Martin L G, Demers G W, Galloway D A
Program in Cancer Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98104, USA.
J Virol. 1998 Feb;72(2):975-85. doi: 10.1128/JVI.72.2.975-985.1998.
The development of neoplasia frequently involves inactivation of the p53 and retinoblastoma (Rb) tumor suppressor pathways and disruption of cell cycle checkpoints that monitor the integrity of replication and cell division. The human papillomavirus type 16 (HPV-16) oncoproteins, E6 and E7, have been shown to bind p53 and Rb, respectively. To further delineate the mechanisms by which E6 and E7 affect cell cycle control, we examined various aspects of the cell cycle machinery. The low-risk HPV-6 E6 and E7 proteins did not cause any significant change in the levels of cell cycle proteins analyzed. HPV-16 E6 resulted in very low levels of p53 and p21 and globally elevated cyclin-dependent kinase (CDK) activity. In contrast, HPV-16 E7 had a profound effect on several aspects of the cell cycle machinery. A number of cyclins and CDKs were elevated, and despite the elevation of the levels of at least two CDK inhibitors, p21 and p16, CDK activity was globally increased. Most strikingly, cyclin E expression was deregulated both transcriptionally and posttranscriptionally and persisted at high levels in S and G2/M. Transit through G1 was shortened by the premature activation of cyclin E-associated kinase activity. Elevation of cyclin E levels required both the CR1 and CR2 domains of E7. These data suggest that cyclin E may be a critical target of HPV-16 E7 in the disruption of G1/S cell cycle progression and that the ability of E7 to regulate cyclin E involves activities in addition to the release of E2F.
肿瘤形成的发展常常涉及p53和视网膜母细胞瘤（Rb）肿瘤抑制途径的失活以及监测复制和细胞分裂完整性的细胞周期检查点的破坏。已证明人乳头瘤病毒16型（HPV - 16）癌蛋白E6和E7分别与p53和Rb结合。为了进一步阐明E6和E7影响细胞周期调控的机制，我们研究了细胞周期机制的各个方面。低风险HPV - 6 E6和E7蛋白在所分析的细胞周期蛋白水平上未引起任何显著变化。HPV - 16 E6导致p53和p21水平极低，并使细胞周期蛋白依赖性激酶（CDK）活性整体升高。相比之下，HPV - 16 E7对细胞周期机制的多个方面有深远影响。一些细胞周期蛋白和CDK水平升高，尽管至少两种CDK抑制剂p21和p16水平升高，但CDK活性整体增加。最引人注目的是，细胞周期蛋白E的表达在转录和转录后均失调，并在S期和G2/M期持续高水平。细胞周期蛋白E相关激酶活性的过早激活缩短了G1期的进程。细胞周期蛋白E水平的升高需要E7的CR1和CR2结构域。这些数据表明，细胞周期蛋白E可能是HPV - 16 E7破坏G1/S细胞周期进程的关键靶点，并且E7调节细胞周期蛋白E的能力除了释放E2F之外还涉及其他活性。
