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

• 批准号: 7002756
• 负责人: YUJUN ZHANG
• 金额: $ 29.1万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7002756
• 关键词: DNA damage; T lymphocyte; amidohydrolases; apoptosis; carcinogenesis; cell cycle proteins; chromatin immunoprecipitation; gene induction /repression; gene targeting; genetic transcription; genetically modified animals; laboratory mouse; lymphokines; lymphoma; nuclear proteins; posttranslational modifications; protein sequence; protein structure function

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。