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Lechler, Terry H.

Overview:

My lab studies how epithelial tissues of the skin and gut are formed. We are particularly interested in the roles of the cytoskeleton, cell adhesion and cell division orientations in the development and maintenance of tissues. 

Positions:

Associate Professor in Dermatology

Dermatology
School of Medicine

Associate Professor of Cell Biology

Cell Biology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2001

Ph.D. — Harvard University

Postdoctoral Associate,

Rockefeller University

Grants:

Spindle Orientation in Skin Development and Homeostasis

Administered By
Dermatology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 01, 2015
End Date
August 31, 2020

Role of Cell Adhesion and the Cytoskeleton in Epidermal Integrity

Administered By
Dermatology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 2008
End Date
June 30, 2020

Differentiation Induced Changes in Centrosomes and Microtubule Organization

Administered By
Dermatology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 01, 2014
End Date
July 31, 2018

Cell and tissue responses to desmosome disruption

Administered By
Dermatology
AwardedBy
Dermatology Foundation
Role
Principal Investigator
Start Date
July 01, 2014
End Date
June 30, 2015

Mechanisms Driving Asymmetric Cell Division in the Epidermis

Administered By
Cell Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 2011
End Date
June 30, 2012
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Publications:

Divergent regulation of functionally distinct γ-tubulin complexes during differentiation

Authors
Muroyama, A; Seldin, L; Lechler, T
MLA Citation
Muroyama, A, Seldin, L, and Lechler, T. "Divergent regulation of functionally distinct γ-tubulin complexes during differentiation." The Journal of Cell Biology 213.6 (June 20, 2016): 679-692.
Source
crossref
Published In
The Journal of Cell Biology
Volume
213
Issue
6
Publish Date
2016
Start Page
679
End Page
692
DOI
10.1083/jcb.201601099

FRA1 promotes squamous cell carcinoma growth and metastasis through distinct AKT and c-Jun dependent mechanisms.

FRA1 (Fos-like antigen 1) is highly expressed in many epithelial cancers including squamous cell carcinoma of the skin (cSCC) and head and neck (HNSCC). However, the functional importance and the mechanisms mediating FRA1 function in these cancers are not fully understood. Here, we demonstrate that FRA1 gene silencing in HNSCC and cSCC cells resulted in two consequences - impaired cell proliferation and migration. FRA1 regulation of cell growth was distinct from that of c-Jun, a prominent Jun group AP-1 factor. While c-Jun was required for the expression of the G1/S phase cell cycle promoter CDK4, FRA1 was essential for AKT activation and AKT-dependent expression of CyclinB1, a molecule required for G2-M progression. Exogenous expression of a constitutively active form of AKT rescued cancer cell growth defect caused by FRA1-loss. Additionally, FRA1 knockdown markedly slowed cell adhesion and migration, and conversely expression of an active FRA1 mutant (FRA1DD) expedited these processes in a JNK/c-Jun-dependent manner. Through protein and ChIP-PCR analyses, we identified KIND1, a cytoskeletal regulator of the cell adhesion molecule β1-integrin, as a novel FRA1 transcriptional target. Restoring KIND1 expression rescued migratory defects induced by FRA1 loss. In agreement with these in vitro data, HNSCC cells with FRA1 loss displayed markedly reduced rates of subcutaneous tumor growth and pulmonary metastasis. Together, these results indicate that FRA1 promotes cancer growth through AKT, and enhances cancer cell migration through JNK/c-Jun, pinpointing FRA1 as a key integrator of JNK and AKT signaling pathways and a potential therapeutic target for cSCC and HNSCC.

Authors
Zhang, X; Wu, J; Luo, S; Lechler, T; Zhang, JY
MLA Citation
Zhang, X, Wu, J, Luo, S, Lechler, T, and Zhang, JY. "FRA1 promotes squamous cell carcinoma growth and metastasis through distinct AKT and c-Jun dependent mechanisms." Oncotarget 7.23 (June 2016): 34371-34383.
PMID
27144339
Source
epmc
Published In
Oncotarget
Volume
7
Issue
23
Publish Date
2016
Start Page
34371
End Page
34383
DOI
10.18632/oncotarget.9110

NuMA-microtubule interactions are critical for spindle orientation and the morphogenesis of diverse epidermal structures

© Seldin et al.Mitotic spindle orientation is used to generate cell fate diversity and drive proper tissue morphogenesis. A complex of NuMA and dynein/dynactin is required for robust spindle orientation in a number of cell types. Previous research proposed that cortical dynein/dynactin was sufficient to generate forces on astral microtubules (MTs) to orient the spindle, with NuMA acting as a passive tether. In this study, we demonstrate that dynein/dynactin is insufficient for spindle orientation establishment in keratinocytes and that NuMA’s MT-binding domain, which targets MT tips, is also required. Loss of NuMA-MT interactions in skin caused defects in spindle orientation and epidermal differentiation, leading to neonatal lethality. In addition, we show that NuMA-MT interactions are also required in adult mice for hair follicle morphogenesis and spindle orientation within the transit-amplifying cells of the matrix. Loss of spindle orientation in matrix cells results in defective differentiation of matrix-derived lineages. Our results reveal an additional and direct function of NuMA during mitotic spindle positioning, as well as a reiterative use of spindle orientation in the skin to build diverse structures.

Authors
Seldin, L; Muroyama, A; Lechler, T
MLA Citation
Seldin, L, Muroyama, A, and Lechler, T. "NuMA-microtubule interactions are critical for spindle orientation and the morphogenesis of diverse epidermal structures." eLife 5.JANUARY2016 (January 14, 2016).
Source
scopus
Published In
eLife
Volume
5
Issue
JANUARY2016
Publish Date
2016
DOI
10.7554/eLife.12504.001

Studying cell biology in the skin

Authors
Morrow, A; Lechler, T
MLA Citation
Morrow, A, and Lechler, T. "Studying cell biology in the skin." Molecular Biology of the Cell 26.23 (November 15, 2015): 4183-4186.
Source
crossref
Published In
Molecular Biology of the Cell
Volume
26
Issue
23
Publish Date
2015
Start Page
4183
End Page
4186
DOI
10.1091/mbc.E15-04-0246

The Arp2/3 complex has essential roles in vesicle trafficking and transcytosis in the mammalian small intestine

Authors
Zhou, K; Sumigray, KD; Lechler, T
MLA Citation
Zhou, K, Sumigray, KD, and Lechler, T. "The Arp2/3 complex has essential roles in vesicle trafficking and transcytosis in the mammalian small intestine." Molecular Biology of the Cell 26.11 (June 1, 2015): 1995-2004.
Source
crossref
Published In
Molecular Biology of the Cell
Volume
26
Issue
11
Publish Date
2015
Start Page
1995
End Page
2004
DOI
10.1091/mbc.E14-10-1481

Cell adhesion in epidermal development and barrier formation.

