MECHANISMS OF CELL PROLIFERATION FOLLOWING PERTURBATIONS

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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.