The SWI/SNF chromatin remodeling subunit BRG1 is a critical regulator of p53 necessary for proliferation of malignant cells

S. R. Naidu, I. M. Love, A. N. Imbalzano, S. R. Grossman, E. J. Androphy

Research output: Contribution to journalArticle

86 Scopus citations

Abstract

The tumor suppressor p53 preserves genome integrity by inducing transcription of genes controlling growth arrest or apoptosis. Transcriptional activation involves nucleosomal perturbation by chromatin remodeling enzymes. Mammalian SWI/SNF remodeling complexes incorporate either the Brahma-related gene 1 (BRG1) or Brahma (Brm) as the ATPase subunit. The observation that tumor cell lines harboring wild-type p53 specifically maintain expression of BRG1 and that BRG1 complexes with p53 prompted us to examine the role of BRG1 in regulation of p53. Remarkably, RNAi depletion of BRG1, but not Brm, led to the activation of endogenous wild-type p53 and cell senescence. We found a proline-rich region unique to BRG1 was required for binding to the histone acetyl transferase protein, CBP, as well as to p53. Ectopic expression of a proline-rich region deletion mutant BRG1 that is defective for CBP binding inhibited p53 destabilization. Importantly, RNAi knockdown of BRG1 and CBP reduced p53 poly-ubiquitination in vivo. In support of p53 inactivation by the combined activities of BRG1 and CBP, we show that DNA damage signals promoted disassociation of BRG1 from CBP, thereby allowing p53 accumulation. Our data demonstrate a novel function of the evolutionarily conserved chromatin remodeling subunit BRG1, which cooperates with CBP to constrain p53 activity and permit cancer cell proliferation.

Original languageEnglish (US)
Pages (from-to)2492-2501
Number of pages10
JournalOncogene
Volume28
Issue number27
DOIs
StatePublished - Jul 9 2009

Keywords

  • Chromatin remodeling
  • P53
  • Proteasomal degradation

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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