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HTLV deregulation of NF-kappaB2 p100 processing in tumor

HTLV 对肿瘤中 NF-kappaB2 p100 加工的失调

基本信息

批准号：
7822944
负责人：
GUTIAN XIAO
金额：
$ 22.75万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7822944
关键词：
Adult Atypical lymphocyte Binding Proteins Biochemical Genetics Biological Models C-terminal Catalytic Domain Cells Complex Development Disease Gene Targeting Genetic Techniques Goals Human Human T-Cell Leukemia Viruses Human T-lymphotropic virus 1 Investigation Knowledge Lead Link Lymphoma Malignant Neoplasms Mediating Molecular Mus N-terminal Nuclear Nuclear Protein Nuclear Proteins Nuclear Translocation Nucleic Acid Regulatory Sequences Oncogene Deregulation Oncogene Proteins Phenotype Phosphorylation Physiological Processes Play Preventive Process Proteins Recruitment Activity Regulation Research Research Personnel Research Project Grants Role Serine T-Cell Leukemia T-Cell Transformation T-Lymphocyte Taxes Therapeutic Ubiquitination Viral base cell growth cell immortalization cell transformation human disease inhibitor/antagonist leukemia leukemia/lymphoma leukemogenesis lymphocyte hyperplasia lymphocyte proliferation lyt-10 protein mutant novel therapeutics numb protein prevent programs tumor tumorigenesis ubiquitin ligase ubiquitin-protein ligase

项目摘要

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.

NF-KB 2 p100前体蛋白的加工产生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。异常持续 p100的加工引起异常的淋巴细胞增殖和转化。因此，委员会认为，增强的p100加工与各种人类恶性肿瘤有关，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的第一致病诱导物在由HTLV-I转化的白血病T细胞中加工并负责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，阐明p100加工调节和参与的分子机制肿瘤发生，用于预防和治疗目的。这个问题的核心假设是研究发现p100的失调加工有助于肿瘤发生。的理由这项研究提出，一旦p100处理机制被解除管制，在已经确定的致病条件下，该信息可以用于特异性地阻断p100加工以预防和治疗淋巴瘤/白血病，包括ATL，以及其他与p100加工有关的疾病。本提案的目的是调查 HTLV-1/Tax诱导的p100加工及其参与肿瘤发生的机制。的该建议的具体目标是：（1）表征调节Tax诱导的细胞因子 p100的加工;（2）定义p-TrCP（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）确定其机制 p100加工通过其调节HTLV-1/Tax诱导的细胞转化和肿瘤发生。这些研究的完成可能会导致p100的新治疗策略。加工相关的人类疾病。