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Transcriptional repression by wild-type p53 utilizes histone deacetylases, mediated by interaction with mSin3a

M Murphy1, J Ahn, K K Walker

  • 1Department of Pharmacology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA. ME_Murphy@FCCC.edu

Genes & Development
|October 16, 1999
PubMed

Insights

The p53 tumor suppressor protein represses gene transcription, a function crucial for apoptosis. This study reveals p53 interacts with histone deacetylases (HDACs) via mSin3a, impacting gene expression and cell death.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • The p53 tumor suppressor protein plays a dual role in gene regulation, activating and repressing transcription.
  • The mechanism underlying p53's transcriptional repression activity, particularly its role in apoptosis, is not well understood.

Purpose of the Study:

  • To investigate the molecular mechanisms of p53-mediated transcriptional repression.
  • To elucidate the role of p53's repression function in apoptosis induction.

Main Methods:

  • Utilized trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, to assess p53's repression activity.
  • Investigated in vivo physical association between p53, HDACs, and the corepressor mSin3a.
  • Analyzed p53 and mSin3a binding to the Map4 promoter and histone acetylation status.

Main Results:

  • TSA treatment abrogated p53's repression of Map4 and stathmin gene transcription.
  • p53 was found to physically associate with HDACs through the corepressor mSin3a.
  • Wild-type p53 and mSin3a bound to the Map4 promoter, correlating with deacetylated histones, an interaction disrupted by mutant p53.
  • Inhibition of p53-mediated transcriptional repression by TSA significantly impaired p53-induced apoptosis.

Conclusions:

  • This study provides the first mechanistic insights into p53-mediated transcriptional repression.
  • The interaction of p53 with HDACs via mSin3a is critical for repressing target genes.
  • p53's transcriptional repression function is essential for its role in inducing apoptosis.

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