Cell-cell adhesions are necessary for structural integrity and barrier formation of the epidermis. Here, we discuss insights from genetic and cell biological studies into the roles of individual cell-cell junctions and their composite proteins in regulating epidermal development and function. In addition to individual adhesive functions, we will discuss emerging ideas on mechanosensation/transduction of junctions in the epidermis, noncanonical roles for adhesion proteins, and crosstalk/interdependencies between the junctional systems. These studies have revealed that cell adhesion proteins are connected to many aspects of tissue physiology including growth control, differentiation, and inflammation.

Authors
Sumigray, KD; Lechler, T
MLA Citation
Sumigray, KD, and Lechler, T. "Cell adhesion in epidermal development and barrier formation." Current topics in developmental biology 112 (January 2015): 383-414. (Review)
PMID
25733147
Source
epmc
Published In
Current topics in developmental biology
Volume
112
Publish Date
2015
Start Page
383
End Page
414
DOI
10.1016/bs.ctdb.2014.11.027

Arp2/3 complex function in the epidermis

Authors
Lechler, T
MLA Citation
Lechler, T. "Arp2/3 complex function in the epidermis." Tissue Barriers 2.4 (August 8, 2014): e944445-e944445.
Source
crossref
Published In
Tissue Barriers
Volume
2
Issue
4
Publish Date
2014
Start Page
e944445
End Page
e944445
DOI
10.4161/21688362.2014.944445

Developmental stratification of the mammary epithelium occurs through symmetry-breaking vertical divisions of apically positioned luminal cells.

Mammary ducts are elongated during development by stratified epithelial structures, known as terminal end buds (TEBs). TEBs exhibit reduced apicobasal polarity and extensive proliferation. A major unanswered question concerns the mechanism by which the simple ductal epithelium stratifies during TEB formation. We sought to elucidate this mechanism using real-time imaging of growth factor-induced stratification in 3D cultures of mouse primary epithelial organoids. We hypothesized that stratification could result from vertical divisions in either the apically positioned luminal epithelial cells or the basally positioned myoepithelial cells. Stratification initiated exclusively from vertical apical cell divisions, both in 3D culture and in vivo. During vertical apical divisions, only the mother cell retained tight junctions and segregated apical membranes. Vertical daughter cells initiated an unpolarized cell population located between the luminal and myoepithelial cells, similar to the unpolarized body cells in the TEB. As stratification and loss of apicobasal polarity are early hallmarks of cancer, we next determined the cellular mechanism of oncogenic stratification. Expression of activated ERBB2 induced neoplastic stratification through analogous vertical divisions of apically positioned luminal epithelial cells. However, ERBB2-induced stratification was accompanied by tissue overgrowth and acute loss of both tight junctions and apical polarity. Expression of phosphomimetic MEK (MEK1DD), a major ERBB2 effector, also induced stratification through vertical apical cell divisions. However, MEK1DD-expressing organoids exhibited normal levels of growth and retained apicobasal polarity. We conclude that both normal and neoplastic stratification are accomplished through receptor tyrosine kinase signaling dependent vertical cell divisions within the luminal epithelial cell layer.

Authors
Huebner, RJ; Lechler, T; Ewald, AJ
MLA Citation
Huebner, RJ, Lechler, T, and Ewald, AJ. "Developmental stratification of the mammary epithelium occurs through symmetry-breaking vertical divisions of apically positioned luminal cells." Development (Cambridge, England) 141.5 (March 2014): 1085-1094.
PMID
24550116
Source
epmc
Published In
Development (Cambridge)
Volume
141
Issue
5
Publish Date
2014
Start Page
1085
End Page
1094
DOI
10.1242/dev.103333

Cell-cell adhesions and cell contractility are upregulated upon desmosome disruption.

Desmosomes are perturbed in a number of disease states - including genetic disorders, autoimmune and bacterial diseases. Here, we report unexpected changes in other cell-cell adhesion structures upon loss of desmosome function. We found that perturbation of desmosomes by either loss of the core desmosomal protein desmoplakin or treatment with pathogenic anti-desmoglein 3 (Dsg3) antibodies resulted in changes in adherens junctions consistent with increased tension. The total amount of myosin IIA was increased in desmoplakin-null epidermis, and myosin IIA became highly localized to cell contacts in both desmoplakin-null and anti-Dsg3-treated mouse keratinocytes. Inhibition of myosin II activity reversed the changes to adherens junctions seen upon desmosome disruption. The increased cortical myosin IIA promoted epithelial sheet fragility, as myosin IIA-null cells were less susceptible to disruption by anti-Dsg3 antibodies. In addition to the changes in adherens junctions, we found a significant increase in the expression of a number of claudin genes, which encode for transmembrane components of the tight junction that provide barrier function. These data demonstrate that desmosome disruption results in extensive transcriptional and posttranslational changes that alter the activity of other cell adhesion structures.

Authors
Sumigray, K; Zhou, K; Lechler, T
MLA Citation
Sumigray, K, Zhou, K, and Lechler, T. "Cell-cell adhesions and cell contractility are upregulated upon desmosome disruption." PloS one 9.7 (January 2014): e101824-.
PMID
25006807
Source
epmc
Published In
PloS one
Volume
9
Issue
7
Publish Date
2014
Start Page
e101824
DOI
10.1371/journal.pone.0101824

Actin-related protein2/3 complex regulates tight junctions and terminal differentiation to promote epidermal barrier formation.

The epidermis provides an essential seal from the external environment and retains fluids within the body. To form an effective barrier, cells in the epidermis must form tight junctions and terminally differentiate into cornified envelopes. Here, we demonstrate that the branched actin nucleator, the actin-related protein (Arp)2/3 complex, is unexpectedly required for both these activities. Loss of the ArpC3 subunit of the Arp2/3 complex resulted in minimal changes in the morphogenesis and architecture of this stratified squamous epithelium, but resulted in profound defects in its physiology. Mutant embryos did not develop an effective barrier to the external environment and died within hours of birth. We discovered two underlying causes for these effects. First, ArpC3 was essential for robust assembly and function of tight junctions, specialized cell-cell adhesions that restrict water loss in the epidermis. Second, there were defects in differentiation of the epidermis and the production of cornified envelopes, structures essential for barrier activity. Underlying this defect, we found that YAP was inappropriately active not only in the ArpC3 mutant tissue, but also in cultured cells. Inhibition of YAP activity rescued the differentiation and barrier defects caused by loss of ArpC3. These results demonstrate previously unappreciated roles for the Arp2/3 complex and highlight the functions of branched actin networks in a complex tissue.

