HVS STP-C ONCOPROTEIN TARGETS TRAFS TO INDUCE CELL GROWTH TRANSFORMATION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 几种病毒蛋白已经开发出不同的策略来靶向肿瘤坏死因子受体相关因子(TRAF)来激活NF-kB转录活性，这表明这一途径在病毒生命周期和致病过程中具有重要意义。虽然不是病毒复制所必需的，但疱疹病毒塞米里(HVS)癌蛋白被称为塞米里转化蛋白(STP)，在培养的淋巴细胞永生化和灵长类动物的淋巴瘤诱导中是必需的。我们先前已经证明，HVS C亚组STP-C癌蛋白与TRAF2相互作用，导致NF-kB活性的激活。在这项研究中，我们进一步阐明了TRAF结合在STP-C信号转导中的作用，该信号转导导致了NF-kB的激活和细胞生长转化。我们证明了STP-C通过其氨基末端短序列P10IE12ETG15与TRAF6相互作用，该序列与TRAF2-相互作用基序完全重叠。精氨酸(P10R)突变抑制了TRAF2结合和核因子-kB的激活。相反，谷氨酸到丙氨酸(E12A)突变取消了TRAF6的结合，但部分抑制了NF-kB的激活活性，表明TRAF2在STP-C介导的NF-kB激活中起主要作用。与此一致的是，在缺乏TRAF2和TRAF5基因的小鼠胚胎成纤维细胞(MEF)中，STP-C诱导的NF-kB活性完全受损，而在缺乏TRAF6基因的MEF中，STP-C诱导的NF-kB活性降低。与艾滋病有关。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Several viral proteins have developed diverse strategies for targeting tumor necrosis factor (TNF) receptor-associated factors (TRAFs) to activate NF-kB transcriptional activity, suggesting the importance of this pathway in viral lifecycle and pathogenesis. Although not required for viral replication, Herpesvirus saimiri (HVS) oncoprotein, termed saimiri transforming protein (STP), is necessary for lymphoid cell immortalization in culture and lymphoma induction in primates. We have previously shown that HVS subgroup C STP-C oncoprotein interacts with TRAF2, resulting in the activation of NF-kB activity. In this study, we further elucidated the role of TRAF binding in STP-C signal transduction leading to NF-kB activation and cell growth transformation. We demonstrate that STP-C interacts with TRAF6 through its amino-terminal short sequence P10IE12ETG15 that completely overlaps with the TRAF2-interaction motif. The proline to arginine (P10R) mutation abrogated TRAF2 binding and NF-kB activation. In contrast, the glutamic acid to alanine (E12A) mutation abolished TRAF6 binding but partially abrogated NF-kB activation activity, indicating a major role of TRAF2 in STP-C mediated NF-kB activation. Consistent with this, the induction of NF-kB activity by STP-C was completely impaired in mouse embryonic fibroblasts (MEFs) deficient for TRAF2 and TRAF5 genes but reduced in MEFs deficient for TRAF6 gene. AIDS related.