SCF complex and the Drosophila centrosome cycle

描述(申请人提供)：中心体在有丝分裂器官的形态发生和功能中起着重要作用。这种细胞器的调节缺陷，如过度复制，会导致遗传不稳定性增加，并与多种类型的人类癌细胞有关。这项提案中提出的研究路线将导致中心体功能的调节成分的表征，建立调节中心体复制终止的机制，并发现新的中心体相关蛋白。在这些实验中使用的实验系统非常适合我们提出的遗传学、细胞学和分子方法。我们在果蝇中对SLimb的研究旨在分析SCF复合体的这个亚单位的细胞周期功能，并表征可能与SLimb相互作用的中心体途径组件。我们的遗传分析将揭示肢体通路的其他组成部分，并开始阐明它们的功能。由于这一策略可以潜在地识别sLimb途径的其他成分，而不是与sLimb直接接触的蛋白质，因此我们的方法是对现有的SCF成分的生化纯化努力的补充。最后，随着对SLimb影响中心体功能的机制的研究取得进展，对额外中心体相关蛋白的无偏见遗传筛选将为我们理解中心体在细胞分裂中的功能提供额外的拼图。这些发现将为癌症的预防或治疗提供新的诊断或治疗靶点。

DESCRIPTION (provided by applicant): Centrosomes play an important role in the morphogenesis and function of the mitotic apparatus. Defects in the regulation of this organelle, such as over-replication, result in increased genetic instability and are associated with numerous types of human cancer cells. The line of investigation presented in this proposal will result in the characterization of regulatory components of centrosome function, establish a mechanism for the regulation of the termination of centrosome replication and discover new centrosome-associated proteins. The experimental system utilized in these experiments is well suited for the genetic, cytological, and molecular approaches that we propose. Our studies of Slimb in Drosophila are designed to analyze cell cycle functions for this subunit of the SCF complex, and to characterize putative Slimb-interacting centrosome pathway components. Our genetic analyses will reveal additional components of the slimb pathway and begin to elucidate their functions. Because this strategy can potentially identify other components of the slimb pathway besides proteins that come into direct contact with Slimb, our approach compliments existing efforts at biochemical purification of SCF components. Finally, as inroads are made toward a mechanism by which Slimb affects centrosome function, an unbiased genetic screen for additional centrosome-associated proteins will provide additional puzzle pieces in our understanding of the function of centrosomes in cell division. These discoveries will provide new diagnostic or therapeutic targets for the prevention or treatment of cancer.