Regulation and Functions of Human Histone Deacetylase 8

人组蛋白脱乙酰酶 8 的调控和功能

• 批准号: 6814106
• 负责人: EDWARD SETO
• 金额: $ 30.07万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-15 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6814106
• 关键词: acetylation; amidohydrolases; chromatin immunoprecipitation; enzyme activity; enzyme mechanism; gene expression; microarray technology; phosphorylation; protein kinase A; protein structure function; tissue /cell culture

DESCRIPTION (provided by applicant): Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl groups from conserved lysine residues in histones' amino terminal tails. They are found in all eukaryotic organisms and are believed to have a key role in the regulation of gene transcription. Importantly, recent studies suggest that HDACs are critically involved in cell cycle regulation, cell proliferation, differentiation, and the development of human cancer. The human class I HDACs, which possess homology to the yeast RPD3 protein, include HDAC1, HDAC2, HDAC3, and HDAC8. Although HDAC1, HDAC2, and HDAC3 have been extensively characterized, almost nothing is known about the functions, mechanisms of action, and regulation of HDAC8. In this proposal, the overall hypothesis is that, like other class I HDACs, HDAC8 plays an indispensable role in gene regulation. The long-term goal of this project is to obtain a greater mechanistic understanding of how HDAC8 regulates many cellular processes and how HDAC8 itself might be intricately regulated. Particular emphasis will be devoted to a detailed structure-function analysis of the HDAC8 protein and to the elucidation of how phosphorylation of HDAC8 by cAMP-dependent protein kinase A alters its activity. Additionally, genes that are regulated by HDAC8 will be rigorously identified. Given the importance of HDACs in health and disease, a thorough understanding of HDAC8 will not only increase our knowledge of chromatin structure and gene control, but will contribute directly to our overall understanding of normal and abnormal cellular processes.

描述（由申请人提供）：组蛋白脱乙酰酶（HDAC）是催化从组蛋白氨基末端尾部的保守赖氨酸残基中去除乙酰基的酶。它们存在于所有真核生物中，并且被认为在基因转录的调节中具有关键作用。重要的是，最近的研究表明，HDAC 在细胞周期调节、细胞增殖、分化和人类癌症的发展中发挥着重要作用。人类 I 类 HDAC 与酵母 RPD3 蛋白具有同源性，包括 HDAC1、HDAC2、HDAC3 和 HDAC8。尽管 HDAC1、HDAC2 和 HDAC3 已被广泛表征，但对 HDAC8 的功能、作用机制和调节几乎一无所知。在该提案中，总体假设是，与其他 I 类 HDAC 一样，HDAC8 在基因调控中发挥着不可或缺的作用。该项目的长期目标是更好地了解 HDAC8 如何调节许多细胞过程以及 HDAC8 本身如何受到复杂的调节。将特别强调 HDAC8 蛋白的详细结构功能分析，以及阐明 cAMP 依赖性蛋白激酶 A 对 HDAC8 的磷酸化如何改变其活性。此外，受 HDAC8 调控的基因将被严格鉴定。鉴于 HDAC 在健康和疾病中的重要性，对 HDAC8 的透彻了解不仅将增加我们对染色质结构和基因控制的了解，而且将直接有助于我们对正常和异常细胞过程的整体理解。