and CBP acetyltransferases. Overexpression of either p300 or CBP, but not an acetyltransferase-deficient mutant, efficiently induces specific p53 acetylation. In contrast, MDM2, a negative regulator of p53, actively suppresses p300/CBP-mediated p53 acetylation in vivo and in vitro. This inhibitory activity of MDM2 on p53 acetylation is in turn abrogated by tumor suppressor p19(ARF), indicating that regulation of acetylation is a central target of the p53-MDM2-p19(ARF) feedback loop. Functionally, inhibition of deacetylation promotes p53 stability, suggesting that acetylation plays a positive role in the accumulation of p53 protein in stress response. Our results provide evidence that p300/CBP-mediated acetylation may be a universal and critical modification for p53 function.

Authors
Ito, A; Lai, CH; Zhao, X; Saito, S; Hamilton, MH; Appella, E; Yao, TP
MLA Citation
Ito, A, Lai, CH, Zhao, X, Saito, S, Hamilton, MH, Appella, E, and Yao, TP. "p300/CBP-mediated p53 acetylation is commonly induced by p53-activating agents and inhibited by MDM2." EMBO J 20.6 (March 15, 2001): 1331-1340.
PMID
11250899
Source
pubmed
Published In
EMBO Journal
Volume
20
Issue
6
Publish Date
2001
Start Page
1331
End Page
1340
DOI
10.1093/emboj/20.6.1331

Role of T-bet in commitment of TH1 cells before IL- 12-dependent selection

How cytokines control differentiation of helper T (TH) cells is controversial. We show that T-bet, without apparent assistance from interleukin 12 (IL-12)/STAT4, specifies TH1 effector fate by targeting chromatin remodeling to individual interferon-γ (IFN-γ) alleles and by inducing IL-12 receptor β2 expression. Subsequently, it appears that IL- 12/STAT4 serves two essential functions in the development of TH1 cells: as growth signal, inducing survival and cell division; and as trans-activator, prolonging IFN-γ synthesis through a genetic interaction with the coactivator, CREB-binding protein. These results suggest that a cytokine does not simply induce TH fate choice but instead may act as an essential secondary stimulus that mediates selective survival of a lineage.

Authors
Mullen, AC; High, FA; Hutchins, AS; Lee, HW; Villarino, AV; Livingston, DM; Kung, AL; Cereb, N; Yao, T-P; Yang, SY; Reiner, SL
MLA Citation
Mullen, AC, High, FA, Hutchins, AS, Lee, HW, Villarino, AV, Livingston, DM, Kung, AL, Cereb, N, Yao, T-P, Yang, SY, and Reiner, SL. "Role of T-bet in commitment of TH1 cells before IL- 12-dependent selection." Science 292.5523 (2001): 1907-1910.
PMID
11397944
Source
scival
Published In
Science
Volume
292
Issue
5523
Publish Date
2001
Start Page
1907
End Page
1910
DOI
10.1126/science.1059835

Gene dose-dependent control of hematopoiesis and hematologic tumor suppression by CBP

Mice with monoallelic inactivation of the CBP gene develop highly penetrant, multilineage defects in hematopoietic differentiation and, with advancing age, an increased incidence of hematologic malignancies. The latter are characterized, at least in some cases, by loss of heterozygosity (LOH) at the CBP locus. No such pathology was observed in wild-type or p300 heterozygous null mice of the same age and genetic background. Thus, a full complement of CBP, but not p300, is required for normal hematopoietic differentiation. These results also provide the first experimental evidence for the hypothesis that CBP has tumor-suppressing activity.

