【摘 要】
：
In liver, TGF-beta limits the regenerative tissue growth after injury by inhibiting DNA synthesis and inducing apoptosis.Derangement of TGF-beta signaling is associated with an increased incidence of
【机 构】
：
Laboratory of Cellular and Molecular Biology Center for Cancer Research National Cancer Institute, N
【出 处】
：
BIT Life Sciences 1st Annual World Cancer Congess-2008(2008中
论文部分内容阅读
In liver, TGF-beta limits the regenerative tissue growth after injury by inhibiting DNA synthesis and inducing apoptosis.Derangement of TGF-beta signaling is associated with an increased incidence of hepatocellular carcinoma (HCC), a common visceral malignancy and the third leading cause of cancer death worldwide.However, the exact mechanism by which TGF-beta induces apoptosis and suppresses liver tumorigenesis is not clear.To investigate the role of TGF-beta/Smad3 in tumorigenesis, we generated several lines of transgenic mice expressing Smad3 and its mutated variants using the tetracycline repressible system and specifically induced the expression of Smad3 transgenes in liver.We found that ectopic expression of Smad3 in liver reduces susceptibility to HCC in a chemically induced murine model.This protection is conferred by the ability of Smad3 to promote apoptosis by repressing Bcl-2 transcription.Surprisingly, eetopic expression alone is not sufficient to activate the pro-apoptotic activity of Smad3 or ostensibly alter normal liver physiology; this is even true for Smad3SD, a mutant that is enriched in the nucleus due to two aspartic acid substitutions at the c-terminus.Additional input from p38 MAPK kinase, which is activated in liver tumor cells but not in normal hepatocytes, is required.Thus, Bcl-2 is a direct target in the TGFbeta/ Smad3-mediated apoptosis and the tumor-suppression exhibited by gain-of-function Smad3 expression holds significant therapeutic implications for HCC.
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