POSITIVE REGULATION OF CDC2 GENE ACTIVITY BY PROTEIN PHOSPHATASE TYPE2A

Several lines of evidence indicate that serine/threonine protein phosp hatases may act as negative regulators of cellular growth. For example , treatment of cells with the tumor-promoter okadaic acid, an inhibito r of certain types of these phosphatases, resulted in the increased ex pression of several proto-oncogenes, indicating a negative role of the respective phosphatases in gene regulation. However, it was puzzling to find that okadaic acid-treated cells, even in the presence of highl y expressed proto-oncogenes, did not proliferate, but were arrested at certain points of the cell cycle. To further analyze this discrepancy , we investigated the involvement of protein phosphatases in the contr ol of other cell cycle regulatory genes, such as cdc2, which encodes a n essential cell cycle regulatory kinase. We found that cdc2 gene expr ession was blocked by okadaic acid, but stimulated by protein phosphat ase 2A. Protein phosphatase 2A is shown to be a positive regulator of cdc2 gene activity and to be required for cdc2 expression. Thus, our f indings identify protein phosphatase 2A as a positive regulator of a m ajor cell cycle regulatory gene and therefore suggest a stimulatory ro le of this enzyme in this aspect of cellular growth control.