Authors
Kung, AL; Rebel, VI; Bronson, RT; Ch'ng, L-E; Sieff, CA; Livingston, DM; Yao, T-P
MLA Citation
Kung, AL, Rebel, VI, Bronson, RT, Ch'ng, L-E, Sieff, CA, Livingston, DM, and Yao, T-P. "Gene dose-dependent control of hematopoiesis and hematologic tumor suppression by CBP." Genes and Development 14.3 (2000): 272-277.
PMID
10673499
Source
scival
Published In
Genes & development
Volume
14
Issue
3
Publish Date
2000
Start Page
272
End Page
277

A stimulus-specific role for CREB-binding protein (CBP) in T cell receptor-activated tumor necrosis factor α gene expression

The cAMP response element binding protein (CREB)-binding protein (CBP)/p300 family of coactivator proteins regulates gene transcription through the integration of multiple signal transduction pathways. Here, we show that induction of tumor necrosis factor α (TNF-α) gene expression in T cells stimulated by engagement of the T cell receptor (TCR) or by virus infection requires CBP/p300. Strikingly, in mice lacking one copy of the CBP gene, TNF-α gene induction by TCR activation is inhibited, whereas virus induction of the TNF-α gene is not affected. Consistent with these findings, the transcriptional activity of CBP is strongly potentiated by TCR activation but not by virus infection of T cells. Thus, CBP gene dosage and transcriptional activity are critical in TCR-dependent TNF-α gene expression, demonstrating a stimulus-specific requirement for CBP in the regulation of a specific gene.

Authors
Falvo, JV; Brinkman, BMN; Tsytsykova, AV; Tsai, EY; Yao, T-P; Kung, AL; Goldfeld, AE
MLA Citation
Falvo, JV, Brinkman, BMN, Tsytsykova, AV, Tsai, EY, Yao, T-P, Kung, AL, and Goldfeld, AE. "A stimulus-specific role for CREB-binding protein (CBP) in T cell receptor-activated tumor necrosis factor α gene expression." Proceedings of the National Academy of Sciences of the United States of America 97.8 (2000): 3925-3929.
PMID
10760264
Source
scival
Published In
Proceedings of the National Academy of Sciences of the United States of America
Volume
97
Issue
8
Publish Date
2000
Start Page
3925
End Page
3929
DOI
10.1073/pnas.97.8.3925

SMRTER, a Drosophila nuclear receptor coregulator, reveals that EcR-mediated repression is critical for development

The Drosophila ecdysone receptor (EcR)/ultraspiracle (USP) heterodimer is a key regulator in molting and metamorphoric processes, activating and repressing transcription in a sequence-specific manner. Here, we report the isolation of an EcR-interacting protein, SMRTER, which is structurally divergent but functionally similar to the vertebrate nuclear corepressors SMRT and N-CoR. SMRTER mediates repression by interacting with Sin3A, a repressor known to form a complex with the histone deacetylase Rpd3/HDAC. Importantly, we identify an EcR mutant allele that fails to bind SMRTER and is characterized by developmental defects and lethality. Together, these results reveal a novel nuclear receptor cofactor that exhibits evolutionary conservation in the mechanism to achieve repression and demonstrate the essential role of repression in hormone signaling.

Authors
Tsai, C-C; Kao, H-Y; Yao, T-P; McKeown, M; Evans, RM
MLA Citation
Tsai, C-C, Kao, H-Y, Yao, T-P, McKeown, M, and Evans, RM. "SMRTER, a Drosophila nuclear receptor coregulator, reveals that EcR-mediated repression is critical for development." Molecular Cell 4.2 (1999): 175-186.
PMID
10488333
Source
scival
Published In
Molecular Cell
Volume
4
Issue
2
Publish Date
1999
Start Page
175
End Page
186
DOI
10.1016/S1097-2765(00)80365-2

Lineage-specific signaling in melanocytes. C-kit stimulation recruits p300/CBP to microphthalmia.

During melanocyte development, the cytokine Steel factor activates its receptor c-Kit, initiating a signal transduction cascade, which is vital for lineage determination via unknown downstream nuclear targets. c-Kit has recently been found to trigger mitogen-activated protein kinase-mediated phosphorylation of Microphthalmia (Mi), a lineage-restricted transcription factor, which, like Steel factor and c-Kit, is essential for melanocyte development. This cascade results in increased Mi-dependent transcriptional reporter activity. Here we examine the mechanism by which Mi is activated by this pathway. Phosphorylation does not significantly alter Mi's nuclear localization, DNA binding, or dimerization. However, the transcriptional coactivator p300/CBP selectively associates with mitogen-activated protein kinase-phosphorylated Mi, even under conditions in which non-MAPK phospho-Mi is more abundant. Moreover, p300/CBP coactivates Mi transcriptional activity in a manner dependent upon this phosphorylation. Mi thus joins CREB as a transcription factor whose signal-responsive phosphorylation regulates coactivator recruitment, in this case modulating lineage development in melanocytes.

