Dynamic Interplay Between Kaposi's Sarcoma-Associated Herpesvirus Latent Proteins in the Control of Oncogene-Induced Senescence
dc.contributor.author | Leidal, Andrew Michael | |
dc.contributor.copyright-release | Not Applicable | en_US |
dc.contributor.degree | Doctor of Philosophy | en_US |
dc.contributor.department | Department of Microbiology & Immunology | en_US |
dc.contributor.ethics-approval | Not Applicable | en_US |
dc.contributor.external-examiner | Dr. Gerardo Ferbeyre | en_US |
dc.contributor.graduate-coordinator | Dr. Brent Johnston | en_US |
dc.contributor.manuscripts | Yes | en_US |
dc.contributor.thesis-reader | Dr. Richard Singer | en_US |
dc.contributor.thesis-reader | Dr. Roy Duncan | en_US |
dc.contributor.thesis-supervisor | Dr. Patrick W.K. Lee and Dr. Craig McCormick | en_US |
dc.date.accessioned | 2012-04-30T16:18:26Z | |
dc.date.available | 2012-04-30T16:18:26Z | |
dc.date.defence | 2012-04-10 | |
dc.date.issued | 2012-04-30 | |
dc.description.abstract | Acute oncogenic stress can activate autophagy and facilitate permanent arrest of the cell cycle through a failsafe mechanism known as oncogene-induced senescence (OIS). Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi’s Sarcoma (KS) and has been reported to encode oncoproteins within its latency program that engage host autophagy and OIS pathways; however, the mechanisms by which KSHV oncoproteins promote KS tumorigenesis remain unclear. Here, I demonstrate that ectopic expression of the latent KSHV protein viral cyclin (v-cyclin) deregulates the cell cycle, induces DNA-damage responses (DDRs) and promotes OIS through an autophagy-dependent mechanism. During latency, v-cyclin is co-expressed from a single transcript with a viral homolog of FLICE-inhibitory protein (v-FLIP) that blocks autophagy by binding and inhibiting Atg3. Co-expression of v-FLIP has no effect on DDRs, but efficiently blocks v-cyclin-induced autophagy and senescence. Remarkably, suppression of v-FLIP function during KSHV latency, through specific inhibitory peptides, rescues host cell autophagy and induces senescence of infected cells. Together, these data reveal a coordinated viral gene-expression program that subverts autophagy, impairs senescence, and facilitates the proliferation of KSHV-infected cells. | en_US |
dc.identifier.uri | http://hdl.handle.net/10222/14813 | |
dc.language.iso | en_US | en_US |
dc.subject | p53 | en_US |
dc.subject | oncogene-induced senescence | en_US |
dc.subject | autophagy | en_US |
dc.subject | Kaposi's sarcoma-associated herpesvirus (KSHV) | en_US |
dc.subject | Kaposi's sarcoma | en_US |
dc.subject | oncovirus | en_US |
dc.subject | DNA damage | en_US |
dc.title | Dynamic Interplay Between Kaposi's Sarcoma-Associated Herpesvirus Latent Proteins in the Control of Oncogene-Induced Senescence | en_US |
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