Authors
Zhou, K; Muroyama, A; Underwood, J; Leylek, R; Ray, S; Soderling, SH; Lechler, T
MLA Citation
Zhou, K, Muroyama, A, Underwood, J, Leylek, R, Ray, S, Soderling, SH, and Lechler, T. "Actin-related protein2/3 complex regulates tight junctions and terminal differentiation to promote epidermal barrier formation." Proc Natl Acad Sci U S A 110.40 (October 1, 2013): E3820-E3829.
PMID
24043783
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
110
Issue
40
Publish Date
2013
Start Page
E3820
End Page
E3829
DOI
10.1073/pnas.1308419110

FRAP analysis reveals stabilization of adhesion structures in the epidermis compared to cultured keratinocytes.

Proper development and tissue maintenance requires cell-cell adhesion structures, which serve diverse and crucial roles in tissue morphogenesis. Epithelial tissues have three main types of cell-cell junctions: tight junctions, which play a major role in barrier formation, and adherens junctions and desmosomes, which provide mechanical stability and organize the underlying cytoskeleton. Our current understanding of adhesion function is hindered by a lack of tools and methods to image junctions in mammals. To better understand the dynamics of adhesion in tissues we have created a knock-in ZO-1-GFP mouse and a BAC-transgenic mouse expressing desmoplakin I-GFP. We performed fluorescence recovery after photobleaching (FRAP) experiments to quantify the turnover rates of the tight junction protein ZO-1, the adherens junction protein E-cadherin, and the desmosomal protein desmoplakin in the epidermis. Proteins at each type of junction are remarkably stable in the epidermis, in contrast to the high observed mobility of E-cadherin and ZO-1 at adherens junctions and tight junctions, respectively, in cultured cells. Our data demonstrate that there are additional mechanisms for stabilizing junctions in tissues that are not modeled by cell culture.

Authors
Foote, HP; Sumigray, KD; Lechler, T
MLA Citation
Foote, HP, Sumigray, KD, and Lechler, T. "FRAP analysis reveals stabilization of adhesion structures in the epidermis compared to cultured keratinocytes." PloS one 8.8 (January 2013): e71491-.
PMID
23977053
Source
epmc
Published In
PloS one
Volume
8
Issue
8
Publish Date
2013
Start Page
e71491
DOI
10.1371/journal.pone.0071491

NuMA localization, stability, and function in spindle orientation involve 4.1 and Cdk1 interactions

The epidermis is a multilayered epithelium that requires asymmetric divisions for stratification. A conserved cortical protein complex, including LGN, nuclear mitotic apparatus (NuMA), and dynein/dynactin, plays a key role in establishing proper spindle orientation during asymmetric divisions. The requirements for the cortical recruitment of these proteins, however, remain unclear. In this work, we show that NuMA is required to recruit dynactin to the cell cortex of keratinocytes. NuMA's cortical recruitment requires LGN; however, LGN interactions are not sufficient for this localization. Using fluorescence recovery after photobleaching, we find that the 4.1-binding domain of NuMA is important for stabilizing its interaction with the cell cortex. This is functionally important, as loss of 4.1/NuMA interaction results in spindle orientation defects, using two distinct assays. Furthermore, we observe an increase in cortical NuMA localization as cells enter anaphase. Inhibition of Cdk1 or mutation of a single residue in NuMA mimics this effect. NuMA's anaphase localization is independent of LGN and 4.1 interactions, revealing two distinct mechanisms responsible for NuMA cortical recruitment at different stages of mitosis. This work highlights the complexity of NuMA localization and reveals the importance of NuMA cortical stability for productive force generation during spindle orientation. © 2013 Polka and Silver. This article is distributed by The American Society for Cell Biology under license from the author(s).

Authors
Seldin, L; Poulson, ND; Foote, HP; Lechler, T
MLA Citation
Seldin, L, Poulson, ND, Foote, HP, and Lechler, T. "NuMA localization, stability, and function in spindle orientation involve 4.1 and Cdk1 interactions." Molecular Biology of the Cell 24.23 (2013): 3651-3662.
PMID
24109598
Source
scival
Published In
Molecular Biology of the Cell
Volume
24
Issue
23
Publish Date
2013
Start Page
3651
End Page
3662
DOI
10.1091/mbc.E13-05-0277

β-Catenin protects the epidermis from mechanical stresses

Many tissues in our body experience mechanical stresses caused by both internal and external forces. The skin, for example, must tolerate diverse mechanical insults. In this paper, we report a role for β-catenin in providing stability to epithelia under stress. Loss of β-catenin during epidermal development caused perinatal lethality. Mutant embryos up-regulated stress responses at sites of active morphogenesis, which became more widespread after the stresses associated with birth. In addition, selective loss of tight junctions occurred in focal regions. This was recapitulated in cultured β-catenin-null cells exposed to externally applied forces. In addition, mutant cells were defective in tensioninduced engagement of adherens junctions. We found that β-catenin was required to recruit vinculin to the cell cortex and to strengthen the junction's association with the underlying cytoskeleton in response to tension. These data demonstrate that a complete understanding of the functions of cell adhesion proteins must take into account their roles in response to mechanical stresses. © 2013 Ray et al.

Authors
Ray, S; Foote, HP; Lechler, T
MLA Citation
Ray, S, Foote, HP, and Lechler, T. "β-Catenin protects the epidermis from mechanical stresses." Journal of Cell Biology 202.1 (2013): 45-52.
PMID
23816618
Source
scival
Published In
The Journal of Cell Biology
Volume
202
Issue
1
Publish Date
2013
Start Page
45
End Page
52
DOI
10.1083/jcb.201212140

Adherens junctions and stem cells.

The specification, maintenance, division and differentiation of stem cells are integral to the development and homeostasis of many tissues. These stem cells often live in specialized anatomical areas, called niches. While niches can be complex, most involve cell-cell interactions that are mediated by adherens junctions. A diverse array of functions have been attributed to adherens junctions in stem cell biology. These include physical anchoring to the niche, control of proliferation and division orientation, regulation of signaling cascades and of differentiation. In this review, a number of model stem cell systems that highlight various functions of adherens junctions are discussed. In addition, a summary of the current understanding of adherens junction function in mammalian tissues and embryonic and induced pluripotent stem cells is provided. This analysis demonstrates that the roles of adherens junctions are surprisingly varied and integrated with both the anatomy and the physiology of the tissue.

