Increased IL6 Transcription by HHV8

描述：（由申请人提供）人疱疹病毒8型（HHV 8）已被 与三种肿瘤相关：原发性渗出性淋巴瘤，卡波西肉瘤， 和多中心Castleman病 （HIV）相关和无关的病例。此外，有证据表明，HHV 8 可能存在于多发性骨髓瘤患者的骨髓中。HHV 8是 在一般人群中并不普遍（10- 15%的血清阳性率）， 暴露于HHV 8的证据在同性恋者中相当高（60- 70%） 艾滋病毒阳性人群。所有与HHV 8相关的 肿瘤的一个重要特征是它们利用白细胞介素6（IL-6）作为肿瘤生长因子。 IL-6还可能促进HIV感染，因为它诱导HIV增殖 在HIV感染的单核细胞和CD 4阳性T细胞中。因此，我们最初 假设HFIV 8编码的蛋白上调IL-6表达。 在初步数据中，我们成功地证明了HHV 8潜伏蛋白， 潜伏相关核抗原（拉娜）和Fas相关死亡结构域样 干扰素转化酶抑制蛋白（vFLIP），上调细胞 IL-ti表达。我们已经证明，拉娜反式激活IL-6启动子 通过API响应元素，拉娜直接绑定到API响应 元件，vFLIP通过激活NF-κ B和API发挥作用 转录因子此外，vFLIP增强LANA诱导的IL-6 表达，反之亦然。 在这一建议中，我们的具体目标是：1。阐明相关的DNA-蛋白质 LANA介导的LL-6启动子的反式激活中涉及的相互作用。2. 鉴定参与拉娜反式激活的蛋白质-蛋白质相互作用， IL-6启动子。3.确定vFLIP和拉娜在 诱导IL-6表达以及增殖和抑制 内源性HHVS感染的细胞凋亡，并表征分子 vFLIP和拉娜之间的相互作用导致其相互作用 IL-6诱导的增强。 我们的长期目标是确定参与的分子机制 HHVS介导的细胞IL-6产生的上调。的识别 参与增强的拉娜或vFLIP的特定结构域 IL-ti表达可能为药物开发提供天然靶点， 这些蛋白质在HHV 8感染的恶性细胞中的作用。

DESCRIPTION: (provided by applicant) The human herpesvirus 8 (HHV8) has been associated with three neoplasms: primary effusion lymphoma, Kaposi's sarcoma, and multicentric Castleman' s disease in human immunodeficiency virus (HIV)-related and -unrelated cases. In addition, there is evidence that HHV8 may be present in the bone marrow of multiple myeloma patients. While HHV8 is not ubiquitous in the general population (10-15 percent seroprevalence), evidence of exposure to HHV8 is quite high (60-70 percent) in the homosexual HIV-positive population. One common feature amongst all HHV8-associated neoplasms is that they utilize interleukin 6 (IL-6) as a tumor growth factor. IL-6 may also facilitate HIV infection, as it induces the proliferation of HTV in HIV infected monocytes and CD4-positive T cells. Thus, we initially hypothesized that an HFIV8 encoded protein upregulates IL-6 expression. In preliminary data we successfully demonstrated that the HHV8 latent proteins, latency associated nuclear antigen (LANA) and Fas associated death domain like interferon converting enzyme inhibitory protein (vFLIP), upregulate cellular IL-ti expression. We have shown that LANA transactivates the IL-6 promoter through the API response element, LANA directly binds to the APi response element, and vFLIP functions through activation of the NF-kappaB and APi transcription factors. Furthermore, vFLIP potentiates LANA-induced IL-6 expression and vice versa. In this proposal, our specific aims are: 1. Elucidate the relevant DNA-protein interactions involved in LANA-mediated transactivation of the LL-6 promoter. 2. Identify the protein-protein interactions involved in LANA transactivation of the IL-6 promoter. 3. Establish the importance of vFLIP and LANA in the induction of IL-6 expression as well as proliferation and inhibition of apoptosis in endogenously HHVS-infected cells, and characterize the molecular interactions between vFLIP and LANA that result in their reciprocal potentiation of IL-6 induction. Our long-term objective is to identify the molecular mechanisms involved in HHVS -mediated upregulation of cellular IL-6 production. The identification of the specific domains of LANA or vFLIP that are involved in the augmentation of IL-ti expression might provide a natural target for drug development to inhibit the effects of these proteins in HHV8 infected malignant cells.