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| Subject Categories: Differentiation & Death | Chromatin & Transcription |
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| The EMBO Journal
(2004) 23, 1155–1165, doi:10.1038/sj.emboj.7600069 Published online 19 February 2004 |
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Integration of TGF- /Smad and Jagged1/Notch signalling in epithelial-to-mesenchymal transition |
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| Jiri Zavadil1, 4, 5, Lukas Cermak1, 2, 5, Noemi Soto-Nieves3 and Erwin P Böttinger1, 3 |
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1 Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA 2 Institute of Molecular Genetics, Czech Academy of Sciences, Videnska, Prague, Czech Republic 3 Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, NY, USA To whom correspondence should be addressed 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 4 Current address: New York University Cancer Institute, 400 East 34th Street, New York, NY 10016, USA 5 These authors contributed equally to this work Received 24 April 2003; Accepted 16 December 2003; Published online 19 February 2004. |
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| Abstract |
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| 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. |
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| Keywords: development, differentiation, epithelial, neoplasm, signal transduction, transforming growth factor- |
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Top of page MORE ARTICLES LIKE THISThese links to content published by NPG are automatically generated RESEARCHTGF-&bgr;1 dissociates human proximal tubule cell growth and Na + -H + exchange activity Kidney International Original Article |
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