VIRAL ONCOPROTEIN ACTIVATION IN AIDS-RELATED TUMORS

描述：（改编自申请人摘要）肿瘤病毒，如KSHV 和EB病毒，是大多数艾滋病相关恶性肿瘤的原因， 包括卡波西肉瘤和中枢神经系统淋巴瘤许多肿瘤病毒共享 直接或间接抑制p53和pRB肿瘤抑制因子的能力 途径。KSHV vIRF和EBV EBNA 2癌蛋白共有第三个共同特征， 抑制可能有助于细胞转化的干扰素信号传导。 这些研究人员发现，vIRF和EBNA 2，像腺病毒E1 A一样， 转录辅衔接子p300参与干扰素， 转录相关的转录。VIRF、EBNA 2和EIA诱导cMYC癌基因 通过干扰素反应元件以p300调节的方式启动子 并且cMYC诱导是vIRF诱导的细胞转化所需的。这 效应是由一个未发现的转录因子介导的， 称为PBF-X，可能对cMYC的失调具有普遍的重要性， 感染性和非感染性癌症。这是一项合作研究成果 旨在将两个研究小组聚集在一起，系统地研究 vIRF和EBNA 2结合p300对MYC诱导和凋亡的影响 通路抑制这将通过绘制vIRF的功能域来实现 和EBNA 2，并通过精细定位cMYC中的应答元件序列， 启动子EBNA 3和vIRF结合p300对p53依赖性和 独立的凋亡转录反应将使用 p53-温度敏感突变细胞。机制研究（例如，使用蛋白质 合成抑制和显性负抑制剂）将广泛地定义 cMYC诱导途径和p300的贡献作用。的身份 PBF-X将从八种已知的转录因子（IRFs 1 -7， 和Blimp-1），新的候选人将从酵母中鉴定出来， 双杂交研究在鉴定出PBF-X后，将产生敲除小鼠 用于转录因子的生理学研究。PBF-X为p电位 肿瘤抑制候选基因和洛缺失以及染色体断裂点数据将被 检查了涉及该位点的突变。一项关于肿瘤的初步研究， 特别是具有生殖系cMYC的非Burkitt's NHL，将检查PBF-X 突变或洛，以测试该转录因子是否在 人类肿瘤发生这些研究将导致新的方法在控制 艾滋病患者中EBV和KSHV相关的恶性肿瘤。

DESCRIPTION: (Adapted from Applicant's Abstract) Tumor viruses, such as KSHV and EBV, are responsible for the majority of AIDS-related malignancies, including Kaposi's sarcoma and CNS lymphoma. Many tumor viruses share the ability to directly or indirectly inhibit p 53 and pRB tumor suppressor pathways. KSHV vIRF and EBV EBNA2 oncoproteins share a third common feature of inhibiting interferon signaling which may contribute to cell transformation. These investigators have found that vIRF and EBNA2, like adenovirus E1A, bind the transscriptional coadaptor p300 involved in interferon and apoptosis-related transcription. VIRF, EBNA2, and EIA induce the cMYC oncogene promotor in a p300 regulated manner through an interferon-responsive element and cMYC induction is required for vIRF-induced cell transformation. This effect is mediated by an undiscovered transcriptional factor, provisionally called PBF-X, may have general importance for the dysregulation of cMYC in both infectious and non-infectious cancers. This is a collaborative research effort designed to bring together two research groups to systematically examine the effects of p300 binding by vIRF and EBNA2 on MYC induction and apoptotic pathway inhibition. This will be achieved by mapping functional domains of vIRF and EBNA2, and by fine mapping the response element sequences in the cMYC promoter. The effects of p300 binding by EBNA3 and vIRF on p53-dependent and independent apoptotic transcriptional responses will be examined using p53-temperature sensitive mutant cells. Mechanistic studies (e.g. using protein synthesis inhibition and dominant negative inhibitors) will broadly define the pathway for cMYC induction and the contributing role of p300. The identity of PBF-X will be sought from among eight known transcription factors (IRFs1-7 , and Blimp-1) and new candidates will be identified from yeast one- and two-hybrid studies. After PBF-X is identified, knockout mice will be generated for physiologic studies of the this transcriptonal factor. PBF-X is p potential tumor suppressor candidate and LOH and chromosomal breakpoint data will be examinded for mutations involving this locus. A pilot study of tumors, particularly non-Burkitt's NHL with germline cMYC will be examined for PBF-X mutations or LOH to test whether this transcription factor plays a role in human tumorigenesis. These studies will lead to novel approaches in the control of EBV and KSHV-related malignancies in AIDS patients.