HTLV deregulation of NF-kappaB2 p100 processing in tumor

描述(由申请人提供)：处理NF-KB2 P100前体蛋白以产生受到严格控制的p52，对于适当调节NF-kB在细胞生长和存活中的功能是重要的。异常持续的P100处理会导致淋巴细胞的异常增殖和转化。因此，增强的P100处理与各种人类恶性肿瘤有关，特别是淋巴瘤/白血病。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)的病原体，是P100加工的第一致病诱导物，是HTLV-I转化的白血病T细胞过度产生P52的原因。因此，本研究项目的长期目标是以HTLV-L/TAX为模型系统，阐明P100加工被调控并参与肿瘤发生的分子机制，以达到预防和治疗的目的。这项研究的中心假设是，P100的非调控加工有助于肿瘤的发生。拟议研究的基本原理是，一旦确定了在致病条件下解除对P100加工的调控的机制，这些信息就可以用来专门阻止P100加工，以预防和治疗包括ATL在内的淋巴瘤/白血病，以及与P100加工相关的其他疾病。本研究的目的是探讨HTLV-L/TAX诱导的P100加工及其在肿瘤发生中的作用机制。本建议的具体目的是：(1)表征调控税收诱导的P100加工的细胞因素；(2)定义？-TrCP(一种E3泛素连接酶)非依赖的机制，参与P100的病理性而不是生理性的加工；(3)确定P100加工调控HTLV-L/税收诱导的细胞转化和肿瘤发生的机制。拟议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.