Authors
Lechler, T
MLA Citation
Lechler, T. "Adherens junctions and stem cells." Sub-cellular biochemistry 60 (January 2012): 359-377. (Review)
PMID
22674079
Source
epmc
Published In
Sub-Cellular Biochemistry
Volume
60
Publish Date
2012
Start Page
359
End Page
377
DOI
10.1007/978-94-007-4186-7_15

Noncentrosomal microtubules and type II myosins potentiate epidermal cell adhesion and barrier formation

During differentiation, many cells reorganize their microtubule cytoskeleton into noncentrosomal arrays. Although these microtubules are likely organized to meet the physiological roles of their tissues, their functions in most cell types remain unexplored. In the epidermis, differentiation induces the reorganization of microtubules to cell-cell junctions in a desmosomedependent manner. Here, we recapitulate the reorganization of microtubules in cultured epidermal cells. Using this reorganization assay, we show that cortical microtubules recruit myosin II to the cell cortex in order to engage adherens junctions, resulting in an increase in mechanical integrity of the cell sheets. Cortical microtubules and engaged adherens junctions, in turn, increase tight junction function. In vivo, disruption of microtubules or loss of myosin IIA and B resulted in loss of tight junction-mediated barrier activity. We propose that noncentrosomal microtubules act through myosin II recruitment to potentiate cell adhesion in the differentiating epidermis, thus forming a robust mechanical and chemical barrier against the external environment. © 2012 Sumigray et al.

Authors
Sumigray, KD; Foote, HP; Lechler, T
MLA Citation
Sumigray, KD, Foote, HP, and Lechler, T. "Noncentrosomal microtubules and type II myosins potentiate epidermal cell adhesion and barrier formation." Journal of Cell Biology 199.3 (2012): 513-525.
PMID
23091070
Source
scival
Published In
The Journal of Cell Biology
Volume
199
Issue
3
Publish Date
2012
Start Page
513
End Page
525
DOI
10.1083/jcb.201206143

Polarity and stratification of the epidermis

Polarity is a fundamental property of epithelial cells. In this review, we discuss our current knowledge of the polarity of a stratified epithelium, the epidermis, focusing on similarities and differences with simple epithelial models. We highlight how the differences in tissue architecture and physiology result in alterations in some aspects of cell polarity. In addition, we discuss one of the most prominent uses for cell polarity in the epidermis-orienting the mitotic spindle to drive the stratification and differentiation of this tissue during development. © 2012 Elsevier Ltd.

Authors
Muroyama, A; Lechler, T
MLA Citation
Muroyama, A, and Lechler, T. "Polarity and stratification of the epidermis." Seminars in Cell and Developmental Biology 23.8 (2012): 890-896.
PMID
22960184
Source
scival
Published In
Seminars in Cell and Developmental Biology
Volume
23
Issue
8
Publish Date
2012
Start Page
890
End Page
896
DOI
10.1016/j.semcdb.2012.08.008

Desmoplakin controls microvilli length but not cell adhesion or keratin organization in the intestinal epithelium

Maintaining proper cell-cell adhesion in the intestine is essential for tissue homeostasis and barrier function. This adhesion is thought to be mediated by cell adhesion structures, including tight junctions, adherens junctions, and desmosomes, which concentrate in the apical junctional region. While clear roles for adherens and tight junctions have been established in simple epithelia, the function of desmosomes has not been addressed. In stratified epithelia, desmosomes impart mechanical strength to tissues by organizing and anchoring the keratin filament network. In this paper, we report that the desmosomal protein desmoplakin (DP) is not essential for cell adhesion in the intestinal epithelium. Surprisingly, when DP is lacking, keratin filament localization is also unperturbed, although keratin filaments no longer anchor at desmosomes. Unexpectedly, DP is important for proper microvillus structure. Our study highlights the tissue-specific functions of desmosomes and reveals that the canonical functions for these structures are not conserved in simple epithelium. © 2012 Sumigray and Lechler.

Authors
Sumigray, KD; Lechler, T
MLA Citation
Sumigray, KD, and Lechler, T. "Desmoplakin controls microvilli length but not cell adhesion or keratin organization in the intestinal epithelium." Molecular Biology of the Cell 23.5 (2012): 792-799.
PMID
22238362
Source
scival
Published In
Molecular Biology of the Cell
Volume
23
Issue
5
Publish Date
2012
Start Page
792
End Page
799
DOI
10.1091/mbc.E11-11-0923

Asymmetric Cell Divisions in the Epidermis

Generation of three-dimensional tissues with distinct cell types is required for the development of all organs. On its own, mitotic spindle orientation allows tissues to change in length or shape. In combination with intrinsic or extrinsic cues, this can also be coupled to the generation of diverse cell fates-a process known as asymmetric cell division (ACD). Understanding ACDs has been greatly aided by studies in invertebrate model systems, where genetics and live imaging have provided the basis for much of what we know. ACDs also drive the development and differentiation of the epidermis in mammals. While similar to the invertebrate models, the epidermis is distinct in balancing symmetric and asymmetric divisions to yield a tissue of the correct surface area and thickness. Here, we review the roles of spindle orientation in driving both morphogenesis and cell fate decisions. We highlight the epidermis as a unique model system to study not only basic mechanisms of ACD but also their regulation during development. © 2012 Elsevier Inc..

Authors
Poulson, ND; Lechler, T
MLA Citation
Poulson, ND, and Lechler, T. "Asymmetric Cell Divisions in the Epidermis." International Review of Cell and Molecular Biology 295 (2012): 199-232.
PMID
22449491
Source
scival
Published In
International review of cell and molecular biology
Volume
295
Publish Date
2012
Start Page
199
End Page
232
DOI
10.1016/B978-0-12-394306-4.00012-5

Lis1 is essential for cortical microtubule organization and desmosome stability in the epidermis

Desmosomes are cell-cell adhesion structures that integrate cytoskeletal networks. In addition to binding intermediate filaments, the desmosomal protein desmoplakin (DP) regulates microtubule reorganization in the epidermis. In this paper, we identify a specific subset of centrosomal proteins that are recruited to the cell cortex by DP upon epidermal differentiation. These include Lis1 and Ndel1, which are centrosomal proteins that regulate microtubule organization and anchoring in other cell types. This recruitment was mediated by a region of DP specific to a single isoform, DPI. Furthermore, we demonstrate that the epidermal-specific loss of Lis1 results in dramatic defects in microtubule reorganization. Lis1 ablation also causes desmosomal defects, characterized by decreased levels of desmosomal components, decreased attachment of keratin filaments, and increased turnover of desmosomal proteins at the cell cortex. This contributes to loss of epidermal barrier activity, resulting in completely penetrant perinatal lethality. This work reveals essential desmosome-associated components that control cortical microtubule organization and unexpected roles for centrosomal proteins in epidermal function. © 2011 Sumigray et al.

