VIRAL ONCOPROTEIN ACTIVATION IN AIDS-RELATED TUMORS

艾滋病相关肿瘤中病毒癌蛋白的激活

• 批准号: 6661928
• 负责人: YUAN CHANG
• 金额: $ 55.05万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-17 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6661928
• 关键词: AIDS; AIDS related neoplasm /cancer; apoptosis; cell line; gene induction /repression; gene mutation; gene targeting; genetic mapping; genetic promoter element; genetic transcription; genetically modified animals; laboratory mouse; neoplastic transformation; oncoproteins; tissue /cell culture; transcription factor; tumor suppressor genes; virus protein; yeast two hybrid system

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.

描述：（改编自申请人的摘要）肿瘤病毒，例如 KSHV 和 EBV，导致大多数与艾滋病相关的恶性肿瘤， 包括卡波西肉瘤和中枢神经系统淋巴瘤。许多肿瘤病毒具有相同的特征 直接或间接抑制 p 53 和 pRB 肿瘤抑制因子的能力 途径。 KSHV vIRF 和 EBV EBNA2 癌蛋白有第三个共同特征： 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 EBNA2 像腺病毒 E1A 一样，结合 参与干扰素的转录辅助接头 p300 和 凋亡相关转录。 VIRF、EBNA2 和 EIA 诱导 cMYC 癌基因 通过干扰素响应元件以 p300 调节方式启动子 vIRF 诱导的细胞转化需要 cMYC 诱导。这 该效应是由尚未发现的转录因子介导的，暂时 称为 PBF-X，可能对 cMYC 的失调具有普遍重要性 传染性和非传染性癌症。这是一项合作研究工作 旨在汇集两个研究小组来系统地研究 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，并通过精细映射 cMYC 中的响应元件序列 发起人。 EBNA3 和 vIRF 结合 p300 对 p53 依赖性和 将使用以下方法检查独立的凋亡转录反应 p53-温度敏感突变细胞。机理研究（例如使用蛋白质 合成抑制和显性失活抑制剂）将广泛定义 cMYC 诱导途径和 p300 的贡献作用。身份 PBF-X将从八种已知的转录因子（IRFs1-7、 和 Blimp-1），新的候选者将从酵母一和 两种杂交研究。 PBF-X被鉴定后，将产生基因敲除小鼠 用于该转录因子的生理学研究。 PBF-X 为 p 电位 候选肿瘤抑制因子以及 LOH 和染色体断点数据将 检查涉及该基因座的突变。肿瘤的初步研究， 特别是具有种系 cMYC 的非伯基特 NHL 将接受 PBF-X 检查 突变或 LOH 来测试该转录因子是否在 人类肿瘤发生。这些研究将带来控制方面的新方法 艾滋病患者中 EBV 和 KSHV 相关恶性肿瘤的发生率。