Chromatin-bound p53 anchors activated Smads and the mSin3A corepressor to confer transforming growth factor β-mediated transcription repression

Deepti Srinivas Wilkinson, Wen Wei Tsai, Maria A. Schumacher, Michelle Craig Barton

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

In hepatic cells, Smad and SnoN proteins converge with p53 to repress transcription of AFP, an oncodevelopmental tumor marker aberrantly reactivated in hepatoma cells. Using p53- and SnoN-depleted hepatoma cell clones, we define a mechanism for repression mediated by this novel transcriptional partnership. We find that p53 anchors activated Smads and the corepressor mSin3A to the AFP distal promoter. Sequential chromatin immunoprecipitation analyses and molecular modeling indicate that p53 and Smad proteins simultaneously occupy overlapping p53 and Smad regulatory elements to establish repression of AFP transcription. In addition to its well-known function in antagonizing transforming growth factor β (TGF-β) responses, we find that SnoN actively participates in AFP repression by positively regulating mSin3A protein levels. We propose that activation of TGF-β signaling restores a dynamic interplay between p53 and TGF-β effectors that cooperate to effectively target mSin3A to tumor marker AFP and reestablish transcription repression.

Original languageEnglish (US)
Pages (from-to)1988-1998
Number of pages11
JournalMolecular and cellular biology
Volume28
Issue number6
DOIs
StatePublished - Mar 2008
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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