MECHANISMS OF CELL PROLIFERATION FOLLOWING PERTURBATIONS

拟议研究的目标是确定 可逆G_1过渡过程中的加速机制 细胞周期进程受阻于前一阶段的S期 一代。这种现象的一种可能机制是 S期进展迟缓可触发生化过程 与完成之前的后续G1阶段有关 有丝分裂。在特定的目标1中，我们将确定细胞周期 在HeLa细胞中导致G1加速的扰动具有类似的 对正常和转化的其他人类细胞系的影响 表型。详细的动力学分析将被用来完全 映射能力窗口，即早期细胞周期时间 S和M期，延缓进展导致G1- 加速。在特定的目标2中，将确定加速的G1 凌日是由于已知的G1-1表达的改变- 调节蛋白。具体目标3中提出的工作将 确定S相后是否有加速的G1期过渡 扰动会导致计划外停用 并确定视网膜母细胞瘤蛋白是否存在这样的机制 可消除电离辐射诱导的G1期阻滞。具体而言 目标4我们将确定哪些特定的信使核糖核酸物种对 在AIM 2中观察到的G1调节蛋白的表达变化 它们与G1加速有关。所获得的结果 从这项研究的完成将表征这种机制 参与从细胞周期扰动中恢复，并验证了这一想法 早期的G1事件可能会受到生化过程的影响 在有丝分裂完成之前发生的。

The objective of the proposed research is to determine the mechanisms of acceleration in G 1- transit following a reversible block of cell cycle progression in S-phase of the preceding generation. A possible mechanism for this phenomenon is that delayed progression in S-phase can trigger biochemical processes pertinent to the subsequent G 1-phase prior to the completion of mitosis. In Specific Aim 1, we will determine if cell cycle perturbations that lead to G 1- acceleration in HeLa cells have similar effects in other human cell lines of both normal and transformed phenotypes. Detailed kinetic analyses will be used to completely map the competence window, i.e., the cell cycle time between early S and M phases in which delayed progression results in G 1- acceleration. In Specific Aim 2, will determine if accelerated G 1 transit is due to an alteration in the expression of known G 1- regulatory proteins. The work proposed in Specific Aim 3 will determine whether accelerated G 1-transit following S-phase perturbation results in an unscheduled inactivation of the Retinoblastoma protein and determine, whether such a mechanism can abrogate the ionizing radiation-induced G 1-arrest. In Specific Aim 4 we will determine which specific mRNA species contribute to the altered expression of G 1-regulatory proteins observed in Aim 2 which are associated with G 1-acceleration. The results obtained from completion of this study will characterize the mechanisms involved in recover from cell-cycle perturbation, and verify the idea that early G1 events can be influenced by biochemical processes occurring prior to the completion of mitosis.