P34CDC2 AND CELL CYCLE CONTROL

本建议的长期目标是了解如何进入 在正常细胞周期（有丝分裂周期）中， 控制），以及如何防止进入有丝分裂时，未复制或 检测到受损的DNA（G2检查点对照）。 在真核生物中， 进入有丝分裂是由协同和相反的调节， 几种不同的蛋白激酶和蛋白 磷酸酶 这种级联反应在Cdc2上收敛，Cdc2是丝氨酸/苏氨酸的一种。 细胞进入有丝分裂所需的蛋白激酶。 两 Cdc2的氨基末端内的相邻氨基酸（苏氨酸 14和酪氨酸15）已被证明是关键要素， 调节Cdc2的激酶活性。 磷酸化这些 残基使Cdc2保持在非活性状态，直到适当的 细胞周期中的时间。 在人类中，Weel和Myt 1蛋白激酶 调节Cdc2在Tyr 15和Thr 14上的磷酸化， Cdc25C蛋白磷酸酶使Thr 14和 Tyr 15. Weel和Cdc25C都与14 - 3 - 3蛋白相互作用，并且在 在Cdc25C，14 - 3 - 3p结合的情况下， Cdc25C和Cdc2之间的相互作用。 旨在阐明 Weel和Myt 1激酶在整个细胞周期中的调节方式 被提议。 此外，Weel和Myt1激酶将被 在人类细胞中功能不同。 作出的贡献 14 - 3 - 3蛋白质与G2检查点对照的比较将在两种细胞中进行检查。 哺乳动物系统和裂殖酵母中， 粟酒 最后，将进行研究，以阐明 DNA损伤后G2期细胞阻滞的机制 因为许多癌症既不能用现有的策略治愈， 也不容易在拆卸阶段拆卸， 新的目标，既可以用作诊断探针， 治疗目标 本提案中概述的研究 探讨细胞周期调控和G2检查点基本机制 控制 参与这些途径的蛋白质可能在白天被用作 诊断标志物或作为设计抗增殖药物的靶点 毒品

The long term objective of this proposal is to understand how entry into mitosis is regulated during a normal cell cycle (mitotic control) and how entry into mitosis is prevented when unreplicated or damaged DNA is detected (G2 checkpoint control). In eukaryotes, entry into mitosis is regulated by the synergistic and opposing activities of several distinct protein kinases and protein phosphatases. This cascade converges on Cdc2, a serine/threonine protein kinase required for the entry of cells into mitosis. Two neighboring amino acids within the amino terminus of Cdc2 (threonine 14 and tyrosine 15) have been shown to be critical elements in regulating the kinase activity of Cdc2. Phosphorylation of these residues maintains Cdc2 in an inactive state until the appropriate time in the cell cycle. In humans, the Weel and Myt1 protein kinases regulate the phosphorylation of Cdc2 on Tyr 15 and Thr 14 whereas the Cdc25C protein phosphatase dephosphorylates Cdc2 on both Thr 14 and Tyr15. Both Weel and Cdc25C interact with 14-3-3 proteins and in the case of Cdc25C, 14-3-3p binding negatively regulates the functional interactions between Cdc25C and Cdc2. Studies aimed at elucidating how the Weel and Myt1 kinases are regulated throughout the cell cycle are proposed. In addition, the Weel and Myt1 kinases will be functionally distinguished in human cells. The contribution made by 14-3-3 proteins to G2 checkpoint control will be examined in both mammalian systems and in the fission yeast, Schizosaccharomyces pombe. Finally studies will be performed to elucidate the mechanistic basis of G2 cell cycle arrest following DNA damage because many cancers are neither curable using existing strategies nor readily detachable at the earl stages there is a need to identify new targets that can be used both as diagnostic probes and as therapeutic targets. The studies outline in this proposal investigate basic mechanisms of cell cycle control and G2 checkpoint control. Proteins involved in these pathways may on day be used as diagnostic markers or as targets for designing anti-proliferative drugs.