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.
Mesh Terms:
Caco-2 Cells, Cytochrome P-450 CYP1A1, DNA-Binding Proteins, Humans, Methylcholanthrene, Nuclear Receptor Co-Repressor 2, Receptors, Aryl Hydrocarbon, Repressor Proteins, Tretinoin
Biochem. Biophys. Res. Commun.
Date: Sep. 17, 2004
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