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Ceramide inhibition of NF-B activation involves reverse translocation of classical protein kinase C (PKC) isoenzymes: requirement for kinase activity and carboxyl-terminal phosphorylation of PKC for the ceramide response

Department of Biochemistry and Molecular Biology; Medical University of South Carolina; Charleston, South Carolina 29425, USA

¹Correspondence: Department of Biochemistry and Molecular Biology, 173 Ashley Ave., P.O. Box 2550509, Charleston, SC 29425, USA. E-mail: hannun{at}musc.edu

Protein kinase C (PKC) is known to activate NF-B whereas the lipid mediator ceramide was recently shown to inhibit activation of this transcription factor (1 , 2) . In this study, the mechanisms by which ceramide interferes with this pathway were examined in Jurkat leukemia and MCF-7 breast cancer cells. Both exogenous and endogenous ceramide inhibited selectively PKC-mediated activation of NF-B by reverting PKC translocation to the membrane. Next, confocal and immunofluorescence studies were performed to evaluate the direct effects of ceramide on PKC. These studies showed that ceramide inhibited translocation of a green fluorescent protein (GFP)-PKCß2 fusion protein in response to PMA. A mutant PKC in which autophosphorylation sites were mutated to alanine (PKC-DA) was resistant to ceramide. A kinase-inactive mutant (PKC-KR) was also resistant to ceramide action, and the results were supported using kinase inhibitors of the enzyme. Finally, overexpression of PKC-DA prevented, at least partly, the ability of ceramide to inhibit activation of NF-B. Taken together, these studies show that ceramide has acute effects on translocation of PKC by inducing reverse translocation, and this reversal requires both the kinase activity of PKC and phosphorylation of the autophosphorylation sites.—Signorelli, P., Luberto, C., Hannun, Y. A. Ceramide inhibition of NF-B activation involves reverse translocation of classical protein kinase C (PKC) isoenzymes: requirement for kinase activity and carboxyl-terminal phosphorylation of PKC for the ceramide response.

Key Words: diacylglycerol • sphingolipid • glycerolipid • C₆-ceramide

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