Knight Jason S, Sharma Nikhil, Robertson Erle S
Department of Microbiology and Abramson Comprehensive Cancer Center, University of Pennsylvania Medical School, 201E Johnson Pavilion, 3610 Hamilton Walk, Philadelphia, PA 19104, USA.
Mol Cell Biol. 2005 Mar;25(5):1749-63. doi: 10.1128/MCB.25.5.1749-1763.2005.
The stability of cell cycle checkpoint and regulatory proteins is controlled by the ubiquitin-proteasome degradation machinery. A critical regulator of cell cycle molecules is the E3 ubiquitin ligase SCFSkp2, known to facilitate the polyubiquitination and degradation of p27, E2F, and c-myc. SCFSkp2 is frequently deregulated in human cancers. In this study, we have revealed a novel link between the essential Epstein-Barr virus (EBV) nuclear antigen EBNA3C and the SCFSkp2 complex, providing a mechanism for cell cycle regulation by EBV. EBNA3C associates with cyclin A/cdk2 complexes, disrupting the kinase inhibitor p27 and enhancing kinase activity. The recruitment of SCFSkp2 activity to cyclin A complexes by EBNA3C results in ubiquitination and SCFSkp2-dependent degradation of p27. This is the first report of a viral protein usurping the function of the SCFSkp2 cell cycle regulatory machinery to regulate p27 stability, establishing the foundation for a mechanism by which EBV regulates cyclin/cdk activity in human cancers.
细胞周期检查点和调节蛋白的稳定性由泛素 - 蛋白酶体降解机制控制。细胞周期分子的一个关键调节因子是E3泛素连接酶SCFSkp2，已知它能促进p27、E2F和c - myc的多聚泛素化和降解。SCFSkp2在人类癌症中经常失调。在这项研究中，我们揭示了重要的爱泼斯坦 - 巴尔病毒（EBV）核抗原EBNA3C与SCFSkp2复合物之间的新联系，为EBV调节细胞周期提供了一种机制。EBNA3C与细胞周期蛋白A/cdk2复合物结合，破坏激酶抑制剂p27并增强激酶活性。EBNA3C将SCFSkp2活性募集到细胞周期蛋白A复合物上，导致p27的泛素化和SCFSkp2依赖性降解。这是关于病毒蛋白篡夺SCFSkp2细胞周期调节机制功能以调节p27稳定性的首次报道，为EBV在人类癌症中调节细胞周期蛋白/cdk活性的机制奠定了基础。
