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

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2017-05-19Author
Felip, Isidre
Dosil Garcia, Maria Alba
Vigezzi, Lucia
Mirantes Barbeito, Cristina
Navaridas Fernández de Bobadilla, Raúl
Santacana Espasa, Maria
Llobet Navàs, David
Yoshimura, Akihiko
Nomura, Masatoshi
Suggested citation
Eritja Sánchez, Núria;
Felip, Isidre;
Dosil Garcia, Maria Alba;
Vigezzi, Lucia;
Mirantes Barbeito, Cristina;
Yeramian Hakim, Andree;
...
Dolcet Roca, Xavier.
(2017)
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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.
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Show full item recordAbstract
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.