CELL CYCLE GENES AND CELLULAR SENESCENCE AND AGING

细胞周期转换受激活和失活的调节 细胞周期蛋白依赖性蛋白激酶(CDKs)与阳性细胞的关系 (细胞周期蛋白)和负性(CDK抑制剂，CKI)调节器，并通过 磷酸化。这些因素的平衡控制着CDK的活性和 协调细胞周期转变。Cyclin和CKI水平得到控制 转录和翻译后，后者由泛素(Ub)- 依赖蛋白水解酶。蛋白质的降解需要三个 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。而几个已知的基因参与了Ub介导的 蛋白水解酶及其功能和调控还知之甚少。 此外，目前还不清楚底物是如何识别的。 我们试图更全面地了解这方面的调控机制。 SKPI及其相关F-box蛋白降解途径的研究 蛋白质。Skp1是新发现的该途径的一个组成部分，需要 G1Cyclin和CKI在酵母中的破坏，也是 动毛虫。在酵母中，Skp1与CDC53、CDC4和CDC34协同工作， 一种E2 Ub结合酶，以执行这些功能。人类Skp1p 直接与细胞周期蛋白F结合，并通过 与Skp2p关联。这些是不稳定的气旋，这种联系 可以调节它们的稳定性。已发现Skp1与一个 通过一个被称为F-box的基序的蛋白质数量。F-box蛋白是 假设将底物招募到泛素化机器或 它们本身就是底物。 我们建议研究Skp1和F-box蛋白在细胞中的作用 利用生化和遗传分析对酵母和人类进行周期控制 细胞。我们的广泛目标是了解Skp1p和 破坏机械功能决定细胞周期蛋白和肌钙蛋白I的时机 毁灭。此外，我们希望了解F-box蛋白是如何 以及他们如何识别他们的目标。此外，我们希望 通过延续基因鉴定Skp1p通路的其他组成部分 发现号。特别是，我们感兴趣的是确定 其他哺乳动物F-box蛋白及其靶标，可能包括 细胞周期调节器。的Skp1/F-box网络的剖析 相互作用的基因对理解 正常的细胞周期转变和理解细胞周期的改变是如何 这些途径促成了观察到的不受调控的细胞增殖 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.