Type II DNA topoisomerase (topII) is an essential enzyme and is also the intracellular target for the number of clinically most effective antineoplastic agents. The intracellular level of top II is an import determining factor for the cellular sensitivity to top II-targeting drugs and reduced top II expression is the most commonly observed top II-mediated drug resistance. Of the two top II isoforms, the 170 kD form (top IIalpha) is the predominant form to mediate top II functions and is highly sensitive to top II-targeting agents. Transfection and overexpression of top IIalpha gene by negative feedback mechanism, which is important for a strict regulation of the cellular top IIalpha level and may also contribute to reduced top IIalpha expression in drug resistance. In addition, one cis-element and its respective binding activity was identified in the Chinese hamster top IIalpha promoter and it bears resemblance to a novel inhibitory element in the c-erbB2 promoter. Amplification and overexpression of top IIalpha and c-erbB2 genes have been associated with poor prognosis in breast cancer. Hence, the study of mechanisms by which top IIalpha is regulated has significant biological and clinical relevance. In this proposal, the molecular mechanisms governing the autoregulation of endogenous top IIalpha expression in EMT6 cells that overexpress CHO top IIalpha and the reduced top IIalpha expression in two drug resistant Chinese hamster cell lines will be investigated and compared. The results will then be used in the study of modulating the top IIalpha expression in the resistant cell lines and the drug sensitivity of the cells will be assayed. Based on the high homology between CHO and human to IIalpha promoters and the conserved regulatory elements and binding factors, the results of this study are relevant for the study of top II expression in human cancer and for developing strategies in overcoming top II-mediated drug resistance in cancer chemotherapy. Elucidating the mechanisms of regulating tip Iialpha expression is also important in studying the roles of top II in different cell functions.
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