Retinoids repress Ah receptor CYP1A1 induction pathway through the SMRT corepressor.
CYP1A1 isoform is mainly regulated by the transcription factor AhR and to a lesser extent by the nuclear receptor RAR. The effect of a coexposure with 3MC, a AhR ligand, and RA, a RAR ligand, which are, respectively, strong and weak CYP1A1 inducers, is poorly known. We showed in Caco-2 cells that addition of RA significantly decreased 3MC-induced CYP1A1 expression by -55% for mRNA level and -30% for promoter and enzymatic activities. We further showed that RA decreased AhR protein level. Moreover, a physical interaction between AhR and the RAR-corepressor SMRT has been described in vitro. Using the corepressor inhibitor TSA, transfected-cells with SMRT cDNA, and coimmunoprecipitation experiments, we demonstrated that RA addition repressed AhR function through a marked AhR/SMRT physical interaction. This interaction explains the decrease of 3MC-induced CYP1A1 expression. This new mechanism involving the repression of AhR-induced CYP1A1 expression by retinoids allows better knowledge of the CYP1A1 regulation.
FRE CNRS 2737, Faculté de Pharmacie, Université de la Méditerranée, 27 Bd Jean Moulin, 13385 Marseille Cedex 05, France.
Frédérique
F
Fallone
Pierre-Henri
PH
Villard
Eric
E
Sérée
Odile
O
Rimet
Quock Binh
QB
Nguyen
Véronique
V
Bourgarel-Rey
Francis
F
Fouchier
Yves
Y
Barra
Alain
A
Durand
Bruno
B
Lacarelle
D018938:Caco-2 Cells; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D008748:Methylcholanthrene / Q000378:metabolism; D056985:Nuclear Receptor Co-Repressor 2; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D014212:Tretinoin / Q000378:metabolism*
D004268:DNA-Binding Proteins; C539130:NCOR2 protein, human; D056985:Nuclear Receptor Co-Repressor 2; D018336:Receptors, Aryl Hydrocarbon; D012097:Repressor Proteins; D008748:Methylcholanthrene; D014212:Tretinoin; D019363:Cytochrome P-450 CYP1A1