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Chromatin-bound p53 anchors activated Smads and the mSin3A corepressor to confer

Deepti Srinivas Wilkinson1, Wen-Wei Tsai, Maria A Schumacher

  • 1Department of Biochemistry and Molecular Biology, Unit 1000, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.

Molecular and Cellular Biology
|January 24, 2008
PubMed

Insights

Hepatoma cells reactivate the AFP tumor marker. A novel partnership between p53 and Smad proteins, alongside SnoN, represses AFP transcription by targeting mSin3A to the AFP promoter.

Area of Science:

  • Molecular Biology
  • Oncology
  • Gene Regulation

Background:

  • Alpha-fetoprotein (AFP) is an oncodevelopmental tumor marker reactivated in hepatoma cells.
  • The transcriptional repression of AFP is crucial for understanding hepatoma development.
  • Smad proteins and p53 are known regulators of gene expression in hepatic cells.

Purpose of the Study:

  • To elucidate the mechanism by which p53, Smad, and SnoN proteins cooperate to repress AFP transcription.
  • To define the role of the novel transcriptional partnership between p53 and Smad proteins in hepatoma cells.
  • To investigate the function of SnoN in the repression of the AFP gene.

Main Methods:

  • Utilized p53- and SnoN-depleted hepatoma cell clones.
  • Performed sequential chromatin immunoprecipitation (ChIP) analyses.
  • Employed molecular modeling to study protein-DNA interactions.

Main Results:

  • p53 anchors activated Smads and the corepressor mSin3A to the AFP distal promoter.
  • p53 and Smad proteins bind simultaneously to overlapping regulatory elements, repressing AFP transcription.
  • SnoN positively regulates mSin3A protein levels, actively participating in AFP repression.

Conclusions:

  • A novel transcriptional partnership involving p53, Smad, and SnoN mediates AFP repression in hepatoma cells.
  • Activation of transforming growth factor beta (TGF-beta) signaling re-establishes the interplay between p53 and TGF-beta effectors to repress AFP.
  • This mechanism highlights a potential therapeutic target for reactivated AFP in hepatoma.

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