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(American Journal of Pathology. 2004;165:1955-1967.)
© 2004 American Society for Investigative Pathology

Integrity of Cell-Cell Contacts Is a Critical Regulator of TGF-ß1-Induced Epithelial-to-Myofibroblast Transition

Role for ß-Catenin

András Masszi*{dagger}, Lingzhi Fan*, László Rosivall{dagger}{ddagger}, Christopher A. McCulloch§, Ori D. Rotstein*, István Mucsi{ddagger} and András Kapus*

From the Department of Surgery,* University Health Network and University of Toronto, Ontario, Canada; the Institute of Pathophysiology,{dagger} Semmelweis University, Budapest, Hungary; the Hungarian Academy of Sciences and Semmelweis University Nephrology Research Group,{ddagger} Budapest, Hungary; the Canadian Institutes of Health Research Group (CIHR) in Matrix Dynamics,§ University of Toronto, Toronto, Ontario, Canada; and the First Department of Internal Medicine, Semmelweis University, Budapest, Hungary

Injury of the tubular epithelium and TGF-ß1-induced conversion of epithelial cells to {alpha}-smooth muscle actin (SMA)-expressing myofibroblasts are key features of kidney fibrosis. Since injury damages intercellular junctions and promotes fibrosis, we hypothesized that cell contacts are critical regulators of TGF-ß1-triggered epithelial-to-mesenchymal transition (EMT). Here we show that TGF-ß1 was unable to induce EMT in intact confluent monolayers, but three different models of injury-induced loss of epithelial integrity (subconfluence, wounding, and contact disassembly by Ca2+-removal) restored its EMT-inducing effect. This manifested in loss of E-cadherin, increased fibronectin production and SMA expression. TGF-ß1 or contact disassembly alone only modestly stimulated the SMA promoter in confluent layers, but together exhibited strong synergy. Since ß-catenin is a component of intact adherens junctions, but when liberated from destabilized contacts may act as a transcriptional co-activator, we investigated its role in TGF-ß1-provoked EMT. Contact disassembly alone induced degradation of E-cadherin and ß-catenin, but TGF-ß1 selectively rescued ß-catenin and stimulated the ß-catenin-driven reporter TopFLASH. Moreover, chelation of free ß-catenin with the N-cadherin cytoplasmic tail suppressed the TGF-ß1 plus contact disassembly-induced SMA promoter activation and protein expression. These results suggest a ß-catenin-dependent two-hit mechanism in which both an initial epithelial injury and TGF-ß1 are required for EMT.




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