Authors
Sumigray, KD; Chen, H; Lechler, T
MLA Citation
Sumigray, KD, Chen, H, and Lechler, T. "Lis1 is essential for cortical microtubule organization and desmosome stability in the epidermis." Journal of Cell Biology 194.4 (2011): 631-642.
PMID
21844209
Source
scival
Published In
The Journal of Cell Biology
Volume
194
Issue
4
Publish Date
2011
Start Page
631
End Page
642
DOI
10.1083/jcb.201104009

Regulation of asymmetric cell division in the epidermis

For proper tissue morphogenesis, cell divisions and cell fate decisions must be tightly and coordinately regulated. One elegant way to accomplish this is to couple them with asymmetric cell divisions. Progenitor cells in the developing epidermis undergo both symmetric and asymmetric cell divisions to balance surface area growth with the generation of differentiated cell layers. Here we review the molecular machinery implicated in controlling asymmetric cell division. In addition, we discuss the ability of epidermal progenitors to choose between symmetric and asymmetric divisions and the key regulatory points that control this decision. © 2011 Ray and Lechler; licensee BioMed Central Ltd.

Authors
Ray, S; Lechler, T
MLA Citation
Ray, S, and Lechler, T. "Regulation of asymmetric cell division in the epidermis." Cell Division 6 (2011).
Source
scival
Published In
Cell Division
Volume
6
Publish Date
2011
DOI
10.1186/1747-1028-6-12

Robust control of mitotic spindle orientation in the developing epidermis

Progenitor cells must balance self-amplification and production of differentiated progeny during development and homeostasis. In the epidermis, progenitors divide symmetrically to increase surface area and asymmetrically to promote stratification. In this study, we show that individual epidermal cells can undergo both types of division, and therefore, the balance is provided by the sum of individual cells' choices. In addition, we define two control points for determining a cell's mode of division. First is the expression of the mouse Inscuteable gene, which is sufficient to drive asymmetric cell division (ACD). However, there is robust control of division orientation as excessive ACDs are prevented by a change in the localization of NuMA, an effector of spindle orientation. Finally, we show that p63, a transcriptional regulator of stratification, does not control either of these processes. These data have uncovered two important regulatory points controlling ACD in the epidermis and allow a framework for analysis of how external cues control this important choice. © 2010 Poulson and Lechler.

Authors
Poulson, ND; Lechler, T
MLA Citation
Poulson, ND, and Lechler, T. "Robust control of mitotic spindle orientation in the developing epidermis." Journal of Cell Biology 191.5 (2010): 915-922.
PMID
21098114
Source
scival
Published In
The Journal of Cell Biology
Volume
191
Issue
5
Publish Date
2010
Start Page
915
End Page
922
DOI
10.1083/jcb.201008001

Dissecting cell adhesion cross-talk with micropatterns

Authors
Sumigray, KD; Lechler, T
MLA Citation
Sumigray, KD, and Lechler, T. "Dissecting cell adhesion cross-talk with micropatterns." Proceedings of the National Academy of Sciences of the United States of America 107.30 (2010): 13199-13200.
PMID
20639470
Source
scival
Published In
Proceedings of the National Academy of Sciences of USA
Volume
107
Issue
30
Publish Date
2010
Start Page
13199
End Page
13200
DOI
10.1073/pnas.1008253107

Limiting lumens: A new role for Cdc42

The formation of a single lumen is a necessary step in the formation of biological tubes. Different tissues have developed diverse ways to form their lumens. In this issue, Jaffe et al. (Jaffe, A.B., N. Kaji, J. Durgan, and A. Hall. 2008. J. Cell Biol. 183:625 - 633) report the development of an in vitro system for studying lumen formation that is driven by fl uid transport, recapitulating intestinal lumen formation. Effective ion and fl uid transport requires both cell polarity and proper tissue organization. Surprisingly, polarization of cells in this three-dimensional system does not require Cdc42. Instead, Cdc42 prevents formation of multiple lumens by orienting cell divisions and directing apical membrane biogenesis. © 2008 Lechler.

Authors
Lechler, T
MLA Citation
Lechler, T. "Limiting lumens: A new role for Cdc42." Journal of Cell Biology 183.4 (2008): 575-577.
PMID
19001130
Source
scival
Published In
The Journal of Cell Biology
Volume
183
Issue
4
Publish Date
2008
Start Page
575
End Page
577
DOI
10.1083/jcb.200809174

Terry Lechler: The cytoskeleton is skin deep

Authors
Lechler, T
MLA Citation
Lechler, T. "Terry Lechler: The cytoskeleton is skin deep." Journal of Cell Biology 178.4 (2007): 546-547.
PMID
17698603
Source
scival
Published In
The Journal of Cell Biology
Volume
178
Issue
4
Publish Date
2007
Start Page
546
End Page
547
DOI
10.1083/jcb.1784pi

Desmoplakin: An unexpected regulator of microtubule organization in the epidermis

Despite their importance in cell shape and polarity generation, the organization of microtubules in differentiated cells and tissues remains relatively unexplored in mammals. We generated transgenic mice in which the epidermis expresses a fl uorescently labeled microtubule-binding protein and show that in epidermis and in cultured keratinocytes, microtubules stereotypically reorganize as they differentiate. In basal cells, microtubules form a cytoplasmic network emanating from an apical centrosome. In suprabasal cells, microtubules concentrate at cell-cell junctions. The centrosome retains its ability to nucleate microtubules in differentiated cells, but no longer anchors them. During epidermal differentiation, ninein, which is a centrosomal protein required for microtubule anchoring (Dammermann, A., and A. Merdes. 2002. J. Cell Biol. 159:255-266; Delgehyr, N., J. Sillibourne, and M. Bornens. 2005. J. Cell Sci. 118:1565-1575; Mogensen, M.M., A. Malik, M. Piel, V. Bouckson-Castaing, and M. Bornens. 2000. J. Cell Sci. 113:3013-3023), is lost from the centrosome and is recruited to desmosomes by desmoplakin (DP). Loss of DP prevents accumulation of cortical microtubules in vivo and in vitro. Our work uncovers a differentiation-specific rearrangement of the microtubule cytoskeleton in epidermis, and defines an essential role for DP in the process. © The Rockefeller University Press.

