Abstract
Several lines of evidence indicate that serine/threonine protein phosphatases may act as negative regulators of cellular growth. For example, treatment of cells with the tumor-promoter okadaic acid, an inhibitor of certain types of these phosphatases, resulted in the increased expression 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 highly 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 control of other cell cycle regulatory genes, such as cdc2 which encodes an essential cell cycle regulatory kinase. We found that cdc2 gene expression was blocked by okadaic acid, but stimulated by protein phosphatase 2A. Protein phosphatase 2A is shown to be a positive regulator of cdc2 gene activity and to be required for cdc2 expression. Thus, our findings identify protein phosphatase 2A as a positive regulator of a major cell cycle regulatory gene and therefore suggest a stimulatory role of this enzyme in this aspect of cellular growth control.
Highlights
Reversible protein phosphorylation appears to be one of the most important reactions contributing to cellular growth control and carcinogenesis
When added to cells synchronized in the S phase of the cell cycle, okadaic acid caused an increase in the enzymatic activity of histone H1 kinase, an enzyme that is necessary for cell cycle progression [11]
Because the E2F binding site appears to be regulated by the retinoblastoma tumor suppressor protein (Rb), and because the activity of Rb is strictly controlled by its phosphorylation status, we speculated that inhibition of cdc2 transcription by okadaic acid might be mediated via E2F
Summary
Reversible protein phosphorylation appears to be one of the most important reactions contributing to cellular growth control and carcinogenesis. Treatment of cells with the tumor-promoter okadaic acid, an inhibitor of certain types of these phosphatases, resulted in the increased expression of several proto-oncogenes, indicating a negative role of the respective phosphatases in gene regulation. Our findings identify protein phosphatase 2A as a positive regulator of a major cell cycle regulatory gene and suggest a stimulatory role of this enzyme in this aspect of cellular growth control.
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