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

Cancer Cell. 2006 Jun;9(6):445-57. doi: 10.1016/j.ccr.2006.04.025.


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

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Apoptosis*
  • Carcinoma, Hepatocellular / chemically induced
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / pathology
  • Cells, Cultured
  • Disease Susceptibility
  • Down-Regulation
  • Hepatocytes / metabolism
  • Hepatocytes / pathology*
  • Liver Neoplasms, Experimental / chemically induced
  • Liver Neoplasms, Experimental / metabolism*
  • Liver Neoplasms, Experimental / pathology
  • Mice
  • Mice, Transgenic
  • Promoter Regions, Genetic
  • Protein Transport
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / physiology*
  • Signal Transduction
  • Smad3 Protein / biosynthesis
  • Smad3 Protein / genetics
  • Smad3 Protein / physiology*
  • Transcription, Genetic
  • Transforming Growth Factor beta / physiology
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Proto-Oncogene Proteins c-bcl-2
  • Smad3 Protein
  • Smad3 protein, mouse
  • Transforming Growth Factor beta
  • p38 Mitogen-Activated Protein Kinases