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.
MeSH terms
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Animals
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Apoptosis / drug effects
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Apoptosis / genetics
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Cell Proliferation / drug effects
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Cell Proliferation / genetics
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Endometrium / cytology
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Endometrium / drug effects*
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Endometrium / metabolism
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Epithelial Cells / cytology
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Epithelial Cells / drug effects*
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Epithelial Cells / metabolism
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Feedback, Physiological
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Female
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Gene Expression Regulation
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Mice
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Mice, Knockout
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PTEN Phosphohydrolase / antagonists & inhibitors
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PTEN Phosphohydrolase / deficiency
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PTEN Phosphohydrolase / genetics*
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Signal Transduction
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Smad3 Protein / antagonists & inhibitors
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Smad3 Protein / deficiency
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Smad3 Protein / genetics*
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Transcription, Genetic
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / metabolism
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Transforming Growth Factor beta / pharmacology*
Substances
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RNA, Small Interfering
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Smad3 Protein
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Smad3 protein, mouse
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Transforming Growth Factor beta
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt
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PTEN Phosphohydrolase
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Pten protein, mouse