Naidu S R, Love I M, Imbalzano A N, Grossman S R, Androphy E J
Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
Oncogene. 2009 Jul 9;28(27):2492-501. doi: 10.1038/onc.2009.121. Epub 2009 May 18.
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.
肿瘤抑制因子p53通过诱导控制细胞生长停滞或凋亡的基因转录来维持基因组完整性。转录激活涉及染色质重塑酶对核小体的扰动。哺乳动物的SWI/SNF重塑复合物包含Brahma相关基因1（BRG1）或Brahma（Brm）作为ATP酶亚基。携带野生型p53的肿瘤细胞系特异性维持BRG1表达以及BRG1与p53形成复合物这一观察结果促使我们研究BRG1在p53调控中的作用。值得注意的是，RNA干扰（RNAi）敲低BRG1而非Brm会导致内源性野生型p53激活和细胞衰老。我们发现BRG1特有的富含脯氨酸区域对于与组蛋白乙酰转移酶蛋白CBP以及p53结合是必需的。对CBP结合有缺陷的富含脯氨酸区域缺失突变体BRG1的异位表达抑制了p53的去稳定化。重要的是，RNAi敲低BRG1和CBP可在体内降低p53的多聚泛素化。为支持BRG1和CBP的联合作用使p53失活，我们表明DNA损伤信号促进BRG1与CBP解离，从而使p53积累。我们的数据证明了进化保守的染色质重塑亚基BRG1的一种新功能，它与CBP协同作用以限制p53活性并促进癌细胞增殖。