Authors
Price, ER; Ding, HF; Badalian, T; Bhattacharya, S; Takemoto, C; Yao, TP; Hemesath, TJ; Fisher, DE
MLA Citation
Price, ER, Ding, HF, Badalian, T, Bhattacharya, S, Takemoto, C, Yao, TP, Hemesath, TJ, and Fisher, DE. "Lineage-specific signaling in melanocytes. C-kit stimulation recruits p300/CBP to microphthalmia." J Biol Chem 273.29 (July 17, 1998): 17983-17986.
PMID
9660747
Source
pubmed
Published In
The Journal of biological chemistry
Volume
273
Issue
29
Publish Date
1998
Start Page
17983
End Page
17986

Distinct roles of the co-activators p300 and CBP in retinoic-acid- induced F9-cell differentiation

The related proteins p300 and CBP (cAMP-response-element-binding protein (CREB)-binding protein) are transcriptional co-activators that act with other factors to regulate gene expression and play roles in many cell- differentiation and signal transduction pathways. Both proteins have intrinsic histone-acetyltransferase activity and may act directly on chromatin, of which histone is a component, to facilitate transcription. They are also involved in growth control pathways, as shown by their interaction with the tumor suppressor p53 (refs 13-15) and the viral oncogenes E1A (refs 1, 2, 16) and SV40 T antigen. Here we report functional differences of p300 and CBP in vivo. We examined their roles during retinoic-acid-induced differentiation, cell-cycle exist and programmed cell death (apoptosis) of embryonal carcinoma F9 cells, using hammerhead ribozymes capable of cleaving either p300 or CBP messenger RNAs. F9 cells expressing a p300-specific ribozyme became resistant to retinoic-acid-induced differentiation, whereas cells expressing a CBP-specific ribozyme were unaffected. Similarly, retinoic-acid-induced transcriptional upregulation of the cell-cycle inhibitor p21(Cip1) required normal levels of p300, but not CBP, whereas the reverse was true for p27(Kip1). In contrast, both ribozymes blocked retinoic- acid-induced apoptosis, indicating that both co-activators are required for this process. Thus, despite their similarities, p300 and CBP have distinct functions during retinoic-acid-induced differentiation of F9 cells.

Authors
Kawasaki, H; Eckner, R; Yao, T-P; Taira, K; Chiu, R; Livingston, DM; Yokoyama, KK
MLA Citation
Kawasaki, H, Eckner, R, Yao, T-P, Taira, K, Chiu, R, Livingston, DM, and Yokoyama, KK. "Distinct roles of the co-activators p300 and CBP in retinoic-acid- induced F9-cell differentiation." Nature 393.6682 (1998): 284-289.
PMID
9607768
Source
scival
Published In
Nature
Volume
393
Issue
6682
Publish Date
1998
Start Page
284
End Page
289
DOI
10.1038/30538

Gene dosage-dependent embryonic development and proliferation defects in mice lacking the transcriptional integrator p300

The transcriptional coactivator and integrator p300 and its closely related family member CBP mediate multiple, signal-dependent transcriptional events. We have generated mice lacking a functional p300 gene. Animals nullizygous for p300 died between days 9 and 11.5 of gestation, exhibiting defects in neurulation, cell proliferation, and heart development. Cells derived from p300-deficient embryos displayed specific transcriptional defects and proliferated poorly. Surprisingly, p300 heterozygotes also manifested considerable embryonic lethality. Moreover, double heterozygosity for p300 and cbp was invariably associated with embryonic death. Thus, mouse development is exquisitely sensitive to the overall gene dosage of p300 and cbp. Our results provide genetic evidence that a coactivator endowed with histone acetyltransferase activity is essential for mammalian cell proliferation and development.

