RUI: Mechanism of Action of the ras p21

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Ras proteins are guanine nucleotide-binding proteins which are central to cellular signal transduction. Although the mechanism(s) of action of cellular and mutant forms of the ras protein p21 have not been fully described, microinjection of either form can cause Xenopus oocytes to undergo meiotic cell division. Since ras protein has been found to increase polyphosphatidylinositol turnover, ras may act through the intracellular messengers of this pathway, protein kinase C and inositol 1,4,5-trisphosphate (IP3). Since IP3 has been found to release intracellular calcium in oocytes and other cell types, this suggests that at least some actions of ras may be due to increased intracellular calcium. While other laboratories have concentrated on the protein kinase C pathway, this laboratory has indirect evidence that ras protein can release intracellular calcium. Experiments are proposed to establish directly whether ras protein increases intracellular calcium and whether the cellular or mutant forms of ras induce two responses (meiotic cell division and an increase in intracellular pH) through the calcium increase. The proposed research will examine the mechanism of action of a protein, the "ras" protein, that is important in signal transduction across the cell membrane. Microinjection of ras proteins into frog eggs induces cell division. A variety of evidence suggests that ras effects may involve changes in the level of intracellular free calcium. This research will determine whether the ras protein itself releases calcium from intracellular stores or affects intracellular calcium levels less directly. The results will contribute to a better understanding of the mechanisms of cellular signal transduction.