Glyn Dawson, Ph.D.

Lipid-Derived Second Messengers; Response of Normal and Malignant Brain Cells to Stress

Research Summary

The lab is currently interested in the biochemistry of surface carbohydrates and lipids in multidrug resistance and the use of viral vectors to deliver glycosyltransferase genes to brain tumors in situ. Transfection of the a2,6Sialotransferase gene replaces a2,3-linked Sialic acids with a2,6 sialic acids, resulting in a marked inhibition of glioma cell invasivity, a significant reduction in adhesivity and hence less tumorgenicity. Gliomas are tnormally highly resistant to cell death induced by chemotherapeutic agents and we are investigating the mechanism by which they become more sensitive to apoptosis, induced by chemotherapeutic gents such as etoposide, following overexpression of glycoprotein glycosyltransferases. We observe high levels of palmitoyl:protein thioesterase (PPT) activity in many tumors and have synthesized amide analogs as inhibitors. These compounds improve etoposide killing and we are interested in elucidating the mechanism of action. Work continues on the role of ceramide in tumor death, especially the metabolic origin of ceramide and the use of drugs to promote increased ceramide formation and tumor cell death. Particular emphasis is placed on the role of the two major cellular sphingomyelinases in promoting cell death and we use gene transfection and transgenic mouse technology to study the mechanism of the resulting cell death.

Selected Papers

Ariga T, Blaine GM, Yoshino H, Dawson G, Zeng GC, Kanda T, Kasama T, Kushi Y, and Yu RK. (1995). Glycosphingolipidcomposition of murine neuroblastoma cells: O-Acetylesterase gene downregulates the expression of O-acetylated GD3. Biochemistry. 34: 11500-11507.

Mangoura D, Sogos V, Pelletiere C and Dawson G. (1995) Differential regulation of phospholipases C and D by phorbol esters and the physiological activators carbachol and glutamate in astrocytes from chicken embryo cerebrum and cerebellum. Devel. Brain Res. 87: 12-21.

Mangoura D, Sogos V and Dawson G. (1995) Phorbol esters and PKC signaling regulate proliferation, vimentin cytoskeleton assembly and glutamine synthetase activity of chick embryo cerebrum astrocytes in culture. Devel. Brain Res. 87: 1-11.

Wiesner DA and Dawson G. (1996) Staurosporine induces programmed cell death in embryonic neurons through activation of the ceramide pathway. J. Neurochem. 66: 1418-1425.

Wiesner D, Kilkus J, Gottschalk AR, Quintans J and Dawson G. (1997). Anti-immunoglobulin-induced apoptosis in WEHI-231 cells involves the slow formation of ceramide from sphingomyelin and is blocked by bclxL. J. Biol. Chem. 272: 9868-9846.

Dawson G, Dawson SA and Goswami R. (1997). Chronic exposure to kappa opioids enhances the susceptibility of immortalized neurons (F-11k7) to apoptosis-inducing drugs by a mechanism that involves ceramide. J. Neurochem. 68: 2363-2370

Goswami R, Dawson SA and Dawson G. (1998) Cyclic AMP protects against staurosporine and wortmannin-induced apoptosis and opioid-enhanced apoptosis in both embryonic and immortalized (F-11k7) neurons. J. Neurochem. 70: 1376-1382.

Mangoura DM and Dawson, G (1998) Programmed cell death in cortical chick embryo astrocytes is associated with activation of protein kinase PK60 and ceramide formation. J. Neurochem. 70:130-138.

Goswami R, Kilkus J, Dawson SA, and Dawson G. (1999). Overexpression of Akt (protein kinase B) confers protection against apoptosis and prevents formation of ceramide in response to pro-apoptotic stimuli. J. Neurosci. Res. 57: 884-893.

Cho S, Dawson G. (2000) Palmitoyl protein thioesterase 1 protects against apoptosis mediated by Ras-Akt-caspase pathway in neuroblastoma cells. J Neurochem 74:1478-1488,

Goswami R, Dawson SA, and Dawson G. (2000) Multiple polyphosphoinositide pathways regulate apoptotic signalling in a dorsal root ganglion derived cell line. J. Neurosci. Res. 59:136-144.

Dawson G, Kilkus J, Schieven, GL. ( 2000) Selective phosphotyrosine phosphatase inhibition and increased ceramide formation is associated with B-cell death by apoptosis. FEBS Lett 478:233-236,

Goswami R, Dawson G. (2000) Does ceramide play a role in neural cell apoptosis J Neurosci Res 60:141-149.

Dawson G, Dawson SA and Dawson PE. (2002) Anti-tumor promoting effects of palmitoyl:protein thioesterase inhibitors against human neurotumor cell lines. Cancer Lett. 187: 163-168.

Goswami R, Kilkus J, Scurlock B and Dawson G. (2002) CrmA protects against apoptosis and Ceramide formation in PC12 cells. Neurochem. Res. 27: 735-741.

Kilkus J, Goswami R, Testai FD and Dawson G. (2003) Ceramide in RAFTS (detergent-insoluble fraction) mediates cell death in nurotumor cell lines. J. Neurosci. Res. 72: 65-75.

Testai FD, Landek MA and Dawson G. (2004). Regulation of sphingomyelinases in cells of the oligodendrocyte lineage. J. Neurosci. Res. 75: 66-74.

Testai FD, Landek MA, Goswami R, Ahmed M, and Dawson G. (2004) Acid sphingomyelinase and inhibition by phosphate ion: role of PtdIns(3,4,5)P3 in oligodendrocyte signaling. J. Neurochem. Accepted 1/5/04.

Dawson G, Moskal JR, Kersey D and Dawson SA. (2004). Transfection of 2,6 and 2,3-sialyltransferase genes and GlcNAc-transferase genes into human glioma cell line U373 MG affects glycoconjugate expression and enhances cell death. J. Neurochem. In press.