Tumor cell proliferation following treatment with ionizing radiation or hyperthermia is thought to be major determinant of therapeutic outcome in protocols utilizing these agents. Recent studies have shown that proliferation is controlled by the temporal expression of cell cycle coupled genes. These genes are regulated at multiple levels including both transcriptional and post-transcriptional mechanisms such as mRNA stability. The overall objective of the proposed research is to elucidate the mechanism of x-irradiation and hyperthermia-induced down regulation of cell cycle coupled genes specific to late S and G2-phases. Specifically these investigators will test the hypothesis that mRNA stability plays a significant role in the expression of topoisomerase IIalpha (TopoII) under these conditions. TopoII is a multifunctional protein required during replication, chromosome disjunction at mitosis and other DNA-related activities by virtue of its ability to alter DNA supercoiling. TopoII is maximally expressed in late S and G2- phases, and is down regulated by x-irradiation or heat shock, conditions which delay cell cycle progression. The mechanism by which specific sequences in the 3' untranslated region of the TopoII mRNA regulate turnover will be determined and the polypeptides which interact with those sequences will be identified. Finally, it will be determined if enhanced stability of TopoII mRNA increases the corresponding protein levels thus leading to altered G2-transit.
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