This work was supported by grants from
the National Institutes of Health (Mahoney,
R01AR056067; Riobo, RO1 GM088256). The
funders had no role in study design, data collection
and analysis, decision to publish, or preparation of
the manuscript

A Pavlova

A Rinne

Abhilasha Gupta

AC Steven

AG Barber

AJ Barrett

AJ Merritt

AL Krunic

B Ruffell

B Vray

BD Gelb

BS Parker

BS Sorenson

C Toomes

CC Bitu

D Brennan

D Lazić

Daniela Nitoiu

David P. Kelsell

DC Blaydon

DK Scott

Donna Brennan-Crispi

E Delva

E Hartlieb

EP Parrish

F Galbiati

FW Tsui

G Petrof

G. Dubin

H Kurzen

H Takahashi

JG Zettergren

Johanna M Brandner

JS Morey

K Biedermann

K Iwatsuki

KJ Green

L Foghsgaard

LA Pennacchio

M Amagai

M Bilodeau

M Ishida

M Pasdar

M Strauss

M Yashiro

MG Mahoney

MR Kuracha

MT Teh

MW Butler

Mỹ G. Mahoney

Natalia A. Riobo

ND Rawlings

P Hawley-Nelson

P Strojan

S Estrada

S Kavaklieva

S Magister

SA Keim

SA Mani

Sankar Addya

T Kuopio

T Takai

U Galderisi

UA Nuber

VL Battula

WM Brown

Y Vasilopoulos

PLoS ONE

PubMed

Crossref

Cell Cycle- and Cancer-Associated Gene Networks Activated by Dsg2: Evidence of Cystatin A Deregulation and a Potential Role in Cell-Cell Adhesion

Gupta, A

Nitoiu, D

Brennan-Crispi, D

Addya, S

Riobo, NA

Kelsell, DP

Mahoney, MG

Queen Mary Research Online

<div><p>Cell-cell adhesion is paramount in providing and maintaining multicellular structure and signal transmission between cells. In the skin, disruption to desmosomal regulated intercellular connectivity may lead to disorders of keratinization and hyperproliferative disease including cancer. Recently we showed transgenic mice overexpressing desmoglein 2 (Dsg2) in the epidermis develop hyperplasia. Following microarray and gene network analysis, we demonstrate that Dsg2 caused a profound change in the transcriptome of keratinocytes <i>in vivo</i> and altered a number of genes important in epithelial dysplasia including: calcium-binding proteins (S100A8 and S100A9), members of the cyclin protein family, and the cysteine protease inhibitor cystatin A (CSTA). CSTA is deregulated in several skin cancers, including squamous cell carcinomas (SCC) and loss of function mutations lead to recessive skin fragility disorders. The microarray results were confirmed by qPCR, immunoblotting, and immunohistochemistry. CSTA was detected at high level throughout the newborn mouse epidermis but dramatically decreased with development and was detected predominantly in the differentiated layers. In human keratinocytes, knockdown of Dsg2 by siRNA or shRNA reduced CSTA expression. Furthermore, siRNA knockdown of CSTA resulted in cytoplasmic localization of Dsg2, perturbed cytokeratin 14 staining and reduced levels of desmoplakin in response to mechanical stretching. Both knockdown of either Dsg2 or CSTA induced loss of cell adhesion in a dispase-based assay and the effect was synergistic. Our findings here offer a novel pathway of CSTA regulation involving Dsg2 and a potential crosstalk between Dsg2 and CSTA that modulates cell adhesion. These results further support the recent human genetic findings that loss of function mutations in the CSTA gene result in skin fragility due to impaired cell-cell adhesion: autosomal-recessive exfoliative ichthyosis or acral peeling skin syndrome.</p></div

Abhilasha Gupta (532794)

Daniela Nitoiu (704852)

Donna Brennan-Crispi (704853)

Sankar Addya (127326)

Natalia A. Riobo (704854)

David P. Kelsell (704855)

Mỹ G. Mahoney (704856)

The Francis Crick Institute

Gupta Abhilasha

Nitoiu Daniela

Brennan-Crispi Donna

Addya Sankar

Riobo Natalia A.

Kelsell David P.

Mahoney Mỹ G.

Public Library of Science (PLOS)

Cell-cell adhesion is paramount in providing and maintaining multicellular structure and signal transmission between cells. In the skin, disruption to desmosomal regulated intercellular connectivity may lead to disorders of keratinization and hyperproliferative disease including cancer. Recently we showed transgenic mice overexpressing desmoglein 2 (Dsg2) in the epidermis develop hyperplasia. Following microarray and gene network analysis, we demonstrate that Dsg2 caused a profound change in the transcriptome of keratinocytes in vivo and altered a number of genes important in epithelial dysplasia including: calcium-binding proteins (S100A8 and S100A9), members of the cyclin protein family, and the cysteine protease inhibitor cystatin A (CSTA). CSTA is deregulated in several skin cancers, including squamous cell carcinomas (SCC) and loss of function mutations lead to recessive skin fragility disorders. The microarray results were confirmed by qPCR, immunoblotting, and immunohistochemistry. CSTA was detected at high level throughout the newborn mouse epidermis but dramatically decreased with development and was detected predominantly in the differentiated layers. In human keratinocytes, knockdown of Dsg2 by siRNA or shRNA reduced CSTA expression. Furthermore, siRNA knockdown of CSTA resulted in cytoplasmic localization of Dsg2, perturbed cytokeratin 14 staining and reduced levels of desmoplakin in response to mechanical stretching. Both knockdown of either Dsg2 or CSTA induced loss of cell adhesion in a dispase-based assay and the effect was synergistic. Our findings here offer a novel pathway of CSTA regulation involving Dsg2 and a potential crosstalk between Dsg2 and CSTA that modulates cell adhesion. These results further support the recent human genetic findings that loss of function mutations in the CSTA gene result in skin fragility due to impaired cell-cell adhesion: autosomal-recessive exfoliative ichthyosis or acral peeling skin syndrome

Natalia A Riobo

David P Kelsell

Mỹ G Mahoney

Directory of Open Access Journals

Cell cycle- and cancer-associated gene networks activated by Dsg2: evidence of cystatin A deregulation and a potential role in cell-cell adhesion.

http://dx.doi.org/10.1371/journal.pone.0120091

Cell Cycle- and Cancer-Associated Gene Networks Activated by Dsg2: Evidence of Cystatin A Deregulation and a Potential Role in Cell-Cell Adhesion

Abstract

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Crossref

Queen Mary Research Online

The Francis Crick Institute

Public Library of Science (PLOS)

Directory of Open Access Journals