Cyclosporin A inhibits proteolytic cleavage and degradation of membrane-bound protein kinase C in hepatocytes after stimulation by phorbol ester.
Stimulation of hepatocytes by the tumor promoter phorbol 12-myristate 13-acetate (PMA) caused translocation of cytosolic Ca2+/phospholipid-dependent protein kinase C (PK-C). The major part of PK-C activity (greater than 80%) was associated with the membrane fraction after 30 min. During the following 6 h protein kinase C activity decreased to less than 10%. Minor amounts of Ca2+/phospholipid-independent PK-C activity were found in the cytosol fraction at all times; they temporarily increased 2.5-fold with PMA and decreased after 1 h. Cyclosporin A did not affect the translocation of PK-C from the cytoplasm to the membrane fraction, but the decrease of PK-C activity following translocation was blocked. No marked increase of Ca2+/phospholipid-independent PK-C activity was observed in the cytosol in the presence of cyclosporin A. Leupeptin, which is known to inhibit Ca2+-requiring non-lysosomal proteinases (e.g. calpain), showed an effect similar to cyclosporin A. Both agents reduced proteolytic degradation of cellular proteins observed in isolated hepatocytes after PMA treatment. Ca2+-ionophore A23187 in high doses (greater than 10(5) M) partly reversed cyclosporin A and leupeptin action.
D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002478:Cells, Cultured; D003524:Cyclosporins / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D003524:Cyclosporins; D000001:Calcimycin; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate