KSHV vCyclin counters the senescence/G1 arrest response triggered by NF-κB hyperactivation.
KSHV vCyclin counters the senescence/G1 arrest response triggered by NF-κB hyperactivation.
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作者：
许多致癌病毒激活NF-κB作为其复制周期的一部分。我们最近发现，NF-κB被人T淋巴细胞病毒1（HTLV-1）癌蛋白Tax持续和潜在致癌激活，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 CIP 1/WAF 1（p21）和p27 Kip 1（p27）在此，我们证明了卡波西肉瘤疱疹病毒（KSHV）潜伏蛋白vFLIP激活RelA/NF-κB也导致p21/WAF 1（p21）和p27 Kip 1（p27）。p27上调和G1期细胞阻滞。值得注意的是，KSHV vCyclin，另一种潜伏蛋白与vFLIP共表达的双顺反子潜伏特异性mRNA，被发现可以防止衰老和G1期阻滞分别由HTLV-1 Tax和vFLIP诱导。这是由于vCyclin/CDK 6复合物抵抗p21和p27抑制并引起p27降解的已知能力。在KSHV转化的BCBL-1细胞中，持续的vFLIP表达和shRNA介导的vCyclin耗竭导致G1期阻滞。vFLIP和vCyclin的功能相互依赖性解释了为什么它们从相同的病毒mRNA共同翻译。重要的是，G1周期蛋白依赖性激酶的失调可以促进慢性IKK/NF-κB激活。
Many oncogenic viruses activate 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 up-regulation and G1 cell cycle arrest. Remarkably, KSHV vCyclin, another latency protein co-expressed 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 due to the known ability of vCyclin/CDK6 complex to resist p21 and p27 inhibition and cause p27 degradation. In KSHV-transformed BCBL-1 cells, sustained vFLIP expression with shRNA-mediated vCyclin depletion resulted in G1 arrest. The functional interdependence of vFLIP and vCyclin explains why they are co-translated from the same viral mRNA. Importantly, deregulation of the G1 cyclin-dependent kinase can facilitate chronic IKK/NF-κB activation.
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DOI：
10.1084/jem.20031467
发表时间：
2004-04-05
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Guasparri I;Keller SA;Cesarman E
通讯作者：
Cesarman E
影响因子：
4
作者：
Field, N;Low, W;Collins, M
通讯作者：
Collins, M
影响因子：
5.4
作者：
Liu, Jianyong;Martin, Heather J.;Hayward, Diane
通讯作者：
Hayward, Diane
影响因子：
5.4
作者：
Bieleski, L;Talbot, SJ
通讯作者：
Talbot, SJ
影响因子：
11.4
作者：
Kuo, Yu-Liang;Giam, Chou-Zen
通讯作者：
Giam, Chou-Zen