Retinoids as ligands and coactivators of protein kinase C alpha.
Whereas retinoic acids control nuclear events, a second class of retinol metabolites, that is, the hydroxylated forms exemplified by 14-hydroxy-retro-retinol (HRR), operate primarily in the cytoplasm. They function as regulatory cofactors for cell survival/cell death decisions. In accordance with these biological aspects, we demonstrate that these retinoids bound protein kinase C (PKC) alpha with nanomolar affinity and markedly enhance the activation of PKC alpha and the entire downstream MAP kinase pathway by reactive oxygen species. HRR was 10 times more efficient than retinol, and the optimum doses are 10-7 and 10-6 M, respectively. PKC alpha activation was reversed rapidly by imposition of reducing conditions. The retinoid binding site was mapped to the first cysteine-rich region in the regulatory domain, C1A, yet was distinct from the binding sites of diacylglycerol and phorbol esters. The C1B domain bound retinoids poorly. The emerging theme is that retinoids serve as redox regulators of protein kinase C.
Imam
A
A
Program in Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Hoyos
B
B
Swenson
C
C
Levi
E
E
Chua
R
R
Viriya
E
E
Hammerling
U
U
D016475:3T3 Cells; D000818:Animals; D001665:Binding Sites; D003545:Cysteine / Q000378:metabolism; D004224:Diterpenes; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism*; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008954:Models, Biological; D010084:Oxidation-Reduction / Q000187:drug effects; D011485:Protein Binding; D011493:Protein Kinase C / Q000737:chemistry / Q000378:metabolism*; D051571:Protein Kinase C-alpha; D017434:Protein Structure, Tertiary; D017382:Reactive Oxygen Species / Q000378:metabolism; D012176:Retinoids / Q000378:metabolism* / Q000494:pharmacology*; D014801:Vitamin A / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
D004224:Diterpenes; D007527:Isoenzymes; D008024:Ligands; D017382:Reactive Oxygen Species; D012176:Retinoids; D014801:Vitamin A; C072014:14-hydroxy-4,14-retro-retinol; D006861:Hydrogen Peroxide; C496630:Prkca protein, mouse; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D003545:Cysteine