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被认为部分地通过调节DNA结合转录因子的转录活性从而调节基因网络的表达来起作用。因此，了解HDAC如何调节转录以及细胞信号传导如何控制HDAC活性将有助于了解癌症中失调的细胞生长，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II类HDAC，其包括HDAC 4、-5、-6、-9和-10。II类HDAC的成员通过其受限的组织分布特征和值得注意的是其在细胞核和细胞质之间穿梭的能力将其自身与I类HDAC区分开。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的核质穿梭机制。目的II将表征调节HDAC7降解的蛋白水解途径。我们还发现14 - 3 - 3蛋白稳定HDAC7。目的III将剖析HDAC 7的14 - 3 - 3依赖性稳定机制。将采取荧光显微镜、抑制剂和生物化学方法的组合来实现这些目标。这项研究的结果将确定HDAC7活性在分子和细胞水平上调节的机制。了解细胞信号传导如何控制HDAC活性将有助于了解癌症中细胞生长失调，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.