SMAD7 in keratinocytes promotes skin carcinogenesis by activating ATM-dependent DNA repair and an EGFR-mediated cell proliferation pathway

Carcinogenesis
Huyen Trang Ha ThiSuntaek Hong

Abstract

SMA- and MAD-related protein 7 (SMAD7) is a general inhibitor of transforming growth factor-β (TGF-β) signaling that acts through interaction and degradation of TGF-β receptors. SMAD7 has been demonstrated to be transcriptionally upregulated in chemical-induced skin tumors and TGF-β-treated normal keratinocytes. To evaluate the function of SMAD7 in skin carcinogenesis in vivo, Smad7 transgenic mice that specifically express either wild-type (WT) SMAD7 (TG-Smad7-WT) or mutant SMAD7 (TG-Smad7-MT) in keratinocytes, as well as Smad7 keratinocyte-specific knockout (Smad72f/2f-K14Cre) mice, were subjected to chemical-induced skin carcinogenesis. WT-SMAD7-expressing transgenic mice showed significantly greater papilloma formation than did non-TG control and Smad7-MT mice. The expression of WT-SMAD7 attenuated DNA damage-induced apoptosis in epidermal keratinocytes by stimulating the ATM-dependent DNA repair pathway. Nonetheless, overexpression of WT-SMAD7 caused a susceptibility to 12-O-tetradecanoylphorbol-13-acetate-induced epidermal hyperproliferation through activation of epidermal growth factor (EGF) signaling. In agreement with the transgenic mouse data, keratinocyte-specific deletion of SMAD7 markedly suppressed the tumor forma...Continue Reading

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Jun 10, 2015·Molecular and Cellular Biology·Huyen Trang Ha ThiSuntaek Hong

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Citations

Oct 22, 2020·Critical Reviews in Biochemistry and Molecular Biology·Charlotte de Ceuninck van CapellePeter Ten Dijke
Jun 2, 2021·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Yiping HuQingwen Wang

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