A role for Id in the regulation of TGF-beta-induced epithelial-mesenchymal transdifferentiation

Cell Death Differ. 2004 Oct;11(10):1092-101. doi: 10.1038/sj.cdd.4401467.


Epithelial-mesenchymal transdifferentiation (EMT) is a critical morphogenic event that occurs during embryonic development and during the progression of various epithelial tumors. EMT can be induced by transforming growth factor (TGF)-beta in mouse NMuMG mammary epithelial cells. Here, we demonstrate a central role of helix-loop-helix factors, E2A and inhibitor of differentiation (Id) proteins, in TGF-beta-induced EMT. Epithelial cells ectopically expressing E2A adopt a fibroblastic phenotype and acquire migratory/invasive properties, concomitant with the suppression of E-cadherin expression. Id proteins interacted with E2A proteins and antagonized E2A-dependent suppression of the E-cadherin promoter. Levels of Id proteins were dramatically decreased by TGF-beta. Moreover, NMuMG cells overexpressed Id2 showed partial resistance to TGF-beta-induced EMT. Id proteins thus inhibit the action of E2A proteins on the expression of E-cadherin, but after TGF-beta stimulation, E2A proteins are present in molar excess of the Id proteins, thus over-riding their inhibitory function and leading to EMT.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzamides / pharmacology
  • Cadherins / genetics
  • Cadherins / metabolism
  • Cell Differentiation / drug effects*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Dioxoles / pharmacology
  • Epithelial Cells / cytology*
  • Epithelial Cells / drug effects*
  • Epithelial Cells / metabolism
  • Gene Expression
  • Gene Expression Regulation
  • Inhibitor of Differentiation Protein 2
  • Mesoderm / cytology*
  • Mesoderm / drug effects*
  • Mesoderm / metabolism
  • Mice
  • Promoter Regions, Genetic / genetics
  • Receptors, Transforming Growth Factor beta / antagonists & inhibitors
  • Receptors, Transforming Growth Factor beta / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transforming Growth Factor beta / pharmacology*


  • 4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide
  • Benzamides
  • Cadherins
  • DNA-Binding Proteins
  • Dioxoles
  • Idb2 protein, mouse
  • Inhibitor of Differentiation Protein 2
  • Receptors, Transforming Growth Factor beta
  • Repressor Proteins
  • Transcription Factors
  • Transforming Growth Factor beta