The in vivo inhibition of mouse brain protein kinase-C by retinoic acid.
The intracisternal injection of either all-trans-retinoic acid or [alpha]-difluoromethylornithine (DFMO) into the brain of 9-day-old mice blocked (greater than 90%) phorbol ester-induced ornithine decarboxylase (ODC, EC 4.1.1.17) activity in a concentration-dependent fashion; this inhibition was not evident with the use of the biologically impotent furyl analog of retinoic acid. In a similar manner, retinoic acid reduced the soluble protein kinase-C (PK-C) activity by 60% as well as total EGTA-sensitive kinase activity (66%) associated with the plasma membrane. Sixty-six percent of the retinoic acid-induced loss of PK-C activity in the soluble fraction could be accounted for by the translocation of PK-C to the plasma membrane as measured by the specific binding of 12-O-[3H]tetradecanylphorbol-13-acetate (TPA). DFMO and furyl-retinoic acid were not effective in altering PK-C activity or TPA binding to PK-C. In the presence of retinoic acid, however, there was a 2.3-fold increase in specific [3H]TPA binding in the plasma membrane fraction, which was 3.4-fold greater than that lost from the cytosol. Because retinoids do not directly affect TPA binding to PK-C, the data suggest that (i) the presence of retinoic acid results in the exposure of heretofore cryptic TPA-binding sites in the membrane, where this binding is most likely related to the alteration of membrane structure and (ii) de novo ODC induction is not required for retinoid-dependent inhibition of PK-C, although the TPA induction of PK-C appears to be necessary with regard to ODC induction.
D000818:Animals; D001921:Brain / Q000201:enzymology*; D002352:Carrier Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000518:Eflornithine; D051379:Mice; D009952:Ornithine / Q000031:analogs & derivatives / Q000494:pharmacology; D009955:Ornithine Decarboxylase / Q000378:metabolism; D065108:Ornithine Decarboxylase Inhibitors; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D018168:Receptors, Retinoic Acid; D012177:Retinol-Binding Proteins / Q000378:metabolism; D054839:Retinol-Binding Proteins, Plasma; D014212:Tretinoin / Q000494:pharmacology*
D002352:Carrier Proteins; D065108:Ornithine Decarboxylase Inhibitors; D018168:Receptors, Retinoic Acid; D012177:Retinol-Binding Proteins; D054839:Retinol-Binding Proteins, Plasma; D014212:Tretinoin; D009952:Ornithine; D011493:Protein Kinase C; D009955:Ornithine Decarboxylase; D000518:Eflornithine