HTLV deregulation of NF-kappaB2 p100 processing in tumor

HTLV 对肿瘤中 NF-kappaB2 p100 加工的失调

• 批准号: 7102359
• 负责人: GUTIAN XIAO
• 金额: $ 20.98万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7102359
• 关键词: human; leukemia; lymphoma; neoplasm /cancer; proteins

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.

描述（由申请人提供）：加工NF-κ B 2 p100前体蛋白以产生p52，这是严格控制的，对于细胞生长和存活中NF-κ B功能的适当调节是重要的。p100蛋白异常持续加工导致淋巴细胞增殖和转化异常。因此，增强的p100加工与各种人类恶性肿瘤，特别是淋巴瘤/白血病有关。Tax是由人T细胞白血病病毒I型（HTLV-I）编码的癌蛋白，是成人T细胞白血病（ATL）的病原体，是p100加工的第一个致病诱导剂，并负责由HTLV-I转化的白血病T细胞中p52的过度产生。因此，本研究项目的长期目标是使用HTLV-1/Tax作为模型系统来阐明p100加工被调节并参与肿瘤发生的分子机制，用于预防和治疗目的。这项研究的中心假设是，p100的失调加工有助于肿瘤的发生。这项研究的基本原理是，一旦确定了致病条件下p100加工失调的机制，这些信息就可以用来特异性阻断p100加工，以预防和治疗淋巴瘤/白血病，包括ATL，以及其他与p100加工相关的疾病。本研究的目的是探讨HTLV-1/Tax诱导的p100加工及其参与肿瘤发生的机制。该提案的具体目标是：（1）表征调控Tax诱导的p100加工的细胞因子;（2）定义？TrCP（一种E3泛素连接酶）非依赖性机制参与p100的致病性而非生理性加工;（3）确定p100加工调节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。