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

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Abstract
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)- 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--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-. Moreover, NMuMG cells overexpressed Id2 showed partial resistance to TGF--induced EMT. Id proteins thus inhibit the action of E2A proteins on the expression of E-cadherin, but after TGF- stimulation, E2A proteins are present in molar excess of the Id proteins, thus over-riding their inhibitory function and leading to EMT.