Zhi H, Zahoor M A, Shudofsky A M D, Giam C-Z
Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
Oncogene. 2015 Jan 22;34(4):496-505. doi: 10.1038/onc.2013.567. Epub 2014 Jan 27.
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.
许多致癌病毒在其复制周期中会激活核因子-κB（NF-κB）。我们最近发现，人类嗜T淋巴细胞病毒1型（HTLV-1）癌蛋白Tax对NF-κB的持续且潜在致癌性激活会立即触发由细胞周期蛋白依赖性激酶抑制剂介导的宿主衰老反应：p21（CIP1/WAF1）（p21）和p27（Kip1）（p27）。在此，我们证明卡波西肉瘤疱疹病毒（KSHV）潜伏蛋白vFLIP对RelA/NF-κB的激活也会导致p21/p27上调和G1期细胞周期阻滞。值得注意的是，KSHV vCyclin是另一种与vFLIP从双顺反子潜伏特异性mRNA共表达的潜伏蛋白，它分别能阻止HTLV-1 Tax和vFLIP诱导的衰老和G1期阻滞。这是因为vCyclin/细胞周期蛋白依赖性激酶6复合物具有抵抗p21和p27抑制并导致p27降解的已知能力。在KSHV转化的BCBL-1细胞中，用小发夹RNA介导的vCyclin耗竭来持续表达vFLIP会导致G1期阻滞。vFLIP和vCyclin的功能相互依赖性解释了它们为何从同一病毒mRNA共翻译。重要的是，G1期细胞周期蛋白依赖性激酶的失调可促进慢性I-κB激酶/NF-κB激活。
