Naidu SR, Love IM, Imbalzano AN, Grossman SR, Androphy EJ.. The SWI/SNF chromatin remodeling subunit BRG1 is a critical regulator of p53 necessary for proliferation of malignant cells. Oncogene 28: 2492-2501

Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
Oncogene (Impact Factor: 8.46). 06/2009; 28(27):2492-501. DOI: 10.1038/onc.2009.121
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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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    • "This is relevant to our study for a number of reasons: First, the SWI/SNF CRC is a well-characterized ATP-dependent nucleosomal remodeler. Second, multiple components of the SWI/SNF complex have been identified as wild-type p53-binding partners, including INI1 and BRG1 (Lee et al. 2002; Naidu et al. 2009), BAF60A and BAF155 (Oh et al. 2008), ARID1A (Guan et al. 2011), and BRD7 (Burrows et al. 2010). Third, TP53 and SWI/ SNF mutations have a tendency toward mutual exclusivity in cancers, suggestive of a shared mechanism (Kadoch et al. 2013). "
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    ABSTRACT: Mutant p53 impacts the expression of numerous genes at the level of transcription to mediate oncogenesis. We identified vascular endothelial growth factor receptor 2 (VEGFR2), the primary functional VEGF receptor that mediates endothelial cell vascularization, as a mutant p53 transcriptional target in multiple breast cancer cell lines. Up-regulation of VEGFR2 mediates the role of mutant p53 in increasing cellular growth in two-dimensional (2D) and three-dimensional (3D) culture conditions. Mutant p53 binds near the VEGFR2 promoter transcriptional start site and plays a role in maintaining an open conformation at that location. Relatedly, mutant p53 interacts with the SWI/SNF complex, which is required for remodeling the VEGFR2 promoter. By both querying individual genes regulated by mutant p53 and performing RNA sequencing, the results indicate that >40% of all mutant p53-regulated gene expression is mediated by SWI/SNF. We surmise that mutant p53 impacts transcription of VEGFR2 as well as myriad other genes by promoter remodeling through interaction with and likely regulation of the SWI/SNF chromatin remodeling complex. Therefore, not only might mutant p53-expressing tumors be susceptible to anti VEGF therapies, impacting SWI/SNF tumor suppressor function in mutant p53 tumors may also have therapeutic potential. © 2015 Pfister et al.; Published by Cold Spring Harbor Laboratory Press.
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    • "Previous studies identified that the interactions between srGAP3 and its interaction partners, such as Robo1 (Wong et al., 2001), Wave1 (Soderling et al., 2002; Soderling et al., 2007), Gephyrin (Okada et al., 2011) and Lamellipodin (Endris et al., 2011) are mediated by the SH3 domain and the proline-rich motif. The Brg1 protein contains several proline-rich regions that are similar to the consensus SH3 binding site (Naidu et al., 2009; Trotter and Archer, 2008). We first performed some immunoprecipitation experiments to map the interaction sites in srGAP3 and Brg1 (Fig. 3A). "
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    ABSTRACT: The Slit-Robo GTPase activating protein 3 (srGAP3) is an important modulator of actin cytoskeletal dynamics and has an important influence on a variety of neurodevelopmental processes. Mutations in the SRGAP3 gene on chromosome 3p25 have been found in patients with intellectual disability. Genome-wide association studies and behavioral assays of knockout mice had also revealed SRGAP3 as a risk gene for schizophrenia. We have recently shown that srGAP3 protein undergoes regulated shuttling between the cytoplasm and the nucleus during neuronal development. It is shown here that nuclear-localized srGAP3 interacts with the SWI/SNF remodeling factor Brg1. This interaction is mediated by the C-terminal of srGAP3 and the ATPase motif of Brg1. In the primary cultured rat cortical neurons, the levels of nuclear-localized srGAP3 and its interaction with Brg1 have a significant impact on dendrite complexity. Furthermore, the interaction between srGAP3 and Brg1 was also involved in valporic acid (VPA) -induced neuronal differentiation of Neuro2a cells. We then show that GTP-bound Rac1 and GAP-43 may be potential mediators of nuclear srGAP3 and Brg1. Our results not only indicate a novel signaling pathway that contributes to neuronal differentiation and dendrite morphology, but also implicate a novel molecular mechanism underlying srGAP3 regulation of gene expression.
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    • "Besides, SMARCA4 heterozygotes are predisposed to differentiated epithelial tumors, which supports that SMARCA4 plays an important role in the regulation of cellular proliferation32. In addition, SMARCA4 has shown to involve in tumor suppression by physical interaction with other tumor suppressors including pRb, p53, and c-Myc333435. Meanwhile, SMARCA4 has also been found under expressed in human hepatocellular carcinoma by searching gene expression atlas ( "
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    ABSTRACT: Chromatin remodeling has been newly established as an important cancer genome characterization and recent exome and whole-genome sequencing studies of hepatocellular carcinoma (HCC) showed that recurrent inactivating mutations in SWI/SNF subunits involved in the molecular basis of hepatocarcinogenesis. To test the hypothesis that genetic variants in the key subunits of SWI/SNF complexes may contribute to HCC susceptibility, we systematically assessed associations of genetic variants in SWI/SNF complexes with HCC risk using a two-staged case-control study in Chinese population. A set of 24 single nucleotide polymorphisms (SNPs) in SWI/SNF complexes were examined in stage 1 with 502 HCC patients and 487 controls and three promising SNPs (SMARCA4 rs11879293, rs2072382 and SMARCB1 rs2267032) were further genotyped in stage 2 comprising 501 cases and 545 controls for validation. SMARCA4 rs11879293 presented consistently significant associations with the risk of HCC at both stages, with an OR of 0.73 (95% CI: 0.62-0.87) using additive model in combined analysis. Moreover, the decreased risk of HCC associated with SMARCA4 rs11879293 AG/AA was more evident among HBsAg positive individuals (OR = 0.47, 95% CI: 0.27-0.80) in combined analysis. The study highlighted the potential role of the SWI/SNF complexes in conferring susceptibility to HCC, especially modified HCC risk by HBV infection.
    Scientific Reports 02/2014; 4:4147. DOI:10.1038/srep04147 · 5.58 Impact Factor
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