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.
Fallone
Frédérique
F
FRE CNRS 2737, Faculté de Pharmacie, Université de la Méditerranée, 27 Bd Jean Moulin, 13385 Marseille Cedex 05, France.
Villard
Pierre-Henri
PH
Sérée
Eric
E
Rimet
Odile
O
Nguyen
Quock Binh
QB
Bourgarel-Rey
Véronique
V
Fouchier
Francis
F
Barra
Yves
Y
Durand
Alain
A
Lacarelle
Bruno
B
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