Regulation and Functions of Human Histone Deacetylase 8

描述（由申请人提供）：组蛋白去乙酰化酶（hdac）是催化从组蛋白氨基末端末端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，被认为在基因转录调控中起着关键作用。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起着关键作用。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HDAC8的功能、作用机制和调控却几乎一无所知。在本提案中，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获得对HDAC8如何调节许多细胞过程以及HDAC8本身如何复杂调节的更大的机制理解。特别强调将致力于HDAC8蛋白的详细结构-功能分析，并阐明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识别。鉴于hdac在健康和疾病中的重要性，深入了解HDAC8不仅会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全面了解。

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.