组蛋白去乙酰化酶4与人类疾病.doc

组蛋白去乙酰化酶4与人类疾病
张頔穆冠群杨洋
北京大学基础医学院生物化学与分子生物学系
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摘    要:
组蛋白去乙酰化酶4 (histone deacetylase 4, HDAC4) 是一类依赖锌的去乙酰化酶, 属于Ⅱ类组蛋白去乙酰化酶(histone deacetylases, HDACs) , 主要具有去乙酰化酶的活性。HDAC4由去乙酰化酶结构域发挥去乙酰化酶的作用, 还具有核定位序列和核输出序列, 通过转录后与翻译后水平的修饰可在细胞核和细胞质之间穿梭, 进而参与多种调节过程。近年来的研究发现, HDAC4可参与基因的转录调控、细胞凋亡、代谢等诸多生物进程, 在多种疾病的发生发展中发挥重要作用。本文主要从HDAC4的结构、去乙酰作用、自身的修饰及其在核浆中的穿梭作用对其进行概述, 同时对其在骨关节炎、心血管疾病、肌萎缩性侧索硬化症等不同疾病中的作用、相关的分子机制及组蛋白抑制剂在肿瘤中的应用等方面的研究进展进行综述。
关键词:
组蛋白去乙酰化酶4; 骨关节炎; 癌症; 组蛋白去乙酰化酶抑制剂;
作者简介:杨洋, Tel:010-82801602;E-mail:******@bjmu.
基金:国家自然科学基金(, 81372165)
Histone Deacetylase 4 and Human Diseases
ZHANG Di MU Guan-Qun YANG Yang
Department of Biochemistry and Molecular Biology, Peking University Health Science Center;
Abstract:
Histone deacetylase 4 ( HDAC4) , a member of class Ⅱ histone deacetylases ( HDACs) , has originally been defined as a family of zinc-dependent histone deacetylases with a main activity of histone deacetylation. HDAC4 has a deacetylase domain, a nuclear localization sequence and a nuclear export sequence. It shuttles between the nucleus and cytoplasm by post-transcription and post-translation modifications. It has been reported that HDAC4 is involved in many biological processes such as gene transcription, cell apoptosis, metabolism as well as in the development of many diseases. This review focuses on the structure, deacetylation function and post-translational modifications of HDAC4, and discusses related molecular mechanisms of HDAC4 in osteoarthritis, cardiovascular diseases, amyotrophic lateral sclerosis, cancer and other diseases as well as the therapeutic roles of HDAC inhibitors.
Keyword:
histone deacetylase 4; osteoarthritis; cancer; histone deacetylase inhibitor;
组蛋白的乙酰化和去乙酰作用在基因转录调控中发挥着重要的作用。组蛋白通过组蛋白乙酰基转移酶(histone acetyltransferase, HAT) 发生乙酰化, 参与染色质重塑与激活基因转录。相反, 组蛋白去乙酰化酶(histone deacetylases, HDACs) 可从组蛋白的ε-N-乙酰赖氨酸中去除乙酰基, 使染色质凝集, 抑制基因转录激活。根据其与酵母细胞去乙酰化酶的同源性