KSHV vCyclin counters the senescence/G1 arrest response triggered by NF-κB hyperactivation.
Many oncogenic viruses activate nuclear factor-κB (NF-κB) as a part of their replicative cycles. We have shown recently that persistent and potentially oncogenic activation of NF-κB by the human T-lymphotropic virus 1 (HTLV-1) oncoprotein Tax immediately triggers a host senescence response mediated by cyclin-dependent kinase inhibitors: p21(CIP1/WAF1) (p21) and p27(Kip1) (p27) Here we demonstrate that RelA/NF-κB activation by Kaposi sarcoma herpesvirus (KSHV) latency protein vFLIP also leads to p21/p27 upregulation and G1 cell cycle arrest. Remarkably, KSHV vCyclin, another latency protein coexpressed with vFLIP from a bicistronic latency-specific mRNA, was found to prevent the senescence and G1 arrest induced by HTLV-1 Tax and vFLIP, respectively. This is because of the known ability of vCyclin/cyclin-dependent kinase 6 complex to resist p21 and p27 inhibition and cause p27 degradation. In KSHV-transformed BCBL-1 cells, sustained vFLIP expression with small hairpin RNAs-mediated vCyclin depletion resulted in G1 arrest. The functional interdependence of vFLIP and vCyclin explains why they are cotranslated from the same viral mRNA. Importantly, deregulation of the G1 cyclin-dependent kinase can facilitate chronic I-κB kinases/NF-κB activation.
Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
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H
Zhi
Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
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MA
Zahoor
Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
A M D
AM
Shudofsky
Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
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CZ
Giam
D051361:Cyclin-Dependent Kinase 6 / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000502:physiology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000502:physiology; D059585:G1 Phase Cell Cycle Checkpoints; D016356:Gene Products, tax; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism*; D014764:Viral Proteins / Q000502:physiology*
D050759:Cyclin-Dependent Kinase Inhibitor p21; D016356:Gene Products, tax; C118264:HHV8-Vcyc protein, Human herpesvirus 8; D016328:NF-kappa B; D014764:Viral Proteins; C481275:viral FLIP protein, Human herpesvirus 8; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051550:I-kappa B Kinase; D051361:Cyclin-Dependent Kinase 6