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Cancer Cell. 2006 Jun;9(6):445-57.

Smad3 reduces susceptibility to hepatocarcinoma by sensitizing hepatocytes to apoptosis through downregulation of Bcl-2.

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1
Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.

Abstract

In the liver, derangement of TGF-beta signaling is associated with an increased incidence of hepatocellular carcinoma (HCC), but the mechanism is not clear. We report here that forced expression of a major TGF-beta signaling transducer, Smad3, reduces susceptibility to HCC in a chemically induced murine model. This protection is conferred by Smad3's ability to promote apoptosis by repressing Bcl-2 transcription in vivo through a GC-rich element in the Bcl-2 promoter. We also show that the proapoptotic activity of Smad3 requires both input from TGF-beta signaling and activation of p38 MAPK, which occurs selectively in the liver tumor cells. Thus, Smad3 enables the tumor suppression function of TGF-beta by serving as a physiological mediator of TGF-beta-induced apoptosis.

PMID:
16766264
PMCID:
PMC2708973
DOI:
10.1016/j.ccr.2006.04.025
[Indexed for MEDLINE]
Free PMC Article
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