Control Of The Mitotic Exit The Xnf7 Ubiquitin Ligase

Xnf7 泛素连接酶有丝分裂退出的控制

• 批准号: 6936534
• 负责人: Leta K Nutt
• 金额: $ 4.99万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6936534
• 关键词: Xenopus; Xenopus oocyte; cell cycle; cell cycle proteins; cell growth regulation; cell proliferation; cyclin dependent kinase; cyclins; enzyme activity; laboratory rabbit; ligands; ligase; mitotic spindle apparatus; postdoctoral investigator; protein kinase; protein structure function; ubiquitin

DESCRIPTION (provided by applicant): Exit from mitosis is promoted by the proteolysis of a group of substrates including the Cdc2 activator, Cyclin B and the chromosome cohesion regulator, securin. These and several other mitotically- degraded substrates are ubiquitinated by the anaphase promoting complex (APC), a multiprotein E3 ubiquitin ligase, and are thereby targeted for proteasomal degradation. We recently found that a previously identified protein of unknown function called Xnf7 can regulate mitotic exit and modulate the degradation of APC substrates. Using a ceIl-free extract that can reconstitute mitotic exit in a synchronous and controlled manner, we have found that Xnf7 depletion accelerates mitotic exit, promoting rapid degradation of APC substrates. Therefore, we hypothesize that Xnf7 antagonizes APC function, either directly or indirectly, interestingly, Xnf7 itself appears to be a ubiquitin ligase, raising the possibility that it might ubiquitinate either APC components or its upstream regulators. It is the goal of this proposal to understand how Xnf7 regulates the destruction of mitotic substrates to control mitotic exit. We propose the following: 1) To determine if Xnf7 is a direct APC regulator; 2) To determine if Xnf7 ligase activity is required for modulation of mitotic exit; 3) To identify and characterize Xnf7 interactors/substrates involved in promoting mitotic exit. A more thorough understanding of how cell proliferation is controlled will enable us to intervene more effectively to prevent uncontrolled cell proliferation during carcinogenesis. As many chemotherapeutic agents trigger a checkpoint to block APC function, it is of particular interest to understand ways in which the APC may be regulated.

描述（由申请人提供）： 通过包括CDC2激活剂Cyclin B和染色体凝聚力调节剂Secuin（Secuin）在内的一组底物的蛋白水解促进了有丝分裂的退出。这些和其他几种有丝分裂降解的底物是由促进复合物（APC）的多蛋白E3泛素连接酶泛素化的，因此靶向蛋白酶体降解。我们最近发现，先前鉴定出的称为XNF7的未知功能的蛋白质可以调节有丝分裂出口并调节APC底物的降解。使用可以同步和控制的方式重建有丝分裂出口的无天花提取物，我们发现XNF7耗竭会加速有丝分裂出口，从而促进APC底物的快速降解。 因此，我们假设XNF7直接或间接地拮抗APC函数，有趣的是，XNF7本身似乎是泛素连接酶，从而增加了可能泛素化APC组件或其上游调节剂的可能性。该提案的目的是了解XNF7如何调节有丝分裂底物的破坏以控制有丝分裂出口。我们提出以下建议：1）确定XNF7是否是直接的APC调节器； 2）确定XNF7连接酶的活性是否需要调节有丝分裂出口； 3）识别和表征与促进有丝分裂出口有关的XNF7相互作用者/底物。对如何控制细胞增殖的更透彻的了解将使我们能够更有效地干预，以防止癌变期间不受控制的细胞增殖。由于许多化学治疗剂触发了一个检查点以阻止APC功能，因此了解可以调节APC的方式特别有趣。