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Integrity of cell-cell contacts is a critical regulator of TGF-beta 1-induced epithelial-to-myofibroblast transition: role for beta-catenin.
Masszi, András; Fan, Lingzhi; Rosivall, László; McCulloch, Christopher A; Rotstein, Ori D; Mucsi, István; Kapus, András.
Affiliation
  • Masszi A; Department of Surgery, University Health Network and University of Toronto, Ontario, Canada.
Am J Pathol ; 165(6): 1955-67, 2004 Dec.
Article in En | MEDLINE | ID: mdl-15579439
Injury of the tubular epithelium and TGF-beta1-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-beta 1-triggered epithelial-to-mesenchymal transition (EMT). Here we show that TGF-beta 1 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 Ca(2+)-removal) restored its EMT-inducing effect. This manifested in loss of E-cadherin, increased fibronectin production and SMA expression. TGF-beta 1 or contact disassembly alone only modestly stimulated the SMA promoter in confluent layers, but together exhibited strong synergy. Since beta-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-beta 1-provoked EMT. Contact disassembly alone induced degradation of E-cadherin and beta-catenin, but TGF-beta1 selectively rescued beta-catenin and stimulated the beta-catenin-driven reporter TopFLASH. Moreover, chelation of free beta-catenin with the N-cadherin cytoplasmic tail suppressed the TGF-beta1 plus contact disassembly-induced SMA promoter activation and protein expression. These results suggest a beta-catenin-dependent two-hit mechanism in which both an initial epithelial injury and TGF-beta 1 are required for EMT.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Cell Adhesion / Cell Communication / Trans-Activators / Transforming Growth Factor beta / Cytoskeletal Proteins / Myocytes, Smooth Muscle / Epithelial Cells / Fibroblasts Type of study: Prognostic_studies Limits: Animals Language: En Journal: Am J Pathol Year: 2004 Document type: Article Affiliation country: Country of publication:

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Cell Adhesion / Cell Communication / Trans-Activators / Transforming Growth Factor beta / Cytoskeletal Proteins / Myocytes, Smooth Muscle / Epithelial Cells / Fibroblasts Type of study: Prognostic_studies Limits: Animals Language: En Journal: Am J Pathol Year: 2004 Document type: Article Affiliation country: Country of publication: