Office: 843-792-0273
Lab: 843-792-0273
Fax: 843-792-4850
Email: bielawsk@musc.edu
BSB-748

Research Interests

Sphingolipid metabolism assumes a key role in the complex mechanisms regulating cellular stress responses to environment. Several sphingolipid metabolites have recently been shown to have bioactivity, and their individual contributions to the regulatory pathways that govern cell growth are currently being established. The Sphingomyelin (SM) cycle, a ubiquitous signaling system linking a specific set of cell-surface receptors to the nucleus and cellular events, represents a novel antiproliferative, signal transduction pathway that regulates cell cycle arrest, differentiation, and apoptosis. Ceramide, the putative second messenger of the SM cycle has been proposed as a molecular sensor of injury and assumes a fundamental role in the cullular stress response. Sphingosine-1-phosphate, a product of ceramide metabolism, promotes cell growth and opposes ceramide-mediated apoptosis. This discovery has emphasized the need to examine the chemistry and biochemistry of the lipid components into tumor growth and metastasis.  Laboratory goal is to develop a solid chemical and biochemical foundation to understand the role of sphingolipids in signal transudation and cell regulation in the area of cancer biology. Our synthetic research program focuses on the generation of a library of sphingolipid standards as basic tools for research, and on designing new molecular probes based on the stereochemical foundation of the sphingosine backbone and functional groups in complex sphingolipids. Our biochemical goal is to develop insight into the mechanism of action of sphingolipids through the tools generated by synthesis. Furthermore, we are developing specific metabolic inhibitors of key enzymes involved in sphingolipid signal transduction and discovering novel chemotherapeutic agents. Our analytical goal is to develop new techniques for qualitative and quantitative analysis of sphingolipids isolated from biological samples.  Using a set of compounds synthesized in our laboratory, we have already shown that biological effects of sphingolipids are stereospecific, and we discovered the first known inhibitor of alkaline ceramidase, which may play important roles in attenuating ceramide signals.