Authors
Yao, T-P; Oh, SP; Fuchs, M; Zhou, N-D; Ch'ng, L-E; Newsome, D; Bronson, RT; Li, E; Livingston, DM; Eckner, R
MLA Citation
Yao, T-P, Oh, SP, Fuchs, M, Zhou, N-D, Ch'ng, L-E, Newsome, D, Bronson, RT, Li, E, Livingston, DM, and Eckner, R. "Gene dosage-dependent embryonic development and proliferation defects in mice lacking the transcriptional integrator p300." Cell 93.3 (1998): 361-372.
PMID
9590171
Source
scival
Published In
Cell
Volume
93
Issue
3
Publish Date
1998
Start Page
361
End Page
372
DOI
10.1016/S0092-8674(00)81165-4

The nuclear hormone receptor coactivator SRC-1 is a specific target of p300

p300 and its family member, CREB-binding protein (CBP), function as key transcriptional coactivators by virtue of their interaction with the activated forms of certain transcription factors. In a search for additional cellular targets of p300/CBP, a protein-protein cloning strategy, surprisingly identified SRC-1, a coactivator involved in nuclear hormone receptor transcriptional activity, as a p300/CBP interactive protein. p300 and SRC-1 interact, specifically, in vitro and they also form complexes in vivo. Moreover, we show that SRC-1 encodes a new member of the basic helix- loop-helix-PAS domain family and that it physically interacts with the retinoic acid receptor in response to hormone binding. Together, these results implicate p300 as a component of the retinoic acid signaling pathway, operating, in part, through specific interaction with a nuclear hormone receptor coactivator, SRC-1.

Authors
Yao, T-P; Ku, G; Zhou, N; Scully, R; Livingston, DM
MLA Citation
Yao, T-P, Ku, G, Zhou, N, Scully, R, and Livingston, DM. "The nuclear hormone receptor coactivator SRC-1 is a specific target of p300." Proceedings of the National Academy of Sciences of the United States of America 93.20 (1996): 10626-10631.
PMID
8855229
Source
scival
Published In
Proceedings of the National Academy of Sciences of USA
Volume
93
Issue
20
Publish Date
1996
Start Page
10626
End Page
10631
DOI
10.1073/pnas.93.20.10626

Ecdysone-inducible gene expression in mammalian cells and transgenic mice

During metamorphosis of Drosophila melanogaster, a cascade of morphological changes is triggered by the steroid hormone 20-OH ecdysone via the ecdysone receptor, a member of the nuclear receptor superfamily. In this report, we have transferred insect hormone responsiveness to mammalian cells by the stable expression of a modified ecdysone receptor that regulates an optimized ecdysone responsive promoter. Inductions reaching 4 orders of magnitude have been achieved upon treatment with hormone. Transgenic mice expressing the modified ecdysone receptor can activate an integrated ecdysone responsive promoter upon administration of hormone. A comparison of tetracyline-based and ecdysone-based inducible systems reveals the ecdysone regulatory system exhibits lower basal activity and higher inducibility. Since ecdysone administration has no apparent effect on mammals, its use for regulating genes should be excellent for transient inducible expression of any gene in transgenic mice and for gene therapy.

Authors
No, D; Yao, T-P; Evans, RM
MLA Citation
No, D, Yao, T-P, and Evans, RM. "Ecdysone-inducible gene expression in mammalian cells and transgenic mice." Proceedings of the National Academy of Sciences of the United States of America 93.8 (1996): 3346-3351.
PMID
8622939
Source
scival
Published In
Proceedings of the National Academy of Sciences of USA
Volume
93
Issue
8
Publish Date
1996
Start Page
3346
End Page
3351
DOI
10.1073/pnas.93.8.3346

Interaction and functional collaboration of p300/CBP and bHLH proteins in muscle and B-cell differentiation

Differentiation of skeletal muscle cells and B lymphocytes is regulated by basic helix-loop-helix (bHLH) proteins. Both differentiation programs are inhibited by the adenovirus E1A oncoprotein. Analysis of E1A mutants has implicated two of its cellular-binding proteins, p300 and CBP, in controlling certain aspects of differentiation. We find that p300 can cooperate with tissue-specific bHLH proteins in activating target genes and requires only the bHLH domain of such proteins to stimulate E box-directed transcription. Importantly, the ability of bHLH proteins to activate transcription correlates with the presence of p300/CBP in E box-dependent DNA-binding complexes, because both phenomena require at least two adjacent E-box motifs. Microinjection of p300/CBP antibodies into myoblasts blocks terminal differentiation, cell fusion, and transcriptional activity of myogenic bHLH proteins. These results suggest that the function of p300/CBP is essential for the execution of key aspects of cellular differentiation.

