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

7 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

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Endometrium
Phosphatidylinositol 3-Kinases
Apoptosis
Cell Proliferation
Carcinogens
Transcriptional Activation
Neoplasms
Epithelial Cells

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Eritja, N., Felip, I., Dosil, M. A., Vigezzi, L., Mirantes, C., Yeramian, A., ... Dolcet, X. (2017). A Smad3-PTEN regulatory loop controls proliferation and apoptotic responses to TGF-β in mouse endometrium. Cell Death and Differentiation, 24(8), 1443-1458. https://doi.org/10.1038/cdd.2017.73

A Smad3-PTEN regulatory loop controls proliferation and apoptotic responses to TGF-β in mouse endometrium. / Eritja, Nuria; Felip, Isidre; Dosil, Mari Alba; Vigezzi, Lucia; Mirantes, Cristina; Yeramian, Andree; Navaridas, Raúl; Santacana, Maria; Llobet-Navas, David; Yoshimura, Akihiko; Nomura, Masatoshi; Encinas, Mario; Matias-Guiu, Xavier; Dolcet, Xavi.

In: Cell Death and Differentiation, Vol. 24, No. 8, 01.08.2017, p. 1443-1458.

Research output: Contribution to journalArticle

Eritja, N, Felip, I, Dosil, MA, Vigezzi, L, Mirantes, C, Yeramian, A, Navaridas, R, Santacana, M, Llobet-Navas, D, Yoshimura, A, Nomura, M, Encinas, M, Matias-Guiu, X & Dolcet, X 2017, 'A Smad3-PTEN regulatory loop controls proliferation and apoptotic responses to TGF-β in mouse endometrium', Cell Death and Differentiation, vol. 24, no. 8, pp. 1443-1458. https://doi.org/10.1038/cdd.2017.73
Eritja, Nuria ; Felip, Isidre ; Dosil, Mari Alba ; Vigezzi, Lucia ; Mirantes, Cristina ; Yeramian, Andree ; Navaridas, Raúl ; Santacana, Maria ; Llobet-Navas, David ; Yoshimura, Akihiko ; Nomura, Masatoshi ; Encinas, Mario ; Matias-Guiu, Xavier ; Dolcet, Xavi. / A Smad3-PTEN regulatory loop controls proliferation and apoptotic responses to TGF-β in mouse endometrium. In: Cell Death and Differentiation. 2017 ; Vol. 24, No. 8. pp. 1443-1458.
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