Cell Cycle Regulatory Mechanisms of Aurora/Ipl1Kinases

这个项目的长期目标是剖析调节脊椎动物染色体分离的机制。这一过程受三种酶的调节：CDc2、plk1和Aurora/Ipll。我们的方法是确定这些激酶本身是如何调节的，然后确定它们如何控制染色体分离。Aurora/IPLL激酶调节染色体分离中的四个不同事件：中心体分离、染色质组装、动粒附着和细胞发生。当Aurora激酶被错误表达时，它们可以促进异倍体和转化，这表明Aurora激酶的调节调节。我们提供了极光激酶是受多种机制调节的细胞周期的证据，并提出了一个强大的体外系统来剖析这些调节途径。本提案中的实验将1)确定Aurora/IPLL细胞周期磷酸化的作用；20确定细胞调节因子(Aurora/IPLL活性的S0)；30确定Aurora/IPLL蛋白分解的调节因子。一种新出现的编程转变是，染色体分离的缺陷会导致染色体缺失并促进癌症。通过专注于染色体分离的空间和时间控制，这项工作应该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.