The PI's laboratory has focused on the study of novel lipid mediators and their role in cell regulation. Recent work in the PI's laboratory has led to the identification and doning of two yeast sphingosine-1-phosphate phosphatases (SPPase). These enzymes dephosphorylate and inactivate an extremely important bioactive lipid mediator namely sphingosine-1-phosphate (S1P). These enzymes also regulate the cellular levels of two other bioactive sphingolipids, sphingosine (SPH) and ceramide. S1P has recently emerged as a critical lipid second messenger and ligand for the Edg receptor family whereby it mediates cell growth and inhibits apoptosis. SPH is also a potent lipid mediator that inhibits cell growth and inhibits protein kinase C. Ceramide has also recently emerged as a key sphingolipid mediator involved in the regulation of mammalian and yeast stress responses. Regulation of cellular S1P, SPH, and ceramide levels therefore becomes critical to regulation of cell growth. Our specific hypothesis is that SPPase is a key regulator of SiP, SPH, and ceramide levels and of cellular responses to these bioactive lipids. Therefore, the main goals of this proposal are focused on: 1) doning the murine and human SPPases and determining their tissue, cellular and subcellular distribution. We have already identified an EST and begun the mammalian cloning, we will tag these enzymes, purify them, prove their activity, and study their tissue and cellular distribution. 2) Characterizing and studying the regulation of these novel mammalian SPPases, by determining KM for substrate, pH profile, cation dependence, and substrate specificity. At the cellular level we will study its regulation in response to inducers of cell growth and apoptosis. 3) determining the role of SPPase in regulaling cellular levels of SiP, SPH, and ceramide by determining changes in these bioactive lipids in cells where the SPPase has been overexpressed or knocked-out; and 4) determining the role of SPPase in cell regulation, by determining the effect of over-expression or knock-out of SPPase on cell growth and apoptosis. These studies should provide fundamental insight into the biochemical action of this enzyme. These studies will also allow important insight into mechanisms of its regulation and its role in the regulation of basal sphingolipid metabolism. Finally, these studies should provide key insight into the physiologic function of this enzyme and its role in cell regulation.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM062887-01
Application #
6317852
Study Section
Physiological Chemistry Study Section (PC)
Program Officer
Chin, Jean
Project Start
2001-05-01
Project End
2005-04-30
Budget Start
2001-05-01
Budget End
2002-04-30
Support Year
1
Fiscal Year
2001
Total Cost
$214,500
Indirect Cost
Name
Medical University of South Carolina
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Carroll, Brittany L; Bonica, Joseph; Shamseddine, Achraf A et al. (2018) A role for caspase-2 in sphingosine kinase 1 proteolysis in response to doxorubicin in breast cancer cells - implications for the CHK1-suppressed pathway. FEBS Open Bio 8:27-40
Williams, Bianca; Correnti, Jason; Oranu, Amanke et al. (2018) A novel role for ceramide synthase 6 in mouse and human alcoholic steatosis. FASEB J 32:130-142
Schwartz, Nicholas U; Linzer, Ryan W; Truman, Jean-Philip et al. (2018) Decreased ceramide underlies mitochondrial dysfunction in Charcot-Marie-Tooth 2F. FASEB J 32:1716-1728
Senkal, Can E; Salama, Mohamed F; Snider, Ashley J et al. (2017) Ceramide Is Metabolized to Acylceramide and Stored in Lipid Droplets. Cell Metab 25:686-697
Carroll, Brittany L; Pulkoski-Gross, Michael J; Hannun, Yusuf A et al. (2016) CHK1 regulates NF-?B signaling upon DNA damage in p53- deficient cells and associated tumor-derived microvesicles. Oncotarget 7:18159-70
Carroll, Brittany; Donaldson, Jane Catalina; Obeid, Lina (2015) Sphingolipids in the DNA damage response. Adv Biol Regul 58:38-52
Salama, Mohamed F; Carroll, Brittany; Adada, Mohamad et al. (2015) A novel role of sphingosine kinase-1 in the invasion and angiogenesis of VHL mutant clear cell renal cell carcinoma. FASEB J 29:2803-13
Adada, Mohamad; Canals, Daniel; Hannun, Yusuf A et al. (2014) Sphingolipid regulation of ezrin, radixin, and moesin proteins family: implications for cell dynamics. Biochim Biophys Acta 1841:727-37
Snider, Ashley J; Ali, Wahida H; Sticca, Jonathan A et al. (2014) Distinct roles for hematopoietic and extra-hematopoietic sphingosine kinase-1 in inflammatory bowel disease. PLoS One 9:e113998
Adada, Mohamad; Canals, Daniel; Hannun, Yusuf A et al. (2013) Sphingosine-1-phosphate receptor 2. FEBS J 280:6354-66

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