IRE-ABP (INSULIN-RESPONSE ELEMENT-A BINDING-PROTEIN), AN SRY-LIKE PROTEIN, INHIBITS C EBP-ALPHA (CCAAT/ENHANCER-BINDING PROTEIN ALPHA)-STIMULATED EXPRESSION OF THE SEX-SPECIFIC CYTOCHROME-P450 2C12 GENE/

In primary hepatocytes, overexpression of an insulin response element- a binding protein (IRE-ABP), a member of the SRY family of high-mobili ty group (HMG) proteins, inhibits CCAAT/enhancer-binding protein alpha (C/EBP alpha)-mediated activation of the female-specific cytochrome P 450 2C12 (CYP2C12) gene, but not the male-specific cytochrome P450 2C1 1 (CYP2C11) gene. IRE-ABP and C/EBP alpha have overlapping specificity for the C/EBP alpha target site in the CYP2C12 promoter and compete f or binding to CYP2C12 DNA in vitro. In contrast, IRE-ABP and C/EBP alp ha bind distinct sequences in the CYP2C11 promoter. A single amino aci d substitution in the HMG domain of IRE-ABP impairs its ability to bin d DNA and to inhibit the effect of C/EBP alpha on CYP2C12 gene express ion. Therefore, the ability of IRE-ABP to inhibit C/EBP alpha-stimulat ed CYP2C12 gene expression requires a functional DNA-binding domain. T aken together, our findings suggest that SRY-like proteins can bind to a subset of sequences recognized by the C/EBP family of DNA-binding p roteins and modulate gene transcription in a context-specific manner.