HTLV deregulation of NF-kappaB2 p100 processing in tumor

加工NF-KB2 P100前体蛋白以产生受到严格控制的p52，是 对于适当调节细胞生长和存活中的核因子-kB功能非常重要。反常的坚持 P100蛋白的处理会导致淋巴细胞的异常增殖和转化。因此， 增强的p100处理与多种人类恶性肿瘤有关，尤其是 淋巴瘤/白血病。Tax是一种由人类T细胞白血病病毒I型(HTLV-1)编码的癌蛋白。 I)是成人T细胞白血病(ATL)的病原体，是P100的第一个致病诱因 在HTLV-I转化的白血病T细胞中加工并过度产生p52。 因此，本研究项目的长期目标是使用HTLV-L/Tax作为模型系统来 阐明调控和参与P100加工的分子机制 肿瘤发生学，用于预防和治疗目的。这一点的中心假设是 研究表明，P100的非调控处理有助于肿瘤的发生。其基本原理是 拟议的研究是，一旦P100处理被放松管制的机制 在致病条件已确定的情况下，这一信息可用于特异性地 阻断P100处理以预防和治疗淋巴瘤/白血病，包括ATL等 与P100加工相关的疾病。这项建议的目的是调查 HTLV-L/TAX诱导P100蛋白表达机制及其在肿瘤发生中的作用这个 这项提案的具体目标是：(1)表征调节税收诱导的细胞因素 P100的加工；(2)定义p-TrCP(一种E3泛素连接酶)的非依赖机制 参与病理性而非生理性的P100的加工；(3)确定其机制 其中P100处理通过调控HTLV-L/Tax诱导的细胞转化和肿瘤发生。 拟议研究的完成可能导致针对P100的新的治疗策略 与加工相关的人类疾病。

Processing of the NF-KB2 p100 precursor protein to generate p52, which is tightly controlled, is important for proper regulation of NF-KB function in cell growth and survival. Aberrantly persistent processing of p100 causes abnormal lymphocyte proliferation and transformation. Accordingly, enhanced p100 processing is associated with various human malignancies, particulary lymphomas/leukemia. Tax, an oncoprotein encoded by human T-cell leukemia virus type I (HTLV- I), the etiological agent of adult T-cell leukemia (ATL), is the first pathogenic inducer of p100 processing and responsible for overproduction of p52 in leukemic T cells transformed by HTLV-I. Thus, the long-term objective of this research project is to use HTLV-l/Tax as a model system to elucidate the molecular mechanism by which p100 processing is regulated and involved in tumorigenesis, for preventive and therapeutic purposes. The central hypothesis of this investigation is that deregulated processing of p100 contributes to tumorigenesis. The rationale for the proposed research is that, once the mechanisms by which p100 processing is deregulated under pathogenic conditions have been determined, this information can be used to specifically block p100 processing to prevent and treat lymphomas/leukemia including ATL, and other diseases associated with p100 processing. The objective of this proposal is to investigate the mechanisms of HTLV-l/Tax-induced p100 processing and its involvement in tumorigenesis. The specific aims of this proposal are: (1) to characterize cellular factors regulating Tax-induced processing of p100; (2) to define the p-TrCP (an E3 ubiquitin ligase)-independent mechanism involved in pathogenic, but not physiological, processing of p100; (3) to determine the mechanism by which p100 processing regulates HTLV-l/Tax-induced cell transformation and tumorigenesis. The completion of the proposed studies may lead to new therapeutic strategies for p100 processing-associated human diseases.