Cell cycle regulation by ubiquitin ligases

描述(申请人提供)：在细胞周期转变或对外界条件变化的反应中，细胞生理的快速变化通常是由调节分子的降解所调节的。这些变化通常是通过用小蛋白泛素链修饰蛋白质靶标来实现的。泛素化是由一系列三种酶执行的，有时被称为E1、E2和E3，它们的功能是将泛素转移到底物上。底物特异性通常由E3复合体介导，也称为泛素连接酶。SCF和APC是两个高度保守的多亚基泛素连接酶，对细胞周期进程和细胞生理的许多方面的调节都很重要。我们将研究APC的调节机制，并使用我们最近开发的全面筛选技术来鉴定这些和其他泛素连接酶的底物。与公共卫生相关：癌症是细胞分裂失控的结果。在这项提案中，我们概述了描述负责调节细胞分裂的蛋白质的实验。通过这样做，我们可以更好地了解癌症是如何产生的，以及可以用来选择性地靶向癌症的肿瘤的特征。

DESCRIPTION (provided by applicant): Rapid changes in cell physiology during cell cycle transitions or in response to changes in external conditions are often mediated by the degradation of regulatory molecules. These changes are typically directed by the modification of protein targets with chains of the small protein ubiquitin. Ubiquitinization is carried out by a series of three enzymes, sometimes referred to as E1, E2 and E3, which function in tandem to transfer ubiquitin to a substrate. Substrate specificity is usually mediated by the E3 complex, also called a ubiquitin ligase. The SCF and the APC represent two highly conserved multi-subunit ubiquitin ligases important for both cell cycle progression and the regulation of many aspects of cellular physiology. We will examine mechanisms of APC regulation, and also identify the substrates of these and other ubiquitin ligases using a comprehensive screening technique that we have recently developed. PUBLIC HEALTH RELEVANCE: Cancer is the result of uncontrolled cell division. In this proposal, we outline experiments that characterize proteins responsible for the regulation of cell division. In doing this, we can better understand how cancers arise and the characteristics of tumors that can be used to selectively target them.