IRE-ABP (insulin response element-A binding protein) , an SRY-like protein, inhibits C/EBPalpha (CCAAT/enhancer-binding protein alpha) -stimulated expression of the sex-specific cytochrome P450 2C12 gene

Buggs, C.; Nasrin, N.; Mode, A.; Tollet, P.; Zhao, H.F.; Gustafsson, J.A.; Alexander-Bridges, M.

Molecular Endocrinology 12(9): 1294-1309


ISSN/ISBN: 0888-8809
PMID: 9731699
DOI: 10.1210/mend.12.9.0174
Accession: 008800324

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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 alpha (C/EBPalpha)-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/EBPalpha have overlapping specificity for the C/EBPalpha target site in the CYP2C12 promoter and compete for binding to CYP2C12 DNA in vitro. In contrast, IRE-ABP and C/EBPalpha 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/EBPalpha on CYP2C12 gene expression. Therefore, the ability of IRE-ABP to inhibit C/EBPalpha-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.