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Effect of Phorbol Ester on Cyclic Adenosine 3':5'-Monophosphate-dependent Protein Kinases in PYS Teratocarcinoma-derived Cells and Counteraction with Retinoic Acid¹

Laboratoire de Physiopathologie du Développement, 46 rue d'Ulm, 75005 Paris, France [A. P., P. G., D. E. B.], and National Cancer Institute, Division of Cancer Biology and Diagnosis, Bethesda, Maryland 20892 [W. B. A.]

Treatment of PYS cells with the tumor promoter (TPA) has been previously shown to enhance calcium- and phospholipid-dependent protein kinase (PK.C) in the membranes and to decrease its activity in the cytosol. Evidence is presented that 0.1 µM TPA treatment of PYS cells causes an opposite effect on the cyclic AMP-dependent protein kinases (PK.A). Within 10 min TPA led to an increase in PK.A in the cytosol and a concomitant decrease in the membranes, as measured by both the kemptide phosphorylation activity and photoaffinity labeling of R_I and R_II regulatory subunits of PK.A, with 8-azido-cyclic [³²P]AMP. Moreover, the antitumor promoter retinoic acid (RA, 0.1 µM), when added simultaneously with TPA to the PYS cells, completely abolished the TPA effects on PK.A. When RA was added 25 min before TPA, the counteraction was not observed, indicating that RA was counteracting the TPA effect directly. These results suggest that TPA induces a rapid change in the compartmentalization of PK.A between the membrane and the soluble fraction. This possible translocation of PK.A seems to be blocked by RA, suggesting that the early antagonistic effects of RA toward TPA-mediated events occur at the plasma membranes.

¹ This investigation was supported by a grant of the Comité de Paris de la Ligue Nationale Française contre le Cancer.

² To whom requests for reprints should be addressed.

Received 7/24/87. Revised 12/ 4/87. Accepted 1/29/88.