Sphingolipid-derived lipids, including ceramide, sphingosine and their phosphorylated derivatives exhibit an intriguing range of biological activities. Studies in mammalian systems implicate these lipids in signaling processes involving both activation of cell surface receptors and intracellular targets that play important roles in control of cell growth, death and differentiation. Despite considerable effort, the key enzymes involved in the generation and metabolism of sphingolipid-derived messengers have not been isolated or their genes identified in any species. The broad aim of the proposed research is to use yeast as a model system to study the metabolism and functions of sphingosine 1-phosphate which should ultimately provide valuable insights into sphingosine 1-phosphate signaling in mammalian cells. A gene (bst) that confers resistance to exogenously-added sphingosine in yeast has been isolated and demonstrated to encode sphingosine phosphate lyase, an enzyme involved in the degradation of sphingosine 1 phosphate. Building on this advance, the applicant proposes to further investigate the phenotype of a bst delta yeast strain, which is surprisingly characterized by increased stress tolerance and aberrant growth arrest upon nutrient deprivation, to investigate yeast sphingosine kinase activity and clone the sphingosine kinase gene, and to isolate a human sphingosine phosphate lyase cDNA and characterize this gene.
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