Regulation and Functions of Human Histone Deacetylase 8

描述（由申请人提供）：组蛋白脱乙酰酶（HDAC）是催化乙酰基从组蛋白氨基末端尾部的保守赖氨酸残基上去除的酶。它们存在于所有真核生物中，被认为在基因转录的调节中起关键作用。重要的是，最近的研究表明，HDAC在细胞周期调控，细胞增殖，分化和人类癌症的发展中起着至关重要的作用。与酵母RPD 3蛋白具有同源性的人I类HDAC包括HDAC 1、HDAC 2、HDAC 3和HDAC 8。尽管HDAC 1、HDAC 2和HDAC 3已被广泛表征，但对HDAC 8的功能、作用机制和调节几乎一无所知。在这个提议中，总体假设是，像其他I类HDAC一样，HDAC 8在基因调控中起着不可或缺的作用。该项目的长期目标是更深入地了解HDAC 8如何调节许多细胞过程以及HDAC 8本身如何受到复杂的调节。特别强调将致力于详细的结构-功能分析的HDAC 8蛋白和阐明如何磷酸化的HDAC 8 cAMP依赖性蛋白激酶A改变其活性。此外，由HDAC 8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HDAC 8的深入了解不仅会增加我们对染色质结构和基因控制的了解，而且会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.