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

Oncogene volume 28, pages 2492–2501 (2009)Cite this article

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.

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Acknowledgements

We thank Marius Pop and Andrew King for CBP and p300 shRNA, Andrew Turnell for GST–CBP fusion constructs, Yuval Bibi Nitzan for comments and assistance with the figures and Neal Silverman for assistance with baculovirus protein production. R01 CA107532 to SRG, R01 GM56244 to ANI and R01 CA107394 to EJA supported this work.

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Authors and Affiliations

  1. Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA

    S R Naidu, I M Love, S R Grossman & E J Androphy

  2. Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA, USA

    A N Imbalzano

  3. Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA

    S R Grossman

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  1. S R Naidu
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Correspondence to E J Androphy.

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Naidu, S., Love, I., Imbalzano, A. et al. The SWI/SNF chromatin remodeling subunit BRG1 is a critical regulator of p53 necessary for proliferation of malignant cells. Oncogene 28, 2492–2501 (2009). https://doi.org/10.1038/onc.2009.121

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