Xu Yang, Zhang Jin, Chen Xinbin
Center for Comparative Oncology, University of California, Davis, CA 95616, USA.
J Biol Chem. 2007 Dec 28;282(52):37429-35. doi: 10.1074/jbc.M706039200. Epub 2007 Oct 15.
Brahma (Brm) and Brahma-related gene-1 (Brg1) ATPases share similarities in structure and function, but their presence in human SWI/SNF chromatin remodeling complexes is mutually exclusive. Although Brm and Brg1 can compensate for each other, it is possible that Brm and Brg1 have their unique properties to differentially regulate gene expression in vivo. To explore this, we examined the requirement of Brm and Brg1 for p53-dependent transcription, especially p53-mediated induction of p21 and MDM2, using cell lines in which Brm or Brg1 could be inducibly knocked down. We found that Brg1, but not Brm, is required for p21 induction in MCF7 cells. However, in Brg1-deficient H1299 cells, Brm is also required for p21 induction. Likewise, Brm is necessary for induction of p21 in MCF7 cells in which Brg1 is stably knocked down. In contrast, Brg1 has little, if any, effect on p53-mediated induction of MDM2 in cells that have Brm and vice versa. In addition, we demonstrated that the impaired induction of p21 upon Brg1 knockdown is at least in part due to decreased p53 binding to the p21 promoter. Taken together, we provided evidence that Brg1 is preferentially recruited by p53 for inducing a subset of target genes through chromatin remodeling. Thus, we hypothesize that the potential tumor suppressor function for Brg1 is mediated in part through the p53 pathway.
BRM（Brahma）和与BRM相关的基因1（Brg1）ATP酶在结构和功能上具有相似性，但它们在人类SWI/SNF染色质重塑复合物中的存在是相互排斥的。尽管BRM和Brg1可以相互补偿，但BRM和Brg1可能具有独特的特性，以在体内差异调节基因表达。为了探究这一点，我们使用可诱导敲低BRM或Brg1的细胞系，研究了BRM和Brg1对p53依赖性转录的需求，特别是p53介导的p21和MDM2的诱导。我们发现，在MCF7细胞中，p21的诱导需要Brg1，而不是BRM。然而，在Brg1缺陷的H1299细胞中，p21的诱导也需要BRM。同样，在稳定敲低Brg1的MCF7细胞中，BRM对于p21的诱导是必需的。相反，在含有BRM的细胞中，Brg1对p53介导的MDM2诱导几乎没有影响，反之亦然。此外，我们证明，敲低Brg1后p21诱导受损至少部分是由于p53与p21启动子的结合减少。综上所述，我们提供了证据表明，p53优先招募Brg1，通过染色质重塑诱导一部分靶基因。因此，我们推测Brg1的潜在肿瘤抑制功能部分是通过p53途径介导的。
