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Modulation by Palmitoylcarnitine of Protein Kinase C Activation

Molecular Mechanisms of Tumor Promotion Section, Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, Bethesda, Maryland 20892

Palmitoylcarnitine, a reported protein kinase C inhibitor, enhanced the phorbol ester dependency of the enzyme, augmenting protein kinase C activity in the presence of phorbol esters such as phorbol 12,13-dibutyrate while inhibiting the basal activity measured in the presence of calcium plus phosphatidylserine. Weakly potent phorbol esters such as phorbol 12,13-diacetate and 4-O-methylphorbol 12-myristate 13-acetate were full agonists like phorbol 12,13-dibutyrate for activation of protein kinase C in the presence of palmitoylcarnitine. On the other hand, 1,2-diacylglycerols such as 1,2-diolein were only partially stimulatory. Palmitoylcarnitine did not interfere with the association of protein kinase C with phosphatidylserine, suggesting that its action was on protein kinase C activation per se rather than on priming. A long fatty acid ester, quaternary amine, and anionic charge were needed for the palmitoylcarnitine-like action. Phosphatidylcholine, which possesses these features, partially mimicked the action of palmitoylcarnitine. Palmitoylcarnitine thus appears to be a lipophilic modulator of protein kinase C rather than a simple inhibitor. The results raise the possibility that differences in response between phorbol esters and diacylglycerols may reflect differential ability to activate protein kinase C in the appropriate lipid environment rather than the existence of unique targets for one or the other compound.

¹ Present address: Department of Pharmacology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160, Japan.

² To whom requests for reprints should be addressed, at Molecular Mechanisms of Tumor Promotion Section, Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, Bldg. 37, 3B25, NIH, Bethesda, MD 20892.

Received 5/ 1/87. Revised 9/21/87. Accepted 9/22/87.

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