Ceramidases are key enzymes in the regulation of the cellular levels of ceramide, sphingosine, and S1P.To explore the physiological functions of ceramidases, we disrupted the gene encoding neutral ceramidase (Asah2) in mice. Asah2 null mice have a normal life span and do not show obvious abnormalities or major alterations in total ceramide levels in tissues. The Asah2-encoded neutral ceramidase is highly expressed in the small intestine along the brush border, suggesting that the neutral ceramidase may be involved in a pathway for the digestion of dietary sphingolipids. Indeed, Asah2 null mice were deficient in the intestinal degradation of ceramide. Thus, the results indicate that the Asah2-encoded neutral ceramidase is a key enzyme for the catabolism of dietary sphingolipids and regulates the levels of bioactive sphingolipid metabolites in the intestinal tract. We are currently utilizing the Asah2 null mice to determine if defective catabolism of sphingolipids alters the growth of intestinal tumors.? ? In collaborative efforts we made the following findings:? ? 1. Sphk1 is expressed and is required for small intestinal tumor cell proliferation in Apc Min/+ mice. The findings suggest that Sphk1 plays a critical role in intestinal tumor cell proliferation and that inhibitors of Sphk1 may be useful in the control of intestinal cancer.? ? 2. Identification of an apoptotic pathway triggered by intracellular accumulation of sphingolipid base phosphates and dependent of Sphk2. This work suggests that sphingoid base substrates for Sphk2 acting intracellularly could be useful in the treatment of lymphoproliferative diseases.
| Kono, Mari; Allende, Maria Laura; Proia, Richard L (2008) Sphingosine-1-phosphate regulation of mammalian development. Biochim Biophys Acta 1781:435-41 |
| Don, Anthony S; Martinez-Lamenca, Carolina; Webb, William R et al. (2007) Essential requirement for sphingosine kinase 2 in a sphingolipid apoptosis pathway activated by FTY720 analogues. J Biol Chem 282:15833-42 |
| Kohno, Masataka; Momoi, Michiko; Oo, Myat Lin et al. (2006) Intracellular role for sphingosine kinase 1 in intestinal adenoma cell proliferation. Mol Cell Biol 26:7211-23 |
| Kono, Mari; Dreier, Jennifer L; Ellis, Jessica M et al. (2006) Neutral ceramidase encoded by the Asah2 gene is essential for the intestinal degradation of sphingolipids. J Biol Chem 281:7324-31 |
