Department of Biochemistry and Molecular Genetics, University of Virginia, School of Medicine, Charlottesville, VA, USA.
Oncogene. 2013 Oct 17;32(42):5017-25. doi: 10.1038/onc.2012.534. Epub 2012 Nov 26.
Adenoviruses are linear double-stranded DNA viruses that infect human and rodent cell lines, occasionally transform them and cause tumors in animal models. The host cell challenges the virus in multifaceted ways to restrain viral gene expression and DNA replication, and sometimes even eliminates the infected cells by programmed cell death. To combat these challenges, adenoviruses abrogate the cellular DNA damage response pathway. Tip60 is a lysine acetyltransferase that acetylates histones and other proteins to regulate gene expression, DNA damage response, apoptosis and cell cycle regulation. Tip60 is a bona fide tumor suppressor as mice that are haploid for Tip60 are predisposed to tumors. We have discovered that Tip60 is degraded by adenovirus oncoproteins EIB55K and E4orf6 by a proteasome-mediated pathway. Tip60 binds to the immediate early adenovirus promoter and suppresses adenovirus EIA gene expression, which is a master regulator of adenovirus transcription, at least partly through retention of the virally encoded repressor pVII on this promoter. Thus, degradation of Tip60 by the adenoviral early proteins is important for efficient viral early gene transcription and for changes in expression of cellular genes.
腺病毒是一种线性双链 DNA 病毒，感染人类和啮齿动物细胞系，偶尔会将它们转化并在动物模型中引发肿瘤。宿主细胞以多种方式挑战病毒，以抑制病毒基因表达和 DNA 复制，有时甚至通过程序性细胞死亡消除受感染的细胞。为了应对这些挑战，腺病毒会阻断细胞的 DNA 损伤反应途径。Tip60 是一种赖氨酸乙酰转移酶，可乙酰化组蛋白和其他蛋白质，以调节基因表达、DNA 损伤反应、细胞凋亡和细胞周期调控。Tip60 是一种真正的肿瘤抑制因子，因为单倍体缺失 Tip60 的小鼠容易发生肿瘤。我们发现，腺病毒致癌蛋白 EIB55K 和 E4orf6 通过蛋白酶体介导的途径使 Tip60 降解。Tip60 结合到早期腺病毒启动子，并抑制腺病毒 EIA 基因的表达，该基因是腺病毒转录的主要调节剂，至少部分是通过保留病毒编码的 repressor pVII 在此启动子上。因此，腺病毒早期蛋白对 Tip60 的降解对于病毒早期基因转录的高效和细胞基因表达的变化非常重要。
