This application seeks support for a research program directed toward a better understanding of the role of the plasma membrane in the regulation of growth in cultured cells. The specific objective of the proposed investigation is to examine the relationship between four membrane-associated, physiological parameters (cell membrane potential, Ca plus 2 influx, cell cAMP levels, and nutrient transport) which are altered upon mitogen stimulation of normal cells and upon cell transformation. The experiments will seek the solution to four major unsolved problems: First, are changes in these four membrane parameters causally interrelated or are they altered independently? Second, does mitogen-stimulation or viral transformation of cells induce a change in one of these parameters which then triggers changes in the other three parameters? Third, does the binding of purified mitogens stimulate changes in these parameters by directly influencing membrane function or indirectly by stimulating changes in cellular metabolism which act to modify membrane function? Fourth, do internally produced growth factors in virally transformed cells influence membrane function by acting through mitogen receptors? Experiments designed to answer these questions involve measurements of fluxes of tracer molecules across cellular membranes and membrane vesicles, and measurement of cAMP concentrations and membrane potentials in quiescent and mitogen-stimulated human fibroblasts and in other mammalian cells transformed by a temperature-sensitive Rous sarcoma virus.
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