KSHV G protein-coupled receptor inhibits lytic gene transcription in primary-effusion lymphoma cells via p21-mediated inhibition of Cdk2
KSHV G protein-coupled receptor inhibits lytic gene transcription in primary-effusion lymphoma cells via p21-mediated inhibition of Cdk2
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DOI：
10.1182/blood-2005-06-2350
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发表时间：
2006-01-01
期刊：
影响因子：
20.3
通讯作者：
Boshoff, C
中科院分区：
文献类型：
--
作者：
Cannon, M;Cesarman, E;Boshoff, C
卡波西肉瘤（KS）仍然是全球最常见的艾滋病相关恶性肿瘤。特别是在撒哈拉以南非洲，这种侵袭性内皮细胞肿瘤是广泛发病和死亡的原因。卡波西肉瘤相关疱疹病毒（KSHV）感染是KS和原发性渗出性淋巴瘤（PEL）的病因。随着时间的推移，KSHV已经窃取了许多人类基因，这些基因的产物调节血管生成、炎症和细胞周期。其中之一KSHV vGPCR是一种裂解产物，是IL-8受体的组成型活性同系物。虽然它被认为是一种病毒致癌基因，并在小鼠中引起KS样病变，但vGPCR表达导致KSHV感染的PEL细胞的细胞周期停滞。在本研究中，我们表明，这种逮捕是由p21介导的p53-独立的方式，所产生的Cdk 2抑制KSHV裂解转录ORF 50和26的化学诱导的效率降低。重要的是，Cdk 2活性对于其他人类疱疹病毒的复制也是必不可少的。vGPCR延迟或中止KSHV复制的能力可以解释尽管是裂解产物，但这种有效的信号传导分子如何通过其诱导各种KS相关细胞因子在肿瘤形成中起重要作用。
Kaposi sarcoma (KS) remains the most common AIDS-associated malignancy worldwide. In sub-Saharan Africa especially, this aggressive endothelial-cell tumor is a cause of widespread morbidity and mortality. Infection with Kaposi sarcoma-associated herpesvirus (KSHV) is now known to be an etiologic force behind KS and primary-effusion lymphoma (PEL). Over time, KSHV has pirated many human genes whose products regulate angiogenesis, inflammation, and the cell cycle. One of these, the KSHV vGPCR, is a lytic product that is a constitutively active homolog of the IL-8 receptor. Although it is considered a viral oncogene and causes KS-like lesions in mice, vGPCR expression results in cell-cycle arrest of KSHV-infected PEL cells. In the present study, we show that this arrest is mediated by p21 in a p53-independent manner; the resulting Cdk2 inhibition decreases the efficiency of chemical induction of KSHV lytic transcripts ORF 50 and 26. Importantly, Cdk2 activity is also essential for replication in other human herpesviruses. The ability of vGPCR to delay or abort KSHV replication may explain how despite being a lytic product, this potent signaling molecule has a vital role in tumor formation via its induction of various KS-associated cytokines.