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.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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Animals
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Apoptosis*
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Carcinoma, Hepatocellular / chemically induced
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Carcinoma, Hepatocellular / metabolism*
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Carcinoma, Hepatocellular / pathology
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Cells, Cultured
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Disease Susceptibility
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Down-Regulation
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Hepatocytes / metabolism
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Hepatocytes / pathology*
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Liver Neoplasms, Experimental / chemically induced
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Liver Neoplasms, Experimental / metabolism*
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Liver Neoplasms, Experimental / pathology
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Mice
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Mice, Transgenic
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Promoter Regions, Genetic
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Protein Transport
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / physiology*
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Signal Transduction
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Smad3 Protein / biosynthesis
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Smad3 Protein / genetics
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Smad3 Protein / physiology*
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Transcription, Genetic
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Transforming Growth Factor beta / physiology
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Proto-Oncogene Proteins c-bcl-2
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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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p38 Mitogen-Activated Protein Kinases