Retinoids repress Ah receptor CYP1A1 induction pathway through the SMRT corepressor
Résumé
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 À55% for mRNA level and À30% 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 inhib-itor 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.
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