Authors
Eckner, R; Yao, T-P; Oldread, E; Livingston, DM
MLA Citation
Eckner, R, Yao, T-P, Oldread, E, and Livingston, DM. "Interaction and functional collaboration of p300/CBP and bHLH proteins in muscle and B-cell differentiation." Genes and Development 10.19 (1996): 2478-2490.
PMID
8843199
Source
scival
Published In
Genes & development
Volume
10
Issue
19
Publish Date
1996
Start Page
2478
End Page
2490

Seven-up inhibits ultraspiracle-based signaling pathways in vitro and in vivo

Seven-up (Svp), the Drosophila homolog of the chicken ovalbumin upstream transcription factor (COUP-TF); Ultraspiracle (Usp), the Drosophila homolog of the retinoid X receptor; and the ecdysone receptor are all members of the nuclear/steroid receptor superfamily. COUP-TF negatively regulates hormonal signaling involving retinoid X receptor in tissue culture systems. Here we demonstrate that Svp, like COUP-TF, can modulate Ultraspiracle-based hormonal signaling both in vitro and in vivo. Transfection assays in CV-1 cells demonstrate that Seven-up can inhibit ecdysone-dependent transactivation by the ecdysone receptor complex, a heterodimeric complex of Usp and ecdysone receptor. This repression depends on the dose of Svp and occurs with two different Drosophila ecdysone response elements. Ectopic expression of Svp in vivo induces lethality during early metamorphosis, the time of maximal ecdysone responsiveness. Concomitant overexpression of Usp rescues the larvae from the lethal effects of Svp. DNA binding studies show that Svp can bind to various direct repeats of the sequence AGGTCA but cannot bind to one of the ecdysone response elements used in the transient transfection assays. Our results suggest that Svp-mediated repression can occur by both DNA binding competition and protein-protein interactions.

Authors
Zelhof, AC; Yao, T-P; Chen, JD; Evans, RM; McKeown, M
MLA Citation
Zelhof, AC, Yao, T-P, Chen, JD, Evans, RM, and McKeown, M. "Seven-up inhibits ultraspiracle-based signaling pathways in vitro and in vivo." Molecular and Cellular Biology 15.12 (1995): 6736-6745.
PMID
8524239
Source
scival
Published In
Molecular and Cellular Biology
Volume
15
Issue
12
Publish Date
1995
Start Page
6736
End Page
6745

Identification and characterization of a Drosophila nuclear receptor with the ability to inhibit the ecdysone response

In a search for retinoid X receptor-like molecules in Drosophila, we have identified an additional member of the nuclear receptor superfamily, XR78E/F. In the DNA-binding domain, XR78E/F is closely related to the mammalian receptor TR2, as well as to the nuclear receptors Coup-TF and Seven-up. We demonstrate that XR78E/F binds as a homodimer to direct repeats of the sequence AGGTCA. In transient transfection assays, XR78E/F represses ecdysone signaling in a DNA-binding-dependent fashion. XR78E/F has its highest expression in third-instar larvae and prepupae. These experiments suggest that XR78E/F may play a regulatory role in the transcriptional cascade triggered by the hormone ecdysone in Drosophila.

Authors
Zelhof, AC; Yao, T-P; Evans, RM; Mckeown, M
MLA Citation
Zelhof, AC, Yao, T-P, Evans, RM, and Mckeown, M. "Identification and characterization of a Drosophila nuclear receptor with the ability to inhibit the ecdysone response." Proceedings of the National Academy of Sciences of the United States of America 92.23 (1995): 10477-10481.
PMID
7479823
Source
scival
Published In
Proceedings of the National Academy of Sciences of USA
Volume
92
Issue
23
Publish Date
1995
Start Page
10477
End Page
10481
DOI
10.1073/pnas.92.23.10477