Authors
Lechler, T; Fuchs, E
MLA Citation
Lechler, T, and Fuchs, E. "Desmoplakin: An unexpected regulator of microtubule organization in the epidermis." Journal of Cell Biology 176.2 (2007): 147-154.
PMID
17227889
Source
scival
Published In
The Journal of Cell Biology
Volume
176
Issue
2
Publish Date
2007
Start Page
147
End Page
154
DOI
10.1083/jcb.200609109

Asymmetric cell divisions promote stratification and differentiation of mammalian skin

The epidermis is a stratified squamous epithelium forming the barrier that excludes harmful microbes and retains body fluids. To perform these functions, proliferative basal cells in the innermost layer periodically detach from an underlying basement membrane of extracellular matrix, move outward and eventually die. Once suprabasal, cells stop dividing and enter a differentiation programme to form the barrier. The mechanism of stratification is poorly understood. Although studies in vitro have led to the view that stratification occurs through the delamination and subsequent movement of epidermal cells, most culture conditions favour keratinocytes that lack the polarity and cuboidal morphology of basal keratinocytes in tissue. These features could be important in considering an alternative mechanism, that stratification occurs through asymmetric cell divisions in which the mitotic spindle orients perpendicularly to the basement membrane. Here we show that basal epidermal cells use their polarity to divide asymmetrically, generating a committed suprabasal cell and a proliferative basal cell. We further demonstrate that integrins and cadherins are essential for the apical localization of atypical protein kinase C, the Par3-LGN-Inscuteable complex and NuMA-dynactin to align the spindle. © 2005 Nature Publishing Group.

Authors
Lechler, T; Fuchs, E
MLA Citation
Lechler, T, and Fuchs, E. "Asymmetric cell divisions promote stratification and differentiation of mammalian skin." Nature 437.7056 (2005): 275-280.
PMID
16094321
Source
scival
Published In
Nature
Volume
437
Issue
7056
Publish Date
2005
Start Page
275
End Page
280
DOI
10.1038/nature03922

Conditional targeting of E-cadherin in skin: Insights into hyperproliferative and degenerative responses

Loss of E-cadherin has been associated with human cancers, and yet in the early mouse embryo and the lactating mammary gland, the E-cadherin null state results in tissue dysfunction and cell death. Here we targeted loss of E-cadherin in skin epithelium. The epidermal basal layer responded by elevating P-cadherin, enabling these cells to maintain adherens junctions. Suprabasal layers up-regulated desmosomal cadherins, but without classical cadherins, terminal differentiation was impaired. Progressive hyperplasia developed with age, a possible consequence of proliferative maintenance in basal cells coupled with defects in terminal differentiation. In contrast, hair follicles lost integrity of the inner root sheath and hair cuticle without apparent elevation of cadherins. These findings suggest that, if no compensatory mechanisms exist, E-cadherin loss may be incompatible with epithelial tissue survival, whereas partial compensation can result in alterations in differentiation and proliferation.

Authors
Tinkle, CL; Lechler, T; Pasolli, HA; Fuchs, E
MLA Citation
Tinkle, CL, Lechler, T, Pasolli, HA, and Fuchs, E. "Conditional targeting of E-cadherin in skin: Insights into hyperproliferative and degenerative responses." Proceedings of the National Academy of Sciences of the United States of America 101.2 (2004): 552-557.
PMID
14704278
Source
scival
Published In
Proceedings of the National Academy of Sciences of the United States of America
Volume
101
Issue
2
Publish Date
2004
Start Page
552
End Page
557
DOI
10.1073/pnas.0307437100

Coordinating cytoskeletal tracks to polarize cellular movements

For many years after the discovery of actin filaments and microtubules, it was widely assumed that their polymerization, organization, and functions were largely distinct. However, in recent years it has become increasingly apparent that coordinated interactions between microtubules and filamentous actin are involved in many polarized processes, including cell shape, mitotic spindle orientation, motility, growth cone guidance, and wound healing. In the past few years, significant strides have been made in unraveling the intricacies that govern these intertwined cytoskeletal rearrangements.

Authors
Kodama, A; Lechler, T; Fuchs, E
MLA Citation
Kodama, A, Lechler, T, and Fuchs, E. "Coordinating cytoskeletal tracks to polarize cellular movements." Journal of Cell Biology 167.2 (2004): 203-207.
PMID
15504907
Source
scival
Published In
Journal of Cell Biology
Volume
167
Issue
2
Publish Date
2004
Start Page
203
End Page
207
DOI
10.1083/jcb.200408047

Rapid de-localization of actin leading edge components with BDM treatment

Background: 2,3-Butanedione monoxime (BDM) has been widely used as a non-muscle myosin inhibitor to investigate the role of non-muscle myosinII in the process of actin retrograde flow and other actin cytoskeletal processes. Recent reports show that BDM does not inhibit any non-muscle myosins so far tested, including nm-myosinII, prompting the question, how were these process affected in BDM studies? Results: We have found that treatment of mammalian cells with BDM for only 1 min blocks actin incorporation at the leading edge in a permeabilized cell system. We show that inhibition of actin incorporation occurs through de-localization of leading edge proteins involved in actin polymerization - the Arp2/3 complex, WAVE, and VASP - that de-localize concomitantly with the leading edge actin network. Conclusion: De-localization of actin leading edge components by BDM treatment is a newly described effect of this compound. It may explain many of the results previously ascribed to inhibition of non-muscle myosinII by BDM, particularly in studies of leading edge dynamics. Though this effect of BDM is intriguing, future studies probing actin dynamics at the leading edge should use more potent and specific inhibitors. © 2003 Yarrow et al; lecensee BioMed Central Ltd.

Authors
Yarrow, JC; Lechler, T; Li, R; Mitchison, TJ
MLA Citation
Yarrow, JC, Lechler, T, Li, R, and Mitchison, TJ. "Rapid de-localization of actin leading edge components with BDM treatment." BMC Cell Biology 4 (2003).
PMID
12783627
Source
scival
Published In
BMC Cell Biology
Volume
4
Publish Date
2003
DOI
10.1186/1471-2121-4-5

Saccharomyces cerevisiae Bzz1p is implicated with type I myosins in actin patch polarization and is able to recruit actin-polymerizing machinery in vitro

In Saccharomyces cerevisiae, the WASP (Wiskott-Aldrich syndrome protein) homologue Las17p (also called Bee1p) is an important component of cortical actin patches. Las17p is part of a high-molecular-weight protein complex that regulates Arp2/3 complex-dependent actin polymerization at the cell cortex and that includes the type I myosins Myo3p and Myo5p and verprolin (Vrp1p). To identify other factors implicated with this complex in actin regulation, we isolated proteins that bind to Las17p by two-hybrid screening and affinity chromatography. Here, we report the characterization of Lsb7/Bzz1p (for Las seventeen binding protein 7), an Src homology 3 (SH3) domain protein that interacts directly with Las17p via a polyproline-SH3 interaction. Bzz1p coimmunoprecipitates in a complex with Las17p, Vrp1p, Myo3/5p, Bbc1p, Hsp70p, and actin. It colocalizes with cortical actin patches and with Las17p. This localization is dependent on Las17p, but not on F-actin. Bzz1p interacts physically and genetically with type I myosins. While deletion of BZZI shows no obvious phenotype, simultaneous deletion of the BZZ1, MY03, and MY05 genes is lethal. Overexpression of Bzz1p inhibits cell growth, and a bzz1ΔA myo5Δ double mutant is unable to restore actin polarity after NaCI stress. Finally, Bzz1p in vitro is able to recruit a functional actin polymerization machinery through its SH3 domains. Its interactions with Las17p, Vrp1p, and the type I myosins are essential for this process. This suggests that Bzz1p could be implicated in the regulation of actin polymerization.

