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)-β 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-β-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-β. Moreover, NMuMG cells overexpressed Id2 showed partial resistance to TGF-β-induced EMT. Id proteins thus inhibit the action of E2A proteins on the expression of E-cadherin, but after TGF-β stimulation, E2A proteins are present in molar excess of the Id proteins, thus over-riding their inhibitory function and leading to EMT.
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Abbreviations
- TGF-β:
-
transforming growth factor-β
- TβR-I:
-
TGF-β type I receptor
- BMPs:
-
bone morphogenetic proteins
- HLH:
-
helix–loop–helix
- Id:
-
inhibitor of differentiation
- EMT:
-
epithelial–mesenchymal transdifferentiation
- Tet:
-
tetracycline
- TRITC:
-
tetramethylrhodamine B isocyanate
- DMEM:
-
Dulbecco's modified Eagle's medium
- FBS:
-
fetal bovine serum
- RT-PCR:
-
reverse transcription-polymerase chain reaction
- GAPDH:
-
glyceraldehyde-3-phosphate dehydrogenase
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Acknowledgements
We thank Dr. N Funato for valuable discussions, and Drs. C Murre, B and H Weintraub for providing crucial reagents. We also thank T Imamura, M Kato, A Hanyu and all the members of the Molecular Pathology Laboratory for critical comments. This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan. KM is also supported by a VRIA grant from Boehringer Ingelheim. EC is supported by a fellowship from the Carlos III Institute.
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Kondo, M., Cubillo, E., Tobiume, K. et al. A role for Id in the regulation of TGF-β-induced epithelial–mesenchymal transdifferentiation. Cell Death Differ 11, 1092–1101 (2004). https://doi.org/10.1038/sj.cdd.4401467
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DOI: https://doi.org/10.1038/sj.cdd.4401467
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