An autoregulatory loop controlling CYP1A1 gene expression: role of H(2)O(2) and NFI.

Détails

ID Serval
serval:BIB_49F672210DC6
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
An autoregulatory loop controlling CYP1A1 gene expression: role of H(2)O(2) and NFI.
Périodique
Molecular and Cellular Biology
Auteur(s)
Morel Y., Mermod N., Barouki R.
ISSN
0270-7306[print], 0270-7306[linking]
Statut éditorial
Publié
Date de publication
1999
Volume
19
Numéro
10
Pages
6825-6832
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
Cytochrome P450 1A1 (CYP1A1), like many monooxygenases, can produce reactive oxygen species during its catalytic cycle. Apart from the well-characterized xenobiotic-elicited induction, the regulatory mechanisms involved in the control of the steady-state activity of CYP1A1 have not been elucidated. We show here that reactive oxygen species generated from the activity of CYP1A1 limit the levels of induced CYP1A1 mRNAs. The mechanism involves the repression of the CYP1A1 gene promoter activity in a negative-feedback autoregulatory loop. Indeed, increasing the CYP1A1 activity by transfecting CYP1A1 expression vectors into hepatoma cells elicited an oxidative stress and led to the repression of a reporter gene driven by the CYP1A1 gene promoter. This negative autoregulation is abolished by ellipticine (an inhibitor of CYP1A1) and by catalase (which catalyzes H(2)O(2) catabolism), thus implying that H(2)O(2) is an intermediate. Down-regulation is also abolished by the mutation of the proximal nuclear factor I (NFI) site in the promoter. The transactivating domain of NFI/CTF was found to act in synergy with the arylhydrocarbon receptor pathway during the induction of CYP1A1 by 2,3,7,8-tetrachloro-p-dibenzodioxin. Using an NFI/CTF-Gal4 fusion, we show that NFI/CTF transactivating function is decreased by a high activity of CYP1A1. This regulation is also abolished by catalase or ellipticine. Consistently, the transactivating function of NFI/CTF is repressed in cells treated with H(2)O(2), a novel finding indicating that the transactivating domain of a transcription factor can be targeted by oxidative stress. In conclusion, an autoregulatory loop leads to the fine tuning of the CYP1A1 gene expression through the down-regulation of NFI activity by CYP1A1-based H(2)O(2) production. This mechanism allows a limitation of the potentially toxic CYP1A1 activity within the cell.
Mots-clé
Benzo(a)pyrene/pharmacology, CCAAT-Enhancer-Binding Proteins, Cytochrome P-450 CYP1A1/biosynthesis, Cytochrome P-450 CYP1A1/genetics, Humans, Hydrogen Peroxide/metabolism, Liver/cytology, Models, Genetic, Mutation, NFI Transcription Factors, Protein Structure, Tertiary, RNA, Messenger/biosynthesis, RNA-Binding Proteins/metabolism, Reactive Oxygen Species/metabolism, Receptors, Aryl Hydrocarbon/metabolism, Response Elements, Signal Transduction, Transcription Factors/metabolism, Transcriptional Activation, Tumor Cells, Cultured
Pubmed
Web of science
Création de la notice
24/01/2008 10:41
Dernière modification de la notice
20/08/2019 13:57
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