Authors
Soulard, A; Lechler, T; Spiridonov, V; Shevchenko, A; Shevchenko, A; Li, R; Winsor, B
MLA Citation
Soulard, A, Lechler, T, Spiridonov, V, Shevchenko, A, Shevchenko, A, Li, R, and Winsor, B. "Saccharomyces cerevisiae Bzz1p is implicated with type I myosins in actin patch polarization and is able to recruit actin-polymerizing machinery in vitro." Molecular and Cellular Biology 22.22 (2002): 7889-7906.
PMID
12391157
Source
scival
Published In
Molecular and Cellular Biology
Volume
22
Issue
22
Publish Date
2002
Start Page
7889
End Page
7906
DOI
10.1128/MCB.22.22.7889-7906.2002

A two-tiered mechanism by which Cdc42 controls the localization and activation of an Arp2/3-activating motor complex in yeast

The establishment of cell polarity in budding yeast involves assembly of actin filaments at specified cortical domains. Elucidation of the underlying mechanism requires an understanding of the machinery that controls actin polymerization and how this machinery is in turn controlled by signaling proteins that respond to polarity cues. We showed previously that the yeast orthologue of the Wiskott-Aldrich Syndrome protein, Bee1/Las17p, and the type I myosins are key regulators of cortical actin polymerization. Here, we demonstrate further that these proteins together with Vrp1p form a multivalent Arp2/3-activating complex. During cell polarization, a bifurcated signaling pathway downstream of the Rho-type GTPase Cdc42p recruits and activates this complex, leading to local assembly of actin filaments. One branch, which requires formin homologues, mediates the recruitment of the Bee1p complex to the cortical site where the activated Cdc42p resides. The other is mediated by the p21-activated kinases, which activate the motor activity of myosin-I through phosphorylation. Together, these findings provide insights into the essential processes leading to polarization of the actin cytoskeleton.

Authors
Lechler, T; Jonsdottir, GA; Klee, SK; Pellman, D; Li, R
MLA Citation
Lechler, T, Jonsdottir, GA, Klee, SK, Pellman, D, and Li, R. "A two-tiered mechanism by which Cdc42 controls the localization and activation of an Arp2/3-activating motor complex in yeast." Journal of Cell Biology 155.2 (2001): 261-270.
PMID
11604421
Source
scival
Published In
The Journal of Cell Biology
Volume
155
Issue
2
Publish Date
2001
Start Page
261
End Page
270
DOI
10.1083/jcb.200104094

Beyond a 'skeleton': Understanding cellular functions of the cytoskeleton

Authors
Egile, C; Lechler, T; Li, R
MLA Citation
Egile, C, Lechler, T, and Li, R. "Beyond a 'skeleton': Understanding cellular functions of the cytoskeleton." Genome Biology 2.3 (2001).
Source
scival
Published In
Genome Biology
Volume
2
Issue
3
Publish Date
2001

Direct involvement of yeast type I myosins in Cdc42-dependent actin polymerization

The generation of cortical actin filaments is necessary for processes such as cell motility and cell polarization. Several recent studies have demonstrated that Wiskott-Aldrich syndrome protein (WASP) family proteins and the actin-related protein (Arp) 2/3 complex are key factors in the nucleation of actin filaments in diverse eukaryotic organisms. To identify other factors involved in this process, we have isolated proteins that bind to Bee1p/Las17p, the yeast WASP-like protein, by affinity chromatography and mass spectroscopic analysis. The yeast type I myosins, Myo3p and Myo5p, have both been identified as Bee1p-interacting proteins. Like Bee1p, these myosins are essential for cortical actin assembly as assayed by in vitro reconstitution of actin nucleation sites in permeabilized yeast cells. Analysis using this assay further demonstrated that the motor activity of these myosins is required for the polymerization step, and that actin polymerization depends on phosphorylation of myosin motor domain by p21- activated kinases (PAKs), downstream effectors of the small guanosine triphosphatase, Cdc42p. The type I myosins also interact with the Arp2/3 complex through a sequence at the end of the tail domain homologous to the Arp2/3-activating region of WASP-like proteins. Combined deletions of the Arp2/3-interacting domains of Bee1p and the type I myosins abolish actin nucleation sites at the cortex, suggesting that these proteins function redundantly in the activation of the Arp2/3 complex.

Authors
Lechler, T; Shevchenko, A; Shevchenko, A; Li, R
MLA Citation
Lechler, T, Shevchenko, A, Shevchenko, A, and Li, R. "Direct involvement of yeast type I myosins in Cdc42-dependent actin polymerization." Journal of Cell Biology 148.2 (2000): 363-373.
PMID
10648569
Source
scival
Published In
The Journal of Cell Biology
Volume
148
Issue
2
Publish Date
2000
Start Page
363
End Page
373
DOI
10.1083/jcb.148.2.363

Activation of the yeast Arp2/3 complex by Bee1p, a WASP-family protein

The Arp2/3 complex is a highly conserved cytoskeletal component that has been implicated in the nucleation of actin filament assembly. Purified Arp2/3 complex has a low intrinsic actin nucleation activity, leading to the hypothesis that an unidentified cellular activator is required for the function of this complex. We showed previously that mutations in the Arp2/3 complex and in Bee1p/Las17p, a member of the Wiskott-Aldrich syndrome protein (WASP) family, lead to a loss of cortical actin structures (patches) in yeast. Bee1p has also been identified as an essential nucleation factor in the reconstitution of actin patches in vitro. Recently, it was reported that WASP-like proteins might interact directly with the Arp2/3 complex through a conserved carboxy-terminal domain. Here, we have shown that Bee1p and the Arp2/3 complex co-immunoprecipitate when expressed at endogenous levels, and that this interaction requires both the Arc15p and Arc19p subunits of the Arp2/3 complex. Furthermore, the carboxyterminal domain of Bee1p greatly stimulated the nucleation activity of purified Arp2/3 complex in vitro, suggesting a direct role for WASP-family proteins in the activation of the Arp2/3 complex. Interestingly, deletion of the carboxy-terminal domain of Bee1p neither abolished the localization of the Arp2/3 complex, as had been suggested, nor resulted in a severe defect in cortical actin assembly. These results indicate that the function of Bee1p is not mediated entirely through its interaction with the Arp2/3 complex, and that factors redundant with Bee1p might exist to activate the nucleation activity of the Arp2/3 complex.

