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Posttranslational Control of Cyclic AMP-dependent Protein Kinase by Phorbol Ester in Normal but not in Chemically Transformed 3T3 Cells¹

Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118

Protein kinase C (PKC) and cyclic AMP-dependent protein kinase (PKA) are important for normal cell proliferation. We show that both kinases are down-regulated by a phorbol ester tumor promoter in nontumorigenic murine BALB/c 3T3 fibroblasts (A31 cells), whereas only PKC responded to the phorbol ester in a chemically transformed derivative cell line (DMBA31 cells). In quiescent A31 cells, phorbol dibutyrate (PDBu) caused a 10-fold reduction in PKC activity and a 5-fold reduction in PKA activity. In contrast, PDBu depleted quiescent DMBA31 cells of PKC activity only and had no effect on the PKA activity. In both cell lines, PDBu did not affect the level of PKA regulatory subunits (determined by a cyclic [³H]-AMP binding assay), the levels of mRNA encoding the catalytic and the abundant regulatory subunit (determined by Northern blotting), or the level of the catalytic subunit protein (determined by Western blotting). An in situ gel activity assay confirmed that PDBu reduced the kinase activity of native PKA complexes from A31 cells but not from DMBA31 cells. These results indicate that phorbol esters down-regulate PKA activity by a posttranslational mechanism. They further suggest that the activity of PKC and PKA may be coordinately regulated in nontumorigenic cells and that transformation can disrupt this coordinate regulation.

¹ Supported by Grant CA45695 from the National Cancer Institute.

² Supported by Training Grant AG00115 from the National Institute of Aging. Current address: USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA 02111.

³ Recipient of an Established Investigator Award from the American Heart Association. To whom requests for reprints should be addressed. Current address: Cell and Molecular Biology Division, Lawrence Berkeley Laboratory, University of California, Berkeley, CA 94720.

Received 4/18/90. Accepted 8/17/90.

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