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

Eritja Sánchez, Núria; Felip, Isidre; Dosil Garcia, Maria Alba; Vigezzi, Lucia; Mirantes Barbeito, Cristina; Yeramian Hakim, Andree; Navaridas Fernández de Bobadilla, Raúl; Santacana Espasa, Maria; Llobet Navàs, David; Yoshimura, Akihiko; Nomura, Masatoshi; Encinas Martín, Mario; Matias-Guiu, Xavier; Dolcet Roca, Xavier

doi:https://doi.org/10.1038/cdd.2017.73

View/Open

Postprint (11.42Mb)

Issue date

2017-05-19

Author

Eritja Sánchez, Núria

Felip, Isidre

Dosil Garcia, Maria Alba

Vigezzi, Lucia

Mirantes Barbeito, Cristina

Yeramian Hakim, Andree

Navaridas Fernández de Bobadilla, Raúl

Santacana Espasa, Maria

Llobet Navàs, David

Yoshimura, Akihiko

Nomura, Masatoshi

Encinas Martín, Mario

Matias-Guiu, Xavier

Dolcet Roca, Xavier

Suggested citation

Eritja Sánchez, Núria; Felip, Isidre; Dosil Garcia, Maria Alba; Vigezzi, Lucia; Mirantes Barbeito, Cristina; Yeramian Hakim, Andree; ... Dolcet Roca, Xavier. (2017) . A Smad3-PTEN regulatory loop controls proliferation and apoptotic responses to TGF-β in mouse endometrium. Cell Death and Differentiation, 2017, vol. 24, núm. 8, p. 1443-1458. https://doi.org/10.1038/cdd.2017.73.

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.

URI

http://hdl.handle.net/10459.1/63501

DOI

https://doi.org/10.1038/cdd.2017.73

Is part of

Cell Death and Differentiation, 2017, vol. 24, núm. 8, p. 1443-1458