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.
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.
Buggs
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C
Diabetes Unit, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA.
Nasrin
N
N
Mode
A
A
Tollet
P
P
Zhao
H F
HF
Gustafsson
J A
JA
Alexander-Bridges
M
M
D016475:3T3 Cells; D019943:Amino Acid Substitution; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001665:Binding Sites; D022762:CCAAT-Enhancer-Binding Proteins; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D000072467:Cytochrome P450 Family 2; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000096:biosynthesis / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C484091:insulin response element binding protein, rat; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; C034694:steroid 15-beta-hydroxylase