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Genetics and Molecular Biology |
Division of Biological Sciences, University of Missouri, Columbia, MO 65211, USA1
Max-Planck-Institut für Biochemie, D-82152 Martinsried, Germany2
Author for correspondence: Stephen Alexander. Tel: +1 573 882 6670. Fax: +1 573 882 0123. e-mail: alexanderst{at}missouri.edu
The efficacy of the widely used chemotherapeutic drug cisplatin is limited by the occurrence of drug-resistant tumour cells. To fully exploit the potential of this drug in cancer therapy, it is imperative to understand the molecular basis of cisplatin resistance. Using an insertional mutagenesis technique in cells of Dictyostelium discoideum, we have identified six genes which are involved in cisplatin resistance. None of these genes has been previously linked to resistance to this drug. Several of these genes encode proteins that are involved in signal transduction pathways which regulate cell death, cell proliferation or gene regulation. The resistance of these mutant strains is specific for cisplatin, since deletion of these genes does not confer resistance to other DNA-damaging agents. Significantly, the disruption of three of these genes, encoding the sphingosine-1-phosphate lyase, the RegA cAMP phosphodiesterase and a phosphatidylinositol-4-phosphate 5-kinase, also results in abnormalities in the multicellular development of this organism, although there is no change in the rate of mitotic cell growth. This study has identified previously unsuspected molecular pathways which function in the cellular response to cisplatin and are required for normal morphogenesis, and underscores the complexity of the cellular response to cisplatin. These pathways provide potential targets for modulating the response to this important drug.
Keywords: ceramide, sphingosine 1-phosphate, chemotherapy, drug-resistance, PKA
Abbreviations: MMS, methyl methanesulfonate; PIP5K, phosphatidylinositol-4-phosphate 5-kinase; PKA, protein kinase A; REMI, restriction-enzyme-mediated integration; S-1-P, sphingosine 1-phosphate
The GenBank accession numbers for the sequences reported in this paper are AF233610 (S-1-P lyase), AF233612 (PIP5K), AF233611 (P2Y purine receptor 1), AF233613 (CAAX prenyl protease) and AF233614 (unidentified gene).
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