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

Nuria Eritja, Isidre Felip, Mari Alba Dosil, Lucia Vigezzi, Cristina Mirantes, Andree Yeramian, Raúl Navaridas, Maria Santacana, David Llobet-Navas, Akihiko Yoshimura, Masatoshi Nomura, Mario Encinas, Xavier Matias-Guiu, Xavi Dolcet

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1443-1458
Number of pages16
JournalCell Death and Differentiation
Volume24
Issue number8
DOIs
Publication statusPublished - 2017 Aug 1

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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