Regulation and Functions of Human Histone Deacetylase 8

描述(申请人提供)：组蛋白脱乙酰酶(HDAC)是催化从组蛋白氨基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至关重要的作用。人类I类HDACs与酵母RPD3蛋白具有同源性，包括HDAC1、HDAC2、HDAC3和HDAC8。虽然HDAC1、HDAC2和HDAC3已经被广泛地描述，但对HDAC8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HDACs一样，HDAC8在基因调控中发挥着不可或缺的作用。这个项目的长期目标是对HDAC8如何调控许多细胞过程以及HDAC8本身可能如何被错综复杂地调控有更好的机械性理解。将特别强调对HDAC8蛋白的详细结构-功能分析，并阐明cAMP依赖的蛋白激酶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HDACs在健康和疾病中的重要性，对HDAC8的深入了解不仅将增加我们对染色质结构和基因控制的知识，而且将直接有助于我们全面了解正常和异常的细胞过程。

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.