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, LANASOCS) motif-mediated recruitment of the EC5S 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 LANASOCS-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.
Highlights
Kaposi’s sarcoma-associated herpesvirus (KSHV), named human herpesvirus 8, is a member of the gamma-herpesviruses and is associated with Kaposi’s sarcoma (KS), multicentric Castleman’s disease (MCD) and primary effusion lymphoma (PEL) [1,2,3,4]
We discovered that latency-associated nuclear antigen (LANA) remarkably enhances Aurora A production, and that elevated Aurora A acts as a negative regulator to induce phosphorylation and LANA-mediated ubiquitylation of p53
Inhibition of Aurora A production leads to cell death of KSHV-positive B lymphoma cells
Summary
Kaposi’s sarcoma-associated herpesvirus (KSHV), named human herpesvirus 8, is a member of the gamma-herpesviruses and is associated with Kaposi’s sarcoma (KS), multicentric Castleman’s disease (MCD) and primary effusion lymphoma (PEL) [1,2,3,4]. Studies have shown that PELs are dependent on KSHV for survival, as loss of the KSHV genome results in cell death [5]. These findings demonstrate that KSHV infection can reprogram cellular gene function and thereby mediate viral oncogenesis. KSHV is predominantly latent in most cells in KSHV-associated lesions and during latency only a few viral genes are expressed. The latency associated nuclear antigen (LANA) encoded by open reading frame (ORF) 73, is one of the critical KSHV encoded latent antigens, and is expressed in viral infected tumor cells of KSHV-associated malignancies [6,7]. At the gene transcription level, LANA exerts broad repressive or activation effects by interacting with a number of transcriptional factors including mSin3A, CBP, RING3, GSK3b and p53 for its transcription repression activities [8,14,15,16], and E2F, Sp1, RBP-Jk, ATF4, CBP, Id-1, and Ets to drive transcriptional activation [17,18,19,20,21,22]
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