Department of Biochemistry and Molecular Genetics, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
Mol Cell. 2010 Jun 11;38(5):700-11. doi: 10.1016/j.molcel.2010.05.020.
The TIP60 tumor suppressor is a histone acetyltransferase involved in transcriptional regulation, checkpoint activation, and p53-directed proapoptotic pathways. We report that human papillomavirus (HPV) E6 destabilizes TIP60 both in vivo and in vitro. TIP60 binds to the HPV major early promoter and acetylates histone H4 to recruit Brd4, a cellular repressor of HPV E6 expression. Both low- and high-risk HPV E6 destabilize TIP60, thereby derepressing their own promoter. Destabilization of TIP60 by HPV E6 also relieves cellular promoters from TIP60-initiated repression and abrogates p53-dependent activation of apoptotic pathway. Degradation of TIP60, therefore, allows low- and high-risk HPV to promote cell proliferation and cell survival.
TIP60 肿瘤抑制因子是一种组蛋白乙酰转移酶，参与转录调控、检查点激活以及 p53 指导的促凋亡途径。我们报告人乳头瘤病毒（HPV）E6 可在体内和体外使 TIP60 不稳定。TIP60 与 HPV 主要早期启动子结合，乙酰化组蛋白 H4，招募 Brd4，Brd4 是 HPV E6 表达的细胞抑制剂。低危和高危 HPV E6 均可使 TIP60 不稳定，从而解除其自身启动子的抑制。HPV E6 对 TIP60 的降解还可使细胞启动子摆脱 TIP60 起始的抑制，并消除 p53 依赖性凋亡途径的激活。因此，TIP60 的降解使得低危和高危 HPV 能够促进细胞增殖和细胞存活。
