title: Kaposi's sarcoma herpesvirus upregulates Aurora A expression to promote p53 phosphorylation and ubiquitylation.
abstract: 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.
authors.affiliation: 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.
authors.forename: Qiliang
authors.initials: Q
authors.lastname: Cai
authors.forename: Bingyi
authors.initials: B
authors.lastname: Xiao
authors.forename: Huaxin
authors.initials: H
authors.lastname: Si
authors.forename: Amanda
authors.initials: A
authors.lastname: Cervini
authors.forename: Jianming
authors.initials: J
authors.lastname: Gao
authors.forename: Jie
authors.initials: J
authors.lastname: Lu
authors.forename: Santosh K
authors.initials: SK
authors.lastname: Upadhyay
authors.forename: Suhbash C
authors.initials: SC
authors.lastname: Verma
authors.forename: Erle S
authors.initials: ES
authors.lastname: Robertson
mesh_terms: D000956:Antigens, Viral / Q000235:genetics / Q000378:metabolism; D064127:Aurora Kinases; D045744:Cell Line, Tumor; D015967:Gene Expression Regulation, Viral; D019288:Herpesvirus 8, Human / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000473:pathology / Q000821:virology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D014158:Transcription, Genetic; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination; D015854:Up-Regulation
chemical_list: D000956:Antigens, Viral; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; C109540:latency-associated nuclear antigen; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases