CELL CYCLE GENES AND CELLULAR SENESCENCE AND AGING

细胞周期的转换受激活和失活的调节 细胞周期蛋白依赖性激酶（Cdks）通过与阳性 （细胞周期蛋白）和负（Cdk抑制剂，CKI）调节剂，并通过 磷酸化这些因素的平衡控制Cdk活性， 协调细胞周期转换。细胞周期蛋白和CKI水平得到控制 转录和后转录，后者通过泛素（Ub）- 依赖性蛋白水解蛋白质降解是三个 酵母中的转变; 5相进入，姐妹染色单体的分离， 退出有丝分裂。虽然有几个已知的基因参与了Ub介导的 蛋白水解，其功能和调节知之甚少。 此外，还不清楚底物是如何识别的。 我们寻求更充分地了解调节这一点的机制 通过分析SKPI及其相关的F-box蛋白水解途径 proteins. SKP 1是一种新发现的该途径的组成部分， G1细胞周期蛋白和CKI的破坏，也是一个组成部分， 动粒在酵母中，SKP 1与CDC 53、CDC 4和CDC 34一起工作， 一种E2 Ub结合酶，来执行这些功能。人Skp 1 p 直接与细胞周期蛋白F结合，并通过 与Skp 2 p的关系这些是不稳定的细胞周期蛋白， 可以调节其稳定性。Skp 1被发现与一种 通过一个被称为F盒的基序来控制蛋白质的数量。F-box蛋白 假设招募底物的泛素化机制或 成为自己的载体。 我们打算研究SKP 1和F-box蛋白在细胞凋亡中的作用。 在酵母和人类中使用生物化学和遗传分析的周期控制 细胞我们的主要目标是了解Skp 1 p和 破坏机制的功能，以确定时间的细胞周期蛋白和CKI 杀伤性此外，我们希望了解F-box蛋白是如何 以及他们如何识别目标。此外，我们希望 通过连续基因识别Skp 1 p途径的其他组分 的发现我们特别感兴趣的是， 其他哺乳动物F-box蛋白及其靶点，包括 细胞周期调节剂。Skp 1/F-box网络的剖析 相互作用的基因对于理解 正常的细胞周期转换，并了解如何改变 这些途径有助于观察到的不受调节的细胞增殖 在癌症中。

Cell cycle transitions are regulated by the activation and inactivation of cyclin dependent kinases (Cdks) through association with positive (cyclins) and negative (Cdk inhibitors, CKI) regulators, and by phosphorylation. The balance of these factors control Cdk activity and coordinate cell cycle transitions. Cyclin and CKI levels are controlled transcriptionally and post-translationally, the latter by ubiquitin (Ub)- dependent proteolysis. Protein degradation is required for three transitions in yeast; 5-phase entry, separation of sister chromatids, and exit from mitosis. While several known genes are involved in Ub-mediated proteolysis, their functions and regulation are poorly understood. Moreover, it is unclear how substrates are recognized. We seek to more fully understand the mechanisms regulating this proteolysis pathway through the analysis of SKPI and its associated F-box proteins. SKP1 a newly discovered component of this pathway required for G1 cyclin and CKI destruction in yeast and is also a component of the kinetochore. In yeast, SKP1 works together with CDC53, CDC4, and CDC34, an E2 Ub-conjugating enzyme, to carry out these functions. Human Skp1p directly binds to cyclin F and indirectly binds cyclin A through association with Skp2p. These are unstable cyclins and this association may regulate their stability. Skp1 has been found to associate with a number of proteins through a motif known as an F-box. F-box proteins are hypothesized to recruit substrates to the ubiquitination machinery or to be substrates themselves. We propose to investigate the role of SKP1 and F-box proteins in cell cycle control using biochemical and genetic analyses in yeast and human cells. Our broad objectives are to understand how Skp1p and the destruction machinery function to determine the timing of cyclin and CKI destruction. In addition, we wish to understand how F-box proteins are regulated and how they recognize their targets. Moreover, we wish to identify other components of the Skp1p pathway through continued gene discovery. In particular, we are interested in the identification of additional mammalian F-box proteins and their targets, which may include cell cycle regulators. Dissection of the Skp1/F-box network of interacting genes has important implications both for understanding normal cell cycle transitions and for understanding how alterations in these pathways contribute to the unregulated cell proliferation observed in cancer.