Increased IL6 Transcription by HHV8

描述：(申请人提供)人类疱疹病毒8型(HHV8)已被 与三种肿瘤有关：原发性渗出性淋巴瘤，卡波西肉瘤， 和多中心卡氏S病在人类免疫缺陷病毒中的作用 (艾滋病毒)相关和非相关病例。此外，有证据表明，HHV8 可能存在于多发性骨髓瘤患者的骨髓中。而HHV8是 在普通人群中并不普遍(血清阳性率为10%-15%)， 同性恋者接触HHV8的证据相当高(60%-70%) 艾滋病毒阳性人群。所有与HHV8相关的病毒有一个共同特征 肿瘤是利用白介素6(IL-6)作为肿瘤生长因子。 IL-6也可能促进HIV感染，因为它诱导HTV的增殖 在HIV感染的单核细胞和CD4阳性的T细胞中。因此，我们最初 假设HFIV8编码的蛋白质上调IL-6的表达。 在初步数据中，我们成功地证明了HHV8潜伏蛋白， 潜伏期相关核抗原和Fas相关死亡域样 干扰素转换酶抑制蛋白(VFLIP)，上调细胞 IL-1的表达。我们已经证明LANA反式激活IL-6启动子 通过API响应元素，LANA直接绑定到API响应 元素，并通过激活核因子-kappaB和API发挥vFLIP功能 转录因子。此外，vFLIP增强LANA诱导的IL-6 表达式，反之亦然。 在这个方案中，我们的具体目标是：1.阐明相关的DNA-蛋白质 参与LANA介导的IL-6启动子反式激活的相互作用。2. 确定参与LANA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LANA在 IL-6的诱导表达及增殖和抑制作用 内源性HHVS感染细胞中的细胞凋亡及其分子特征 VFLIP和LANA之间的相互作用导致其互惠 增强IL-6的诱导作用。 我们的长期目标是确定涉及到的分子机制 HHVS介导的细胞IL-6产生上调。身份的鉴定 涉及增强的LANA或vFLIP的特定结构域 IL-ti的表达可能为药物开发提供了一个天然的靶点来抑制 这些蛋白在HHV8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.