VIRAL ONCOPROTEIN ACTIVATION IN AIDS-RELATED TUMORS

描述：(改编自申请人摘要)肿瘤病毒，如KSHV 和EBV是大多数与艾滋病相关的恶性肿瘤的罪魁祸首， 包括卡波西肉瘤和中枢神经系统淋巴瘤。许多肿瘤病毒都有 直接或间接抑制p53和pRb抑癌基因的能力 小路。KSHV vIRF和EBV EBNA2癌蛋白有第三个共同特征 抑制干扰素信号，这可能有助于细胞转化。 这些研究人员发现，与腺病毒E1a一样，vIRF和EBNA2也可以结合 转录辅适配子p300参与干扰素和 与细胞凋亡相关的转录。VIRF、EBNA2和EIA诱导cMYC癌基因 通过干扰素反应元件以p300调节方式的启动子 VIRF诱导的细胞转化需要cMYC的诱导。这 效应是由一种尚未发现的转录因子暂时介导的 称为PBF-X，可能对两者中cMYC的失调具有普遍重要性 传染性和非传染性癌症。这是一项合作研究成果 旨在将两个研究小组聚集在一起，系统地检查 VIRF和EBNA2结合p300对MYC诱导和凋亡的影响 途径抑制。这将通过映射vIRF的功能域来实现 和EBNA2，并通过精细定位cMYC中的反应元件序列 推动者。EBNA3和vIRF结合p300对P53依赖和 独立的细胞凋亡转录反应将用 P53温度敏感型突变细胞。机械学研究(例如使用蛋白质 合成抑制物和显性负抑制物)将广泛地定义 CMYC诱导途径及p300的作用。的身份 PBF-X将从8个已知的转录因子(IRF1-7， 和Blimp-1)，并将从酵母菌One-和 双杂交研究。在鉴定出PBF-X后，将产生基因敲除小鼠 对这种转录因子进行生理学研究。PBF-X是p势 候选抑癌基因和LOH和染色体断裂点数据将是 检查涉及该基因座的突变。一项针对肿瘤的初步研究， 特别是具有生殖系cMYC的非Burkitt‘s NHL将检查PBF-X 突变或杂合性缺失来测试该转录因子是否在 人类肿瘤发生学。这些研究将导致控制方面的新方法。 EB病毒和KSHV相关恶性肿瘤在艾滋病患者中的发生率。

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.