Selected Publications

• Usta, J., El-Bawab, S., Roddy, P., Szulc, Z., Hannun, Y.A. and Bielawska, A. (2001) Structural Requirements of Ceramide and Sphingosine Based Inhibitors of Mitochondrial Ceramidase. Biochemistry, 40(32): 9657-9668.
• Bielawska, A., Perry, D.K. and Hannun, Y.A. (2001) Determination of Ceramides and Diglycerides by the Diglyceride Kinase Assay. Analytical Biochemistry, (In press).
• El-Bawab, S., Usta, J., Roddy, P., Szulc, Z., Bielawska, A. and Hannun, Y.A. (2001) Substrate specificity of Mitochondrial Ceramidase. J. Lipid Res. (In press).
• Mao, C., Xu, R., Szulc, Z.M., Bielawska, A., Galadari, S.H., Obeid, L.M. (2001) Cloning and Characterization of a Novel Human Alkaline Cermidase. A Mammalian enzyme that hydrolyzes phytoceramide. J. Biol. Chem., 276(28): 26577-26588.
• ElBawab, S., Birbes, H., Roddy, P., Szulc, Z.M., Bielawska, A., and Hannun, Y.A. (2001) Biochemical characterization of the reverse activity of rat brain ceramidase. A CoA-dependent and fumonisin B1-insensitive ceramide synthase. J. Biol. Chem., 276(20): 16758-16766.
•  Selzner, M., Bielawska, A., Morse, M.A., Rudiger, H.A., Sindram, D., Hannun, Y.A., and Clavien, P.A. (2001) Induction of apoptotic cell depth and prevention of tumor growth by ceramide analogues in metastatic human colon cancer. Cancer Res., 61(3): 1233-1240.
• Szulc, Z., Hannun, Y.A., and Bielawska, A. (2000) A Facile Regioselective Synthesis of sphingosine-1-Phosphate and Ceramide-1-Phosphate. Tetrahedron Letters 41: 7821-7824
• Lee, J.Y., Bielawska, A.E., and Obeid, L.M. (2000) Regulation of cyclin-dependent kinase 2 activity by ceramide. Exp. Cell Res., 261(2): 303-311.
• Chalfant, C.E., Kishikawa, K., Bielawska, A., and Hannun, Y.A. (2000) Analysis of ceramide-activated protein phosphatases. Methods in Enzymology: 312: 420-428.
• Perry, D.K., Bielawska, A. and Hannun, Y.A. (2000) Quantitative determination of ceramide using diglyceride kinase. Methods in Enzymology, 312: 22-31.
• Sawai, H., Okamoto, Y., Luberto, C., Mao, C., Bielawska, A., Domae, N. and Hannun, Y.A. (2000) Identification of ISC1 (YER019w) as inositol phosphosphingolipid phospholipase C in Saccharomyces cerevisiae. J. Biol. Chem., 275(50): 39793-39798.
• Mao, C., Xu, R., Bielawska, A., Szulc, Z.M. and Obeid, L.M. (2000) Cloning and characterization of a Saccharomyces cerevisiae alkaline ceramidase with specificity for dihydroceramide. J. Biol. Chem., 275(40): 31369-31378.
• ElBawab, S., Roddy, P., Qian, T., Bielawska, A., Lemasters, J.J. and Hannun, Y.A. (2000) Molecular cloning and characterization of a human mitochondrial ceramidase. J. Biol. Chem., 275(28): 21508-21513.
• Mao, C., Xu, R., Bielawska, A., and Obeid, L.M. (2000) Cloning of an alkaline ceramidase from Saccharomyces cerevisiae. An enzyme with reverse (CoA-dependent) ceramide synthase activity. J. Biol. Chem., 275(10): 6876-6884.
• Bielawska, A., Szulc, Z. and Hannun, Y.A. (2000) Synthesis of key precursors of radiolabeled sphingolipids. Methods in Enzymology, 311: 518-535.
• Bielawska, A. and Hannun, Y.A. (2000) Preparation of radiolabeled ceramides and phosphosphingolipids. Methods in Enzymology, 311: 499-518.
• Bielawska, A., Hannun, Y.A. and Szulc, Z. (2000) Radiolabeling of the sphingolipid backbone. Methods in Enzymology, 311: 480-498.
• ElBawab, S., Bielawska, A. and Hannun, Y.A. (1999) Purification and characterization of a membrane-bound nonlysosomal ceramidase from rat brain. J. Biol. Chem., 274(39): 27948-27955.
• Kishikawa, K., Chalfant, C.E., Perry, D.K., Bielawska, A. and Hannun, Y.A. (1999) Phosphatidic acid is a potent and selective inhibitor of protein phosphatase 1 and an inhibitor of ceramide-mediated responses. J. Biol. Chem., 274(30): 21335-21341.
• Chalfant, C.E., Kishikawa, K., Mumby, M.C., Kamibayashi, C., Bielawska, A. and Hannun, Y.A. (1999) Long chain ceramides activate protein phosphatase-1 and protein phosphatase-2A. Activation is stereospecific and regulated by phosphatidic acid. J. Biol. Chem., 274(29): 20313-20317.
• Bielawska, A., Hannun, Y.A. and Szulc, Z.M. (1999) "Radiolabeled Sphingolipids" Methods in Enzymology: Sphingolipid metabolism and cell signaling, Merril, A.J., Hannun, Y.A., Eds (manuscript accepted for publication).
• Saba, J.D., Nara, F., and Bielawska, A. (1998) The BST1 gene of Saccharomyces cerevisiae is the sphingosine-1-phosphate lyase. J. Biol. Chem., 272: 26087-26090.
• Perry, D.K., Bielawska, A., and Hannun, Y.A. (1998) "The antitumor properties of ceramides" in Liposomes: Rational Design. Marcel Dekker, N.Y., 1999, 145-157.
• Tsung-S, Lai, Bielawska, A.E., Peoples, K.A., Hannun, Y.A., and Greenberg, C.S. (1997) Sphingosylphosphocholine Reduces the Calcium Ion Requirement for Activating Tissue Transflutaminase. J. Biol. Chem. 272: 16295-16300.
• Bielawska, A.E., Shapiro, J.P., Jlang, Li, Melconyan, H.S., Pilot, C., Wolfe, C.L., Tomel, D., Hannun, Y.A., and Umansky, S.R. (1997) Ceramide is Involved in Triggering of Cardiomyocyte Apoptosis Induced by Ischemia and Reperfusion. Amer. J. of Pathology, 151: 1257-1263.