Department of Microbiology and the Tumor Virology Program, Abramson Comprehensive Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States of America.
PLoS Pathog. 2012;8(3):e1002566. doi: 10.1371/journal.ppat.1002566. Epub 2012 Mar 1.
Aberrant expression of Aurora A kinase has been frequently implicated in many cancers and contributes to chromosome instability and phosphorylation-mediated ubiquitylation and degradation of p53 for tumorigenesis. Previous studies showed that p53 is degraded by Kaposi's sarcoma herpesvirus (KSHV) encoded latency-associated nuclear antigen (LANA) through its SOCS-box (suppressor of cytokine signaling, LANA(SOCS)) motif-mediated recruitment of the EC(5)S ubiquitin complex. Here we demonstrate that Aurora A transcriptional expression is upregulated by LANA and markedly elevated in both Kaposi's sarcoma tissue and human primary cells infected with KSHV. Moreover, reintroduction of Aurora A dramatically enhances the binding affinity of p53 with LANA and LANA(SOCS)-mediated ubiquitylation of p53 which requires phosphorylation on Ser215 and Ser315. Small hairpin RNA or a dominant negative mutant of Aurora A kinase efficiently disrupts LANA-induced p53 ubiquitylation and degradation, and leads to induction of p53 transcriptional and apoptotic activities. These studies provide new insights into the mechanisms by which LANA can upregulate expression of a cellular oncogene and simultaneously destabilize the activities of the p53 tumor suppressor in KSHV-associated human cancers.
极光激酶 A 的异常表达常与多种癌症相关，并导致染色体不稳定以及磷酸化介导的 p53 泛素化和降解，从而促进肿瘤发生。先前的研究表明，卡波济肉瘤相关疱疹病毒（KSHV）编码的潜伏相关核抗原（LANA）通过其 SOCS 盒（细胞因子信号转导抑制剂，LANA（SOCS））基序募集 EC（5）S 泛素连接酶复合物，从而使 p53 降解。本研究显示，LANA 可上调极光激酶 A 的转录表达，且在 KSHV 感染的卡波济肉瘤组织和人原代细胞中均显著升高。此外，回补极光激酶 A 可显著增强 p53 与 LANA 的结合亲和力，以及 LANA（SOCS）介导的 p53 泛素化，这需要 Ser215 和 Ser315 位点的磷酸化。短发夹 RNA 或极光激酶 A 的显性失活突变体可有效破坏 LANA 诱导的 p53 泛素化和降解，从而诱导 p53 的转录和凋亡活性。这些研究为 LANA 上调细胞癌基因表达并同时破坏 KSHV 相关人类癌症中 p53 肿瘤抑制因子活性的机制提供了新的见解。
