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Titolo:
A duplicated HNF-3 binding site in the CYP2H2 promoter underlies the weak phenobarbital induction response
Autore:
Davidson, BP; Dogra, SC; May, BK;
Indirizzi:
Univ Adelaide, Dept Mol Biosci, Adelaide, SA 5005, Australia Univ Adelaide Adelaide SA Australia 5005 ci, Adelaide, SA 5005, Australia
Titolo Testata:
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
fascicolo: 11, volume: 33, anno: 2001,
pagine: 1080 - 1093
SICI:
1357-2725(200111)33:11<1080:ADHBSI>2.0.ZU;2-T
Fonte:
ISI
Lingua:
ENG
Soggetto:
CHICK-EMBRYO HEPATOCYTES; RECEPTOR CAR; TRANSCRIPTIONAL ACTIVATION; GENE; SEQUENCE; CYTOCHROME-P-450; RECOGNITION; SYNTHASE; REGION; DOMAIN;
Keywords:
phenobarbital; CYP2H1; CYP2H2; HNF-3; chicken;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
22
Recensione:
Indirizzi per estratti:
Indirizzo: May, BK Univ Adelaide, Dept Mol Biosci, Adelaide, SA 5005, Australia Univ Adelaide Adelaide SA Australia 5005 aide, SA 5005, Australia
Citazione:
B.P. Davidson et al., "A duplicated HNF-3 binding site in the CYP2H2 promoter underlies the weak phenobarbital induction response", INT J BIO C, 33(11), 2001, pp. 1080-1093

Abstract

We are investigating induction of chicken cytochrome P450 genes by the sedative phenobarbital in chick embryo hepatocytes. The steady-state level of induced mRNA for the gene CYP2H1 is about 10-fold higher than that of a second gene, CYP2H2. Here, we show that a difference in drug-responsive enhancer activity does not underlie the differential response of these genes to phenobarbital since upstream enhancer regions are identical in these genes. The first 198 bp of CYP2H2 promoter sequence is identical to the CYP2H1 gene promoter, except that the functional HNF-3 binding site in the CYP2H1 promoter is replaced with a duplicated HNF-3 sequence in the CYP2H2 promoter. Transient expression analysis established that the promoter activity of theCYP2H2 gene was about ninefold lower than the CYP2H1 gene, Mutagenesis of either of the partially overlapping HNF-3 sites in the CYP2H2 gene substantially induced drug induction. Gel-shift analysis established that each of these HNF-3 sites bound HNF-3, most likely HNF-3 beta. In-vitro footprint analysis demonstrated that all the identified sites in the CYP2H2 promoter bound protein except the duplicated HNF-3 region. However, protein binding was observed by in-vitro footprint analysis if either of the HNF-3 sites was mutated in the CYP2H2 promoter. Hence, duplication of the HNF-3 site in theCYP2H2 promoter does not allow binding of HNF-3 in the promoter context and may be predominantly, if not exclusively, responsible for the poor response of the CYP2H2 gene to phenobarbital. (C) 2001 Elsevier Science Ltd. All rights reserved.

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Documento generato il 07/04/20 alle ore 22:46:11