Signaling response to DNA damage in Dictyostelium

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EXCEED THE SPACE PROVIDED. Chemotherapy remains the most common, and often the only effective means of treating human cancer. Unfortunately, tumors frequently develop resistance to many of the most effective and widely used chemotherapeutic agents - an important example of which is cisplatin. The molecular mechanism of developing resistance to cisplatin is not known, and new approaches, to understand the mechanisms are needed. We took a gene discovery approach, using insertional mutagenesis in Dictyostelium discoideum, to identify molecular components that mediate cisplatin resistance. We have identified 6 genes responsible for cisplatin resistance. None of these genes had previously been associated with cisplatin resistance. These genes represent novel targets for reducing the development of resistance to cisplatin, and therefore improving its therapeutic value. .Two of these, gene products, the sphingogsine-1-P lyase (which catalyzes the degradation of sphingosine-1- phosphate to phosphoethanolamine and hexadecanal) and RegA phosphodiesterase (which catalyzes the degradation of cAMP) have been chosen for detailed study because they lie in critical pathways that are known to regulate aspects of cell proliferation and cell death. Furthermore, we have the capability to modulate these pathways pharmacologically as well as genetically to investigate the basic mechanism of cisplatin cytotoxicity and resistance. We present in this proposal readily testable hypotheses to 1) determine the molecular basis of cisplatin resistance in our mutants, 2) determine central biochemical changes that result from cisplatin treatment of normal cells, and 3) predict how the pathways containing the S-l-P lyase and RegA genes are interrelated. These hypotheses will be tested in both the Dictyostelium model, human cells and ovarian tumors. These studies will provide significant insights into drug resistance and identify additional cellular targets which can be modified to increase the efficacy of cisplatin. PERFORMANCE SITE ========================================Section End===========================================