Functional ecdysone receptor is the product of EcR and Ultraspiracle genes

Although the biological activity of the insect moulting hormone ecdysone, is manifested through a hormonally regulated transcriptional cascade associated with chromosomal puffing, a direct association of the receptor with the puff has yet to be established. The cloned ecdysone receptor (EcR) is by itself incapable of high-affinity DNA binding or transcriptional activation. Rather, these activities are dependent on heterodimer formation with Ultraspiracle (USP) the insect homologue of vertebrate retinoid X receptor. Here we report that native EcR and USP are colocalized on ecdysone- responsive loci of polytene chromosomes. Moreover, we show that natural ecdysones selectively promote physical association between EcR and USP, and conversely, that high-affinity hormone binding requires both EcR and USP. Replacement of USP with retinoid X receptor produces heterodimers with distinct pharmacological and functional properties. These results redefine the ecdysone receptor as a dynamic complex whose activity may be altered by combinatorial interactions among subunits ligands.

Authors
Yao, T-P; Forman, BM; Jiang, Z; Cherbas, L; Chen, J-D; McKeown, M; Cherbas, P; Evans, RM
MLA Citation
Yao, T-P, Forman, BM, Jiang, Z, Cherbas, L, Chen, J-D, McKeown, M, Cherbas, P, and Evans, RM. "Functional ecdysone receptor is the product of EcR and Ultraspiracle genes." Nature 366.6454 (1993): 476-479.
PMID
8247157
Source
scival
Published In
Nature
Volume
366
Issue
6454
Publish Date
1993
Start Page
476
End Page
479
DOI
10.1038/366476a0

Drosophila ultraspiracle modulates ecdysone receptor function via heterodimer formation

The vertebrate retinoid X receptor (RXR) has been Implicated in the regulation of multiple hormonal signaling pathways through the formation of heteromeric receptor complexes that bind DMA with high affinity. We now demonstrate that ultraspiracle (usp), a Drosophila RXR homolog, can substitute for RXR in stimulating the DNA binding of receptors for retinoic acid, T3, vitamin D, and peroxisome proliferator activators. These observations led to the search and ultimate identification of the ecdysone receptor (EcR) as a Drosophila partner of usp. Together, usp and EcR bind DNA in a highly cooperative fashion. Cotransfection of both EcR and usp expression vectors is required to render cultured mammalian cells ecdysone responsive. These results implicate usp as an integral component of the functional EcR. By demonstrating that receptor heterodimer formation precedes the divergence of vertebrate and invertebrate lineages, these data underscore a central role for RXR and its homolog usp in the evolution and control of the nuclear receptor-based endocrine system. Copyright © 1992 by Cell Press.

Authors
Yao, T-P; Segraves, WA; Oro, AE; McKeown, M; Evans, RM
MLA Citation
Yao, T-P, Segraves, WA, Oro, AE, McKeown, M, and Evans, RM. "Drosophila ultraspiracle modulates ecdysone receptor function via heterodimer formation." Cell 71.1 (1992): 63-72.
PMID
1327536
Source
scival
Published In
Cell
Volume
71
Issue
1
Publish Date
1992
Start Page
63
End Page
72
DOI
10.1016/0092-8674(92)90266-F

Alternative translation initiation site usage results in two structurally distinct forms of Pit-1

Pit-1 is a pituitary-specific transcription factor that plays a critical role in the normal development of the anterior pituitary gland. Previous analyses have shown that this protein exists in the rat pituitary gland and in rat pituitary-derived cell lines as two forms of relative molecular mass 33 and 31 kDa. This aspect of Pit-1 expression has been conserved throughout the evolution from rodents to humans. Here, we determine the origin of these structurally distinct forms of Pit-1 protein and find that these arise as a consequence of the alternative usage of translation initiation sites present in Pit-1 mRNA.

Authors
Voss, JW; Yao, T-P; Rosenfeld, MG
MLA Citation
Voss, JW, Yao, T-P, and Rosenfeld, MG. "Alternative translation initiation site usage results in two structurally distinct forms of Pit-1." Journal of Biological Chemistry 266.20 (1991): 12832-12835.
PMID
2071572
Source
scival
Published In
Journal of Biological Chemistry
Volume
266
Issue
20
Publish Date
1991
Start Page
12832
End Page
12835
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