Institute of Molecular and Cell Biology, Singapore.
Cell Cycle. 2012 Feb 1;11(3):617-27. doi: 10.4161/cc.11.3.19115.
Integrated high-risk human papillomavirus (HPV) DNA was frequently detected in the genomes of cervical carcinoma cells. The HPV E6 and E7 oncoproteins disrupt the functions of tumor suppressors p53 and Rb; thus, understanding the mechanism by which HPV E6 and E7 gene expression is regulated in cancer cells is highly relevant to cancer biology. Brg1 is a catalytic subunit of the SWI/SNF chromatin remodeling complexes that function in the transcriptional regulation of certain cellular genes. Here, we show that knockdown of Brg1 in HeLa cells leads to cell cycle arrest, p53 and Rb protein accumulation and, interestingly, downregulated expression of HPV18 E6 and E7 genes. Brg1 binds the HPV18 LCR in a JunB- and p300-dependent manner and is required for efficient recruitment of RNA polymerase II to the HPV18 LCR. The function of Brg1 in HPV18 gene regulation is unique given that its homolog Brm does not play a role in this regulatory pathway, and this may help design target-specific intervention strategies.
整合的高危型人乳头瘤病毒（HPV）DNA 经常在宫颈癌细胞的基因组中被检测到。HPV E6 和 E7 癌蛋白破坏肿瘤抑制因子 p53 和 Rb 的功能；因此，了解 HPV E6 和 E7 基因表达在癌细胞中的调控机制与癌症生物学密切相关。BRG1 是 SWI/SNF 染色质重塑复合物的催化亚基，该复合物在某些细胞基因的转录调控中发挥作用。在这里，我们表明在 HeLa 细胞中敲低 Brg1 会导致细胞周期停滞、p53 和 Rb 蛋白积累，有趣的是，HPV18 E6 和 E7 基因的表达下调。Brg1 以 JunB 和 p300 依赖性的方式结合 HPV18 LCR，并且对于 RNA 聚合酶 II 向 HPV18 LCR 的有效募集是必需的。鉴于其同源物 Brm 在此调节途径中不起作用，因此 Brg1 在 HPV18 基因调控中的作用是独特的，这可能有助于设计针对特定靶点的干预策略。
