Jeong Sunam, Cho Il-Rae, An Won Gun, Jhun Byung Hak, Lee BokSoo, Park Keerang, Chung Young-Hwa
Department of Nanomedical Engineering, Joint Research Center of Pusan National University-Fraunhofer IGB, BK21 Nano Fusion Technology Team, Pusan National University, Miryang 627-706, Korea.
Exp Mol Med. 2007 Feb 28;39(1):56-64. doi: 10.1038/emm.2007.7.
Herpesvirus saimiri (HVS), a member of the gamma-herpesvirus family, encodes an oncoprotein called Saimiri Transforming Protein (STP) which is required for lymphoma induction in non-human primates. However, a detailed mechanism of STP-A11-induced oncogenesis has not been revealed yet. We first report that STP-A11 oncoprotein interacts with TNF-alpha receptor-associated factor (TRAF) 6 in vivo and in vitro. Mutagenesis analysis of the TRAF6-binding motif (10)PQENDE(15) in STP-A11 reveals that Glu (E)(12) residue is critical for binding to TRAF6 and NF-kappaB activation. Interestingly, co-expression of E12A mutant, lack of TRAF6 binding, with cellular Src (Src) results in decreased transcriptional activity of Stat3 and AP-1, a novel target of STP-A11 compared to that of wild type. Furthermore, the presence of STP-A11 enhances the association of TRAF6 with Src and induces the translocation of both TRAF6 and Src to a nonionic detergent-insoluble fraction. Taken together, these studies suggest that STP-A11 oncoprotein up-regulates both NF-kappaB and AP-1 transcription activity through TRAF6, which would ultimately contribute cellular transformation.
赛米里疱疹病毒（HVS）是γ-疱疹病毒家族的成员，编码一种名为赛米里转化蛋白（STP）的癌蛋白，该蛋白是非人类灵长类动物淋巴瘤诱导所必需的。然而，STP-A11诱导肿瘤发生的详细机制尚未揭示。我们首次报道STP-A11癌蛋白在体内和体外与肿瘤坏死因子-α受体相关因子（TRAF）6相互作用。对STP-A11中TRAF6结合基序（10）PQENDE（15）的诱变分析表明，谷氨酸（E）（12）残基对于与TRAF6结合和NF-κB激活至关重要。有趣的是，与细胞Src共表达缺乏TRAF6结合的E12A突变体，与野生型相比，Stat3和AP-1（STP-A11的一个新靶点）的转录活性降低。此外，STP-A11的存在增强了TRAF6与Src的结合，并诱导TRAF6和Src向非离子去污剂不溶性部分的转位。综上所述，这些研究表明，STP-A11癌蛋白通过TRAF6上调NF-κB和AP-1转录活性，这最终将导致细胞转化。
