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IRE-ABP (Insulin Response Element-A Binding Protein), an SRY-Like Protein, Inhibits C/EBP (CCAAT/Enhancer-Binding Protein )-Stimulated Expression of the Sex-Specific Cytochrome P450 2C12 Gene

Diabetes Unit and Medical Services (C.B., N.N., M-A.B.) Massachusetts General Hospital Harvard Medical School Boston, Massachusetts 02114
Department of Medical Nutrition (A.M., P.T., J-Å.G.) Karolinska Institute Novum, S-14186 Huddinge, Sweden
National Research Council (H-F.Z.) Biotechnology Research Institute Montreal, Quebec H4P 2R2, Canada

In primary hepatocytes, overexpression of an insulin response element-A binding protein (IRE-ABP), a member of the SRY family of high-mobility group (HMG) proteins, inhibits CCAAT/enhancer-binding protein (C/EBP)-mediated activation of the female-specific cytochrome P450 2C12 (CYP2C12) gene, but not the male-specific cytochrome P450 2C11 (CYP2C11) gene. IRE-ABP and C/EBP have overlapping specificity for the C/EBP target site in the CYP2C12 promoter and compete for binding to CYP2C12 DNA in vitro. In contrast, IRE-ABP and C/EBP bind distinct sequences in the CYP2C11 promoter. A single amino acid substitution in the HMG domain of IRE-ABP impairs its ability to bind DNA and to inhibit the effect of C/EBP on CYP2C12 gene expression. Therefore, the ability of IRE-ABP to inhibit C/EBP-stimulated CYP2C12 gene expression requires a functional DNA-binding domain. Taken together, our findings suggest that SRY-like proteins can bind to a subset of sequences recognized by the C/EBP family of DNA-binding proteins and modulate gene transcription in a context-specific manner.

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