Gangliosides are associated with the abnormal growth and differential of human gliomas, and it has become increasingly clear that one of the major ways that they act is by modulating systems that control protein phosphorylation. Using U-1242MG human glioma cell lines as a model, the investigators have shown that specific gangliosides inhibit platelet-derived growth factor (PDGF) stimulated growth, and this is associated with characteristic changes in both the phosphorylation states of several proteins, and intracellular free calcium concentrations ([Ca2+]i). They are now focusing on the relation of gangliosides to protein phosphorylation and [Ca2+]i because of their universal importance in regulating critical cellular events.During the next funding period they will conduct three groups of experiments to elucidate the molecular mechanisms through which gangliosides cause these biochemical and biological effects. The first group will identify specific proteins whose phosphorylation states are altered by mitogenic stimuli, and determine the effects that exogenous gangliosides have on phosphorylation of these protein. Identification and cellular localization of substrates for the PDGF receptor tyrosine kinase, and determinations of the effects of gangliosides on the activity of this enzyme will also be made. The second group will examine effects of PDGF and gangliosides on [Ca2+]i, which is known to play a major role in signal transduction and protein phosphorylation systems. The third group will gain information on the uptake, metabolism and distribution of exogenous gangliosides in U-1242MG cells. This is essential to understand the specific molecular mechanisms through which gangliosides act. During the first funding period the investigators have established several important phenomena relating gangliosides, growth, protein phosphorylation, and [Ca2+]i. The experiments designed for the next funding period build on these findings, and will provide some of the information essential to develop a more specific and detailed model of how these factors interact.Such knowledge could lead to the development of new diagnostic and therapeutic strategies based on understanding the biological and molecular mechanisms responsible for aberrant growth of human gliomas.
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