Smad3 reduces susceptibility to hepatocarcinoma by sensitizing hepatocytes to apoptosis through downregulation of Bcl-2.
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.
Yang
Yu-An
YA
Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
Zhang
Gen-Mu
GM
Feigenbaum
Lionel
L
Zhang
Ying E
YE
D000818:Animals; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004198:Disease Susceptibility; D015536:Down-Regulation; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D021381:Protein Transport; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D051900:Smad3 Protein / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D019253:Proto-Oncogene Proteins c-bcl-2; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases