Article
- The EMBO Journal (2004) 23, 1155 - 1165
- doi:10.1038/sj.emboj.7600069
Published online: 19 February 2004
Subject Categories:
Integration of TGF-
/Smad and Jagged1/Notch signalling in epithelial-to-mesenchymal transition
Jiri Zavadil1,ab, Lukas Cermak1,2,b, Noemi Soto-Nieves3 and Erwin P Böttinger1,3
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
- Institute of Molecular Genetics, Czech Academy of Sciences, Videnska, Prague, Czech Republic
- Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, NY, USA
Correspondence to:
Erwin P Böttinger, Department of Medicine, Mount Sinai Medical Center, One Gustave L. Levy Place, Box 1118, New York, NY 10029, USA. Tel.: +1 212 659 8242; Fax: +1 212 876 5844; E-mail: Erwin.bottinger@mssm.edu
aCurrent address: New York University Cancer Institute, 400 East 34th Street, New York, NY 10016, USA
bThese authors contributed equally to this work
Received 24 April 2003; Accepted 16 December 2003
Abstract
Epithelial-to-mesenchymal transitions (EMTs) underlie cell plasticity required in embryonic development and frequently observed in advanced carcinogenesis. Transforming growth factor-
(TGF-) induces EMT phenotypes in epithelial cells in vitro and has been associated with EMT in vivo. Here we report that expression of the hairy/enhancer-of-split-related transcriptional repressor Hey1, and the Notch-ligand Jagged1 (Jag1), was induced by TGF- at the onset of EMT in epithelial cells from mammary gland, kidney tubules, and epidermis. The HEY1 expression profile was biphasic, consisting of immediate-early Smad3-dependent, Jagged1/Notch-independent activation, followed by delayed, indirect Jagged1/Notch-dependent activation. TGF--induced EMT was blocked by RNA silencing of HEY1 or JAG1, and by chemical inactivation of Notch. The EMT phenotype, biphasic activation of Hey1, and delayed expression of Jag1 were induced by TGF- in wild-type, but not in Smad3-deficient, primary mouse kidney tubular epithelial cells. Our findings identify a new mechanism for functional integration of Jagged1/Notch signalling and coordinated activation of the Hey1 transcriptional repressor controlled by TGF-/Smad3, and demonstrate functional roles for Smad3, Hey1, and Jagged1/Notch in mediating TGF--induced EMT.
Keywords:
- development,
- differentiation,
- epithelial,
- neoplasm,
- signal transduction,
- transforming growth factor-
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