Role of P80 pro-IL-16 in T Cell Malignancy

P80 pro-IL-16 在 T 细胞恶性肿瘤中的作用

基本信息

批准号：
7323265
负责人：
YUJUN ZHANG
金额：
$ 28.25万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-01-01 至 2009-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7323265
关键词：
Adaptor Signaling Protein Apoptosis Binding CDKN1B gene Cell Cycle Arrest Cell Cycle Deregulation Cell Cycle Regulation Cell Line Cell Proliferation Cells Complex Cyclin-Dependent Kinase Inhibitor Cyclin-Dependent Kinases DNA Binding DNA Damage Data Deacetylase Development Diagnostic Down-Regulation Ectopic Expression Emu species Genes Genetic Transcription Histone Deacetylase Human IL16 gene Interleukin-16 Jurkat Cells Knockout Mice Lead Lymphomagenesis Malignant Neoplasms Mediating Methylnitrosourea Molting Mus Mutation N-ras Genes Nuclear Nuclear Localization Signal Nuclear Protein Nuclear Proteins Nude Mice Patients Play Predisposition Process Proteins Regulation Rest Role Sezary Syndrome Site Syndrome T-Cell Activation T-Cell Development T-Cell Leukemia T-Cell Lymphoma T-Lymphocyte Testing Tumorigenicity base cancer cell chemical carcinogen cyclin-dependent kinase inhibitor 1B histone deacetylase 3 human CREB3 protein in vivo insight interleukin 16 precursor mutant p27 Cell Cycle Protein p27 Enzyme Inhibitor protein degradation protein expression protein function protein p80 protein protein interaction therapeutic target transcription factor ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): T cell malignancy is a complex process involved in deregulation of cell proliferation and/or apoptosis, including down-regulation of cyclin-dependent kinase inhibitor p27 KIP1. We have identified a T-cell specific protein p80 pro-IL-16, the precursor of Interleukin-16 (IL-16), as a critical negative regulator for p27 KIP1. P80 pro-IL-16 is a nuclear protein highly expressed in resting T cells but rapidly diminished upon T cell activation. The p80 pro-IL-16 gene is located to Ch15q26.3, a site frequently deleted in human T cell malignancies. We have shown that p80 pro-IL-16 is inactivated, either by deletion or mutation in the p80 pro-IL-16 gene, in four T cell malignant cell lines examined and in human primary T cells derived from Sezary syndrome patients. Ectopic expression of p80 pro-IL-16 specifically suppresses Skp2 expression leading to accumulation of p27 KIP1 and Go/G1 cell cycle arrest. P80 pro-IL-16 contains three PDZ domains, which specifically interact the histone deacetylase 3 (HDAC3) and the transcription factor cAMP responsive element binding protein 3 (CREB3). Together, these data strongly suggest that p80 pro-IL-16 play an important role in T cell malignancy. We hypothesize that (1) p80 pro-lL-16 is an adaptor protein that functions to assembly a nuclear protein complex in repressing Skp2 gene transcription in a histone deacetylase-dependent manner and (2) the loss of P80 pro-IL-16 plays an important role in the development of T cell malignancies. Two specific aims are proposed in this application including (1) to elucidate the mechanism(s) by which p80 pro-lL-16 regulates p27 KIP1 protein expression; and (2) to investigate the role of p80 pro-lL-16 in the development of T cell malignancies. We will focus on the p80 pro-IL-16-mediated suppression of Skp2 gene transcription and the role of HDAC3/CREB3 in this action.. We will investigate whether p80 pro-IL-16-null mice are predisposed to T cell malignancies induced by the chemical carcinogen N-methyl-N-nitrosourea (MNU). This study will lead to a considerable insight of the role of p80 pro-IL-16 in the T cell cycle regulation and T cell malignancy and help to identify diagnostic and/or therapeutical targets for human T cell malignancies.

描述（由申请人提供）：T细胞恶性肿瘤是一个复杂的过程，涉及细胞增殖和/或凋亡的消失，包括依赖细胞周期蛋白依赖性激酶抑制剂P27 KIP1的下调。我们已经将T细胞特异性蛋白p80 pro-IL-16（白介素-16（IL-16）的前体）确定为P27 KIP1的关键负调节剂。 P80 Pro-IL-16是一种在静息T细胞中高度表达的核蛋白，但在T细胞激活后迅速减少。 P80 Pro-IL-16基因位于CH15Q26.3，该位点经常在人类T细胞恶性肿瘤中删除。我们已经表明，在检查的四种T细胞恶性细胞系和来自SEZARY综合征患者的人类原代T细胞中，P80 Pro-IL-16通过缺失或突变被灭活，无论是通过缺失或突变而被灭活。 p80 Pro-IL-16的异位表达特异性抑制了SKP2表达，导致P27 Kip1和GO/G1细胞周期停滞的积累。 P80 Pro-IL-16包含三个PDZ结构域，这些pdz结构域特异性相互作用脱乙酰基酶3（HDAC3）和转录因子cAMP CAMP响应元件结合蛋白3（CREB3）。总之，这些数据强烈表明p80 pro-IL-16在T细胞恶性肿瘤中起重要作用。我们假设（1）p80 pro-LL-16是一种适配蛋白，在以组蛋白脱乙酰基酶依赖性方式抑制SKP2基因转录方面可以组装核蛋白复合物，并且（2）p80 pro-IL-16在T细胞恶性肿瘤发展中起重要作用。在本应用中提出了两个具体目标，包括（1）阐明P80 Pro-LL-16调节P27 KIP1蛋白表达的机制；（2）研究p80 Pro-LL-16在T细胞恶性肿瘤发展中的作用。我们将重点关注p80 Pro-IL-16介导的SKP2基因转录的抑制和HDAC3/CREB3在此动作中的作用。我们将研究P80 Pro-IL-16-NULL小鼠是否易于由T细胞恶性肿瘤诱发的T细胞恶性肿瘤，由化学癌症N-甲基n-硝基菌（M甲基 - 尼硝属）（MNU）。这项研究将导致对P80 Pro-IL-16在T细胞周期调节和T细胞恶性肿瘤中的作用有很大的见解，并有助于确定人类T细胞恶性肿瘤的诊断和/或治疗靶标。