Cell Cycle Regulatory Mechanisms of Aurora/Ipl1Kinases

该项目的长期目标是剖析调节脊椎动物染色体分离的机制。这一过程由三种激酶调控：Cdc2、plkl和Aurora/Ipll。我们的方法是确定这些激酶本身是如何调节的，然后确定它们是如何控制染色体分离的。Aurora/Ipll激酶调节染色体分离的四个不同事件：中心体分离、染色质组装、着丝粒附着和细胞发生。当极光激酶被错误表达时，它们可以促进非倍性和转化，这表明极光激酶的调控。我们提供的证据表明，极光激酶是由多种机制调控的细胞周期，并提出了一个强大的体外系统来剖析这些调控途径。本提案中的实验将1)确定Aurora/Ipll细胞周期磷酸化的作用；20鉴定Aurora/Ipll活性的细胞调节因子；30鉴定Aurora/Ipll蛋白水解的调节因子。一个新兴的程序转换是，染色体分离的缺陷会导致非倍性和促进癌症。通过关注染色体分离的时空控制，这项工作将确定癌症进展的机制和癌症治疗的新靶点。

The long-term goal of this project is to dissect the mechanism that regulates vertebrate chromosome segregation. This process is regulated by three kinases: Cdc2, plkl and Aurora/Ipll. Our approach is to determine how these kinases are themselves regulated and then determine how they control chromosome segregation. Aurora/Ipll kinases regulate four different events in chromosome segregation: centrosome separation, chromatin assembly, kinetochore attachment and cytogenesis. When Aurora kinases are misexpressed they can promote anuploidy and transformation, suggesting that the regulation of Aurora kinases regulation. We provide evidence that Aurora kinases are cell cycle regulated by multiple mechanisms and present a powerful in vitro system to dissect these regulatory pathways. The experiments in this proposal will 1) identify the role of Aurora/Ipll cell cycle phosphorylation; 20 identify the cell regulator (s0 of Aurora/Ipll activity; 30 identify the regulators of Aurora/Ipll proteolysis. An emerging programming transformation is that defects in chromosome segregation can cause anuploidy and promote cancer. By focusing on the spatial and temporal control of chromosome segregation, this work should identify both mechanisms of cancer progression and new targets for cancer therapies.