Authors
Winter, D; Lechler, T; Li, R
MLA Citation
Winter, D, Lechler, T, and Li, R. "Activation of the yeast Arp2/3 complex by Bee1p, a WASP-family protein." Current Biology 9.9 (1999): 501-504.
PMID
10322115
Source
scival
Published In
Current Biology
Volume
9
Issue
9
Publish Date
1999
Start Page
501
End Page
504
DOI
10.1016/S0960-9822(99)80218-8

Identification, chromosomal mapping and tissue-specific expression of hREV3 encoding a putative human DNA polymerase ζ

The Saccharomyces cerevisiae REV3 gene encodes the catalytic subunit of a non-essential DNA polymerase ζ, which is required for mutagenesis. The rev3 mutants significantly reduce both spontaneous and DNA damage-induced mutation rates. We have identified human cDNA clones from two different libraries whose deduced amino acid sequences bear remarkable homology to the yeast Rev3, and named this gene hREV3. The hREV3 gene was mapped to chromosome 1p32-33 by fluorescence in situ hybridization. The hREV3 encodes an mRNA of > 10 kb, and its expression varies in different tissues and appears to be elevated in some but not all of the tumor cell lines we have examined. In light of recent reports of a putative mouse REV3, these results indicate that mammalian cells may also contain a mutagenic pathway which aids in cell survival at the cost of increased mutation.

Authors
Xiao, W; Lechler, T; Chow, BL; Fontanie, T; Agustus, M; Carter, KC; Wei, Y-F
MLA Citation
Xiao, W, Lechler, T, Chow, BL, Fontanie, T, Agustus, M, Carter, KC, and Wei, Y-F. "Identification, chromosomal mapping and tissue-specific expression of hREV3 encoding a putative human DNA polymerase ζ." Carcinogenesis 19.5 (1998): 945-949.
PMID
9635887
Source
scival
Published In
Carcinogenesis
Volume
19
Issue
5
Publish Date
1998
Start Page
945
End Page
949
DOI
10.1093/carcin/19.5.945

In vitro reconstitution of cortical actin assembly sites in budding yeast

We have developed a biochemical approach for identifying the components of cortical actin assembly sites in polarized yeast cells, based on a permeabilized celt assay that we established for actin assembly in vitro. Previous analysis indicated that an activity associated with the cell cortex promotes actin polymerization in the bud. After inactivation by a chemical treatment, this activity can be reconstituted back to the permeabilized cells from a cytoplasmic extract. Fractionation of the extract revealed that the reconstitution depends on two sequentially acting protein factors. Bee1, a cortical actin cytoskeletal protein with sequence homology to Wiskott- Aldrich syndrome protein, is required for the first step of the reconstitution. This finding, together with the severe defects in actin organization associated with the bee1 null mutation, indicates that Bee1 protein plays a direct role in controlling actin polymerization at the cell cortex. The factor that acts in the second step of the reconstitution has been identified by conventional chromatography. It is composed of a novel protein, Pca1. Sequence analysis suggests that Peal has the potential to interact with SH3 domain-containing proteins and phospholipids.

Authors
Lechler, T; Li, R
MLA Citation
Lechler, T, and Li, R. "In vitro reconstitution of cortical actin assembly sites in budding yeast." Journal of Cell Biology 138.1 (1997): 95-103.
PMID
9214384
Source
scival
Published In
The Journal of Cell Biology
Volume
138
Issue
1
Publish Date
1997
Start Page
95
End Page
103
DOI
10.1083/jcb.138.1.95

Oxidized LDL as mediators of atherogenesis

The formation of atherosclerotic plaques as a consequence of lipid accumulation in arterial walls apperently is not only caused by a complete removal of endothelial cells of the intima but is also observable under intact endothel. The active storage process of lipids is based on hitherto only insufficiently understood molecular mechanisms where oxidative modifications of LDL and macrophages play a pivotal role for the formation of so called, 'foam cells' - a characteristic feature of atherosclerotic lesions. The article tries to describe initial steps of the foam cell formation. It characterizes the pathophysiological importance of oxidative modified LDL and macrophages in atherogenesis. Further on it reports about pathogenetic relevant criteria for the course of oxidative modifications at LDL components and their consequences which encloses the emigration of monocytes in the cellular network of the arterial wall and the internalisation of oxidative modified LDL in macrophages.

Authors
Lechler, T
MLA Citation
Lechler, T. "Oxidized LDL as mediators of atherogenesis." Herz Kreislauf 28.9 (September 26, 1996): 276-281. (Review)
Source
scopus
Published In
Herz Kreislauf
Volume
28
Issue
9
Publish Date
1996
Start Page
276
End Page
281

(Aryloxy)aryl semicarbazones and related compounds: A novel class of anticonvulsant agents possessing high activity in the maximal electroshock screen

A number of (aryloxy)aryl semicarbazones and related compounds were synthesized and evaluated far anticonvulsant activities. After intraperitoneal injection to mice, the semicarbazones were examined in the maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ), and neurotoxicity (NT) screens. The results indicated that greater protection was obtained in the MES test than the scPTZ screen. Quantitation of approximately one-third of the compounds revealed an average protection index (PI, i.e. TD50/ED50) of approximately 9. After oral administration to rats, a number of compounds displayed significant potencies in the MES screen (ED50 of 1-5 mg/kg) accompanied by very high protection indices. In fact over half the compounds had PI figures of greater than 100, and two were in excess of 300. The compounds were essentially inactive in the scPTZ and NT screens after oral administration to rats. Various compounds displayed greater potencies and PI figures in the mouse intraperitoneal and rat oral screens than three reference clinically used drugs. The data generated supported a binding site hypothesis. Quantitative structure-activity relationships indicated a number of physicochemical parameters which contributed to activity in the MES screen. X-ray crystallography of five compounds suggested the importance of certain interatomic distances and bond angles for activity in the mouse and rat MES screens.

Authors
Dimmock, JR; Puthucode, RN; Smith, JM; Hetherington, M; Quail, JW; Pugazhenthi, U; Lechler, T; Stables, JP
MLA Citation
Dimmock, JR, Puthucode, RN, Smith, JM, Hetherington, M, Quail, JW, Pugazhenthi, U, Lechler, T, and Stables, JP. "(Aryloxy)aryl semicarbazones and related compounds: A novel class of anticonvulsant agents possessing high activity in the maximal electroshock screen." Journal of Medicinal Chemistry 39.20 (1996): 3984-3997.
PMID
8831764
Source
scival
Published In
Journal of Medicinal Chemistry
Volume
39
Issue
20
Publish Date
1996
Start Page
3984
End Page
3997
DOI
10.1021/jm9603025
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Research Areas:

  • Asymmetric Cell Division
  • Cell Adhesion
  • Cytoskeleton
  • Epidermis
  • Keratinocytes