A Smad3-PTEN regulatory loop controls proliferation and apoptotic responses to TGF-β in mouse endometrium

Cell Death and Differentiation
Nuria EritjaXavi Dolcet

Abstract

The TGF-β/Smad and the PI3K/AKT signaling pathways are important regulators of proliferation and apoptosis, and their alterations lead to cancer development. TGF-β acts as a tumor suppressor in premalignant cells, but it is a tumor promoter for cancerous cells. Such dichotomous actions are dictated by different cellular contexts. Here, we have unveiled a PTEN-Smad3 regulatory loop that provides a new insight in the complex cross talk between TGF-β/Smad and PI3K/AKT signaling pathways. We demonstrate that TGF-β triggers apoptosis of wild-type polarized endometrial epithelial cells by a Smad3-dependent activation of PTEN transcription, which results in the inhibition of PI3K/AKT signaling pathway. We show that specific Smad3 knockdown or knockout reduces basal and TGF-β-induced PTEN expression in endometrial cells, resulting in a blockade of TGF-β-induced apoptosis and an enhancement of cell proliferation. Likewise Smad3 deletion, PTEN knockout prevents TGF-β-induced apoptosis and increases cell proliferation by increasing PI3K/AKT/mTOR signaling. In summary, our results demonstrate that Smad3-PTEN signaling axis determine cellular responses to TGF-β.

References

Oct 15, 2003·Nature Reviews. Cancer·Peter M Siegel, Joan Massagué
Mar 30, 2004·Nature Cell Biology·Ingrid RemyStephen W Michnick
Sep 24, 2004·Gynecologic Oncology·Dagmara Piestrzeniewicz-UlanskaWanda M Krajewska
Dec 3, 2005·Genes & Development·Joan MassaguéDavid Wotton
Aug 15, 2006·Biochimica Et Biophysica Acta·Katerina Pardali, Aristidis Moustakas
Feb 24, 2007·Current Opinion in Cell Biology·Susumu Itoh, Peter ten Dijke
Mar 7, 2007·Journal of Cellular Biochemistry·Kimberly A BrownHarold L Moses
Jul 3, 2007·Cell·Brendan D Manning, Lewis C Cantley
Nov 15, 2007·Nature Reviews. Molecular Cell Biology·Bernhard Schmierer, Caroline S Hill
Jul 30, 2008·Cell·Joan Massagué
Dec 4, 2008·Cell Research·David Padua, Joan Massagué
Dec 31, 2008·Cell Research·Ying E Zhang
Jan 21, 2009·Cell Research·Jian XuRik Derynck
Feb 25, 2009·Current Opinion in Cell Biology·Carl-Henrik HeldinAristidis Moustakas
Apr 17, 2010·The American Journal of Pathology·Núria EritjaXavi Dolcet
Mar 25, 2011·Nature Reviews. Cancer·M Christine HollanderPhillip A Dennis
May 27, 2011·Molecular Cancer Therapeutics·Laura Muinelo-RomayMiguel Abal
Jun 7, 2011·Cell and Tissue Research·Carl-Henrik Heldin, Aristidis Moustakas
Jun 28, 2011·Cell and Tissue Research·Yabing MuMaréne Landström
Mar 17, 2012·Nature Reviews. Genetics·Cédric Feschotte, Clément Gilbert
Apr 5, 2012·Nature Reviews. Molecular Cell Biology·Min Sup SongPier Paolo Pandolfi
Sep 21, 2012·Nature Reviews. Molecular Cell Biology·Joan Massagué
Feb 13, 2013·Nature Reviews. Clinical Oncology·Jordi RodonJosep Tabernero
Nov 19, 2013·Trends in Biochemical Sciences·Long ZhangPeter ten Dijke
May 16, 2014·Proceedings of the National Academy of Sciences of the United States of America·Zoltán WienerKari Alitalo
Dec 6, 2014·Journal of Animal Science and Biotechnology·Qinglei Li

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Citations

Sep 13, 2018·The Journal of Pathology·Maria A DosilXavier Dolcet
Oct 21, 2018·Genes and Immunity·Giuseppe RaschellàAlessandra Gambacurta
Jul 3, 2021·Animals : an Open Access Journal From MDPI·Marta RybskaJędrzej M Jaśkowski
Dec 12, 2018·Computers in Biology and Medicine·Veronica V RossatoJosé Carlos M Mombach

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