Gangliosides are involved in growth and differentiation of several cell types including gliomas, and experimental evidence suggests that they operate through two major mechanisms: (a) Modulation of growth factor stimulated cell division; (b) Regulation of protein phosphorylation. Experiments outlined in this proposal will investigate ganglioside mediated modulation of cell proliferation and protein phosphorylation using human glioma cell lines. I. Experiments will first delineate the effects of altering the ganglioside composition on PDGF and EGF stimulated growth of glioma cell lines. The ganglioside content of cells will be modulated by adding exogenous gangliosides, sialidases, or a sialidase inhibitor (NeuAc2en) to the growth media. The ganglioside composition of these cells will also be analyzed biochemically. II. The effects of gangliosides on protein phosphorylation in intact cells will be studied by adding agents which stimulate: (a) tyrosine kinases; (b) protein kinase C (PKC); (c) cAMP-dependent kinase (PKA). III. The mechanisms through which gangliosides modulate cell proliferation or protein phosphorylation will be examined using in vitro systems to study the effects of gangliosides on: (a) PDGF and EGF receptor binding, and receptor tyrosine kinase activities; (b) Phosphorylation of plasmalemma protein by endogenous kinases; (c) Phosphorylation of plasmalemma proteins by exogenous tyrosine kinases, PKC, and PKA. The results of these experiments will yield insights into the role of gangliosides in the molecular mechanisms responsible for aberrant biological behaviors of human glioma cells, with possible application to developing future therapeutic strategies for human brain tumors.
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