Involvement of ZIP/p62 in the regulation of PPARalpha transcriptional activity by p38-MAPK.
The peroxisome proliferator-activated receptor alpha (PPARalpha) belongs to the nuclear receptor family and plays a central role in the regulation of lipid metabolism, glucose homeostasis and inflammatory processes. In addition to its ligand-induced activation, PPARalpha is regulated by phosphorylation via ERK-MAPK, PKA and PKC. In this study we examined the effect of p38-MAPK on PPARalpha transcriptional activity. In COS-7 cells, anisomycin, a p38 activator, induced a dose-dependent phosphorylation of PPARalpha and a 50% inhibition of its transcriptional activity. In H4IIE hepatoma cells, anisomycin-induced p38 phosphorylation decreased both endogenous and PPARalpha ligand-enhanced L-CPTI and ACO gene expression. Interestingly, PPARalpha/p38 interaction required the molecular adapter ZIP/p62. Reducing ZIP/p62 expression by siRNA, partially reversed the inhibitory effect of anisomycin on L-CPTI gene expression. In conclusion, we showed that p38 activation induced PPARalpha phosphorylation and inhibition of its transcriptional activity through a trimeric interaction between p38-MAPK, ZIP/p62 and PPARalpha.
Diradourian
Claire
C
Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique, UMR 8104, 24 rue du Faubourg Saint Jacques, Paris, France.
Le May
Cédric
C
Caüzac
Michèle
M
Girard
Jean
J
Burnol
Anne-Françoise
AF
Pégorier
Jean-Paul
JP
D000818:Animals; D000841:Anisomycin / Q000378:metabolism; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D019384:Nucleic Acid Synthesis Inhibitors / Q000378:metabolism; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D000071456:Sequestosome-1 Protein; D014158:Transcription, Genetic; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
D006360:Heat-Shock Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D047493:PPAR alpha; D034741:RNA, Small Interfering; D000071456:Sequestosome-1 Protein; C491079:Sqstm1 protein, rat; D000841:Anisomycin; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases