Integrity of cell-cell contacts is a critical regulator of TGF-β1-induced epithelial-to-myofibroblast transition

Role for β-catenin

András Masszi, Lingzhi Fan, L. Rosivall, Christopher A. McCulloch, Ori D. Rotstein, I. Mucsi, András Kapus

Research output: Contribution to journalArticle

191 Citations (Scopus)

Abstract

Injury of the tubular epithelium and TGF-β1-induced conversion of epithelial cells to α-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-β1-triggered epithelial-to-mesenchymal transition (EMT). Here we show that TGF-β1 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-β1 or contact disassembly alone only modestly stimulated the SMA promoter in confluent layers, but together exhibited strong synergy. Since β-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-β1-provoked EMT. Contact disassembly alone induced degradation of E-cadherin and β-catenin, but TGF-β1 selectively rescued β-catenin and stimulated the β-catenin-driven reporter TopFLASH. Moreover, chelation of free β-catenin with the N-cadherin cytoplasmic tail suppressed the TGF-β1 plus contact disassembly-induced SMA promoter activation and protein expression. These results suggest a β-catenin- dependent two-hit mechanism in which both an initial epithelial injury and TGF-β1 are required for EMT.

Original languageEnglish
Pages (from-to)1955-1967
Number of pages13
JournalAmerican Journal of Pathology
Volume165
Issue number6
Publication statusPublished - Dec 2004

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Catenins
Myofibroblasts
Epithelial-Mesenchymal Transition
Smooth Muscle
Actins
Cadherins
Wounds and Injuries
Fibrosis
Adherens Junctions
Intercellular Junctions
Fibronectins
Epithelium
Epithelial Cells
Kidney
Proteins

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Integrity of cell-cell contacts is a critical regulator of TGF-β1-induced epithelial-to-myofibroblast transition : Role for β-catenin. / Masszi, András; Fan, Lingzhi; Rosivall, L.; McCulloch, Christopher A.; Rotstein, Ori D.; Mucsi, I.; Kapus, András.

In: American Journal of Pathology, Vol. 165, No. 6, 12.2004, p. 1955-1967.

Research output: Contribution to journalArticle

Masszi, András ; Fan, Lingzhi ; Rosivall, L. ; McCulloch, Christopher A. ; Rotstein, Ori D. ; Mucsi, I. ; Kapus, András. / Integrity of cell-cell contacts is a critical regulator of TGF-β1-induced epithelial-to-myofibroblast transition : Role for β-catenin. In: American Journal of Pathology. 2004 ; Vol. 165, No. 6. pp. 1955-1967.
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