Sphingosine 1-phosphate (SIP) is a novel signaling molecule that regulates cell proliferation, migration, apoptosis, and angiogenesis. Recent findings suggest that the gene responsible for SIP synthesis acts as an oncogene in model cell systems, suggesting a direct role for SIP in cancer. Sphingosine phosphate lyase (SIP lyase) is responsible for the irreversible degradation of SIP. Although SIP lyase was previously considered to serve a housekeeping role in the cell, our recent studies in simple metazoan models demonstrate that SIP lyase expression is highly regulated and is essential for normal animal development, reproduction, and viability. Further, we have observed that overexpression of SIP lyase in human cells promotes stress-induced apoptosis and sensitizes cells to chemotherapy agents through a p53-dependent mechanism. Importantly, the effect of SIP lyase on apoptosis is associated with changes in intracellular levels of its substrate SIP and also ceramide, two bioactive sphingolipid metabolites with opposing effects on cell fate. We have found that SIP lyase expression is regulated under physiological conditions, during development and tumor progression, potentially through the actions of three transcription factors implicated in cancer biology. These findings justify our central hypothesis, which is that mammalian SIP lyase is a critical regulator of apoptosis during cellular stress and tumor progression.
Our specific aims are: 1) to identify mechanisms of SIP lyase gene regulation, 2) to characterize the influence of SIP lyase on enzymes of sphingolipid metabolism, and 3) to determine the mechanisms by which SIP lyase promotes apoptosis. The studies described in this proposal should elucidate molecular mechanisms by which this unique enzyme and regulator of SIP influences mammalian cell biology. They address a novel secondary hypothesis, which is that SIP lyase participates in a feedback loop to regulate ceramide metabolism. These studies should place SIP lyase within the context of established cancer-related signaling pathways, enabling future dissection of the role of sphingolipids in cancer biology and, conversely, elucidating mechanisms by which specific transcription factors contribute to cancer biology. Pursuit of these Specific Aims may yield novel insights into the role of SIP lyase in cell function that may ultimately be of diagnostic, prognostic and therapeutic value in cancer and other conditions in which apoptosis contributes to pathophysiology of disease.
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