The growth division cycle of non-neoplastic cells is regulated by a variety of proteins as well as ions, small peptides and phospholipid products. Protein function can be regulated by binding to other proteins or by phosphorylation/dephosphorylation. While the past decade has focused on protein kinases in the regulation of cell proliferation and tumor promotion, recent evidence points to the importance of protein phosphatases in regulation of the cell cycle and in the tumor promotion process. We have found a novel serine/threonine protein phosphatases, type 3, that differs at the biochemical and molecular level from the other known protein phosphatases (PP) 1, 2A, 2B and 2C. Okadaic acid is a non-phorbol ester tumor promoter whose intracellular receptor is PP1, PP2A and PP3, having different affinities for these three enzymes and inhibiting their activities. It is the specific focus of this proposal to: 1) clone a cDNA of PP3 and relate the expression of this gene as well as PP1 and PP2A genes to the cell cycle and carcinogenesis; 2) define the role of PP1, PP2A and PP3 in cell cycle progression; 3) determine the role of PP1, PP2A and PP3 in generation of intracycle Ca2+ transients and 4) determine how PP3 catalytic activity is regulated and identify subcellular substrates of PP3.
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