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KSHV vCyclin counters the senescence/G1 arrest response triggered by NF-κB hyperactivation

Oncogene volume 34, pages 496–505 (2015)Cite this article

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Abstract

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: p21CIP1/WAF1 (p21) and p27Kip1 (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.

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Acknowledgements

We thank Drs Mary Collins, Johnan Kaleeba and Emmy Verschuren for the vFLIP antibody, vFLIP cDNA and vCyclin expression plasmid, respectively. This work was supported by grants from the National Institutes of Health (R01CA140963 and RO1CA115884) and the USU intramural research program (RO73NV).

Accession numbers

The GENBANK accession numbers or ID numbers for genes encoding the proteins described in this article are: KSHV vCyclin, U93872; vFLIP, U90534; HTLV-1 Tax, AB038239; p21, NM_000389; p27, NM_004064; Cyclin B1, NM_031966; I-κBα, NM_020529; p100/p52, NM_002502; p105/p50, NM_003998; RelA, NM_021975; RelB, NM_006509; and c-Rel, NM_002908.

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HZ and C-ZG designed the experiments and wrote the manuscript. HZ, MAZ and AMDS performed experiments and data analyses.

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  1. Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA

    H Zhi, M A Zahoor, A M D Shudofsky & C-Z Giam

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Correspondence to C-Z Giam.

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Zhi, H., Zahoor, M., Shudofsky, A. et al. KSHV vCyclin counters the senescence/G1 arrest response triggered by NF-κB hyperactivation. Oncogene 34, 496–505 (2015). https://doi.org/10.1038/onc.2013.567

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