Wu Shwu-Yuan, Nin Dawn Sijin, Lee A-Young, Simanski Scott, Kodadek Thomas, Chiang Cheng-Ming
Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA; Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Cell Rep. 2016 Aug 9;16(6):1733-1748. doi: 10.1016/j.celrep.2016.07.001. Epub 2016 Jul 28.
Post-translational modification can modulate protein conformation and alter binding partner recruitment within gene regulatory regions. Here, we report that bromodomain-containing protein 4 (BRD4), a transcription co-factor and chromatin regulator, uses a phosphorylation-induced switch mechanism to recruit E2 protein encoded by cancer-associated human papillomavirus (HPV) to viral early gene and cellular matrix metalloproteinase-9 (MMP-9) promoters. Enhanced MMP-9 expression, induced upon keratinocyte differentiation, occurs via BRD4-dependent recruitment of active AP-1 and NF-κB to their target sequences. This is triggered by replacement of AP-1 family members JunB and JunD by c-Jun and by re-localization of NF-κB from the cytoplasm to the nucleus. In addition, BRD4 phosphorylation is critical for E2- and origin-dependent HPV DNA replication. A class of phospho-BRD4-targeting compounds, distinct from the BET bromodomain inhibitors, effectively blocks BRD4 phosphorylation-specific functions in transcription and factor recruitment.
翻译后修饰可以调节蛋白质构象，并改变基因调控区域内结合伴侣的募集。在此，我们报告含溴结构域蛋白4（BRD4），一种转录辅因子和染色质调节剂，利用磷酸化诱导的开关机制将癌症相关人乳头瘤病毒（HPV）编码的E2蛋白募集至病毒早期基因和细胞基质金属蛋白酶9（MMP-9）启动子。角质形成细胞分化时诱导的MMP-9表达增强，是通过BRD4依赖的方式将活性AP-1和NF-κB募集至其靶序列实现的。这是由c-Jun取代AP-1家族成员JunB和JunD以及NF-κB从细胞质重新定位到细胞核所触发的。此外，BRD4磷酸化对于E2和依赖于起始点的HPV DNA复制至关重要。一类靶向磷酸化BRD4的化合物，不同于BET溴结构域抑制剂，能有效阻断BRD4磷酸化特异性的转录和因子募集功能。
