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Molecular and Cellular Biology, October 1999, p. 6825-6832, Vol. 19, No. 10
INSERM U490, Université Paris
V-René Descartes, Centre Universitaire des Saints-Pères,
75006 Paris, France,1 and Laboratoire de
Biotechnologie Moléculaire, Institut de Biologie Animale et
Centre de Biotechnologie, UNIL-EPFL, Université de Lausanne,
1015 Lausanne, Switzerland2
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 H2O2 catabolism), thus
implying that H2O2 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 H2O2, 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 H2O2 production. This
mechanism allows a limitation of the potentially toxic CYP1A1 activity
within the cell.
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
An Autoregulatory Loop Controlling
CYP1A1 Gene Expression: Role of H2O2
and NFI
*
Corresponding author. Mailing address: INSERM U490,
Université Paris V-René Descartes, Centre Universitaire des
Saints-Pères, 45, rue des Saints-Pères, 75006 Paris,
France. Phone: 33-1 42 86 20 75. Fax: 33-1 42 86 20 72. E-mail:
robert.barouki{at}biomedicale.univ-paris5.fr.
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