Regulation of histone deacetylase 7 (HDAC7) activity

描述(由申请人提供)： 许多研究表明，组蛋白脱乙酰酶(HDAC)的异常募集可能导致癌症。HDAC被认为在一定程度上通过调节DNA结合转录因子的转录活性来发挥作用，从而调节基因网络的表达。因此，了解HDAC如何调控转录和细胞信号如何控制HDAC活性将有助于理解癌症中未受调控的细胞生长，并可能对癌症治疗具有治疗意义。HDAC7(组蛋白脱乙酰酶7)属于第二类HDACs，包括HDAC4、-5、-6、-9和-10。II类HDAC的成员因其受限的组织分布图和显著的在细胞核和细胞质之间穿梭的能力而区别于I类HDAC。我们假设HDAC7的亚细胞分布是由其相互作用伙伴之间的相互作用决定的。目的阐明HDAC7核质穿梭的机制。目的II将描述调控HDAC7降解的蛋白分解途径。我们还发现14-3-3蛋白稳定HDAC7。目的研究HDAC7的14-3-3依赖稳定机制。将采用荧光显微镜、抑制剂和生化方法相结合的方法来实现这些目标。这项研究的结果将确定HDAC7活性在分子和细胞水平上的调节机制。了解细胞信号如何控制HDAC活性将有助于理解癌症中未受调控的细胞生长，并可能对癌症治疗具有治疗意义。

DESCRIPTION (provided by applicant): Many studies have indicated that aberrant recruitment of histone deacetylases (HDACs) may lead to cancer. HDACs are thought to function, in part, by regulating transcriptional activity of DNA-binding transcription factors thereby modulating the expression of a network of genes. Thus, understanding how HDACs regulate transcription and how cellular signaling controls HDAC activity will help to understand deregulated cell growth in cancer and may have therapeutic implications for cancer treatment. HDAC7 (Histone deacetylase 7) belongs to the class II HDACs that includes HDAC4, -5, -6, -9, and -10. Members of the class II HDACs distinguish themselves from class I HDACs by their restricted tissue distribution profiles and notably, their ability to shuttle between the nucleus and the cytoplasm. We hypothesize that the subcellular distribution of HDAC7 is determined by the interplay between its interacting partners. Aim I will elucidate the mechanism of nucleocytoplasmic shuttling of HDAC7. Aim II will characterize the proteolytic pathway regulating HDAC7 degradation. We also discovered that 14-3-3 proteins stabilize HDAC7. Aim III will dissect the mechanism of 14-3-3-dependent stabilization of HDAC7. A combination of fluorescence microscopy, inhibitor, and biochemical approaches will be taken to accomplish these objectives. The results from this study will determine the mechanism by which HDAC7 activity is regulated at the molecular and cellular level. Understanding how cellular signaling controls HDAC activities will help to understand deregulated cell growth in cancer and may have therapeutic implications for cancer treatment.