The control of cell growth regulation is currently one of the major problems in cellular biology which remains poorly understood. The discovery that the interaction of the B subunit of cholera toxin with endogenous ganglioside GM1 leads to dramatic alterations in cell growth suggests a fundamental role for endogenous gangliosides as bimodal regulators of positive and negative signals for cell growth. To elucidate the mechanism by which the B subunit can alter cellular proliferation, its effects on several transmembrane signalling systems which play a crucial role in cell growth regulation will be examined. These include: changes in cyclic nucleotide levels and cytoplasmic Ca+2 concentration; activation of protein kinase C, Na+/H+ exchange and phospholipase C; degradation of phosphoinositides; phosphorylation of specific cellular proteins; and changes in the expression of proto-oncogenes. Extension of these studies to the transformed cells lines may help in understanding the complex issue of the lack of growth control in cancer cells. The bimodal responses of cells to the B subunit may be related to the amount, or more importantly, to the distribution of GM1 on the cell surface. The topographical distribution of GM1 will be compared on quiescent versus exponentially growing and transformed cells by immunofluorescent staining. A key event in the regulation of cell growth is the activation of multiple stimulatory and inhibitory protein kinase activities. Therefore, a search for a novel protein kinase which is directly modulated by endogenous gangliosides, will be initiated. Understanding of the role for endogenous gangliosides, which is a complete mystery at present, has important implications not only for the cause underlying the escape of growth control by cancer cells, but also for their potential function in neuronal regenerative processes.
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