A protein kinase C-dependent activity modulates retinoic acid-induced transcription.
The retinoic acid receptors (RARs) and retinoid X receptors, which are members of the nuclear receptor family, mediate the effects of vitamin A derivatives on cellular growth and differentiation. The protein kinase C isozyme family also controls these processes in response to extracellular stimuli. We have investigated the relationship between these two signal transducing pathways using gene transfer techniques. We show that selective inhibition of protein kinase C (PKC) and its depletion by prolonged treatment with 12-O-tetradecanoylphorbol-13-acetate lead to the loss of ligand-dependent transcription of an RA-inducible promoter. The effect of the depletion in cellular PKC could be counteracted by overexpression of PKC alpha and is directly correlated to the loss of the DNA-binding activity of complexes containing the human RAR alpha (hRAR alpha). Indirect immunofluorescence studies demonstrated an altered subcellular localization of hRAR alpha. However, direct in vitro phosphorylation of hRAR alpha by PKC diminished its ability to form heterodimeric or homodimeric complexes on a retinoic acid response element, suggesting that the DNA-binding capacity of hRAR alpha in intact cells is indirectly controlled by a PKC-dependent mechanism. Thus our observations establish a functional link between the PKC and retinoid pathways, which are generally considered to have antagonistic activities on differentiation processes.
Tahayato
A
A
INSERM-CJF 92-03, Faculte de Medecine de Lille, France.
Lefebvre
P
P
Formstecher
P
P
Dautrevaux
M
M
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D004247:DNA / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000502:physiology*; D007546:Isoquinolines / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D008969:Molecular Sequence Data; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D018168:Receptors, Retinoic Acid / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects*; D014212:Tretinoin / Q000494:pharmacology*
D007211:Indoles; D007527:Isoenzymes; D007546:Isoquinolines; D008301:Maleimides; D010879:Piperazines; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D014212:Tretinoin; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D004247:DNA; D011493:Protein Kinase C; C070515:bisindolylmaleimide I; D013755:Tetradecanoylphorbol Acetate