HTLV deregulation of NF-kappaB2 p100 processing in tumor

描述（由申请人提供）：NF-kB2 p100前体蛋白加工生成p52，这是严格控制的，对于NF-kB功能在细胞生长和存活中的适当调节是重要的。异常持续的p100加工导致异常淋巴细胞增殖和转化。因此，p100加工的增强与各种人类恶性肿瘤，特别是淋巴瘤/白血病有关。Tax是人类T细胞白血病病毒I型（HTLV- I）编码的一种癌蛋白，是成人T细胞白血病（ATL）的致病因子，是p100加工的第一个致病诱导剂，负责HTLV-I转化的白血病T细胞中p52的过量产生。因此，本研究项目的长期目标是利用HTLV-l/Tax作为模型系统，阐明调控p100加工并参与肿瘤发生的分子机制，以达到预防和治疗的目的。本研究的中心假设是p100的失调控处理有助于肿瘤的发生。该研究的基本原理是，一旦确定了p100加工在致病性条件下被解除调控的机制，该信息可用于特异性阻断p100加工，以预防和治疗包括ATL在内的淋巴瘤/白血病以及其他与p100加工相关的疾病。本研究旨在探讨htlv - 1 / tax诱导p100加工的机制及其在肿瘤发生中的作用。本提案的具体目的是：(1)表征调节税收诱导p100加工的细胞因子；(2)定义？-不依赖于E3泛素连接酶的trcp机制参与p100的致病性而非生理性加工；(3)确定p100加工调控htlv - 1 / tax诱导的细胞转化和肿瘤发生的机制。这些研究的完成可能会为p100加工相关的人类疾病带来新的治疗策略。

DESCRIPTION (provided by applicant): 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, particularly 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 ?-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.