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Molecular and Cellular Biology, October 2000, p. 7192-7204, Vol. 20, No. 19
U.R. 238 de Nutrition Cellulaire et
Moléculaire, INRA de Theix, 63122 Saint Genès Champanelle,
France,1 and Department of
Immunology and Infectious Diseases, Harvard School of Public Health,
and Department of Medicine, Harvard Medical School, Boston,
Massachusetts 021152
Received 31 January 2000/Returned for modification 2 March
2000/Accepted 7 July 2000
In mammals, plasma concentration of amino acids is affected by
nutritional or pathological conditions. It has been well
established that nutrients, and particularly amino acids, are involved
in the control of gene expression. Here we
examined the molecular mechanisms involved in the regulation of
CHOP (a CCAAT/enhancer-binding protein
[C/EBP]-related gene) expression upon amino acid limitation. We have
previously shown that regulation of CHOP mRNA expression by
amino acid concentration has both transcriptional and
posttranscriptional components. We report the analysis of
cis- and trans-acting elements involved in the
transcriptional activation of the human CHOP
gene by leucine starvation. Using a transient expression assay, we show
that a cis-positive element is essential for amino acid
regulation of the CHOP promoter. This sequence is the
first described that can regulate a basal promoter in response
to starvation for several individual amino acids and
therefore can be called an amino acid response element (AARE).
In addition, we show that the CHOP AARE is
related to C/EBP and ATF/CRE binding sites and binds in vitro the activating transcription factor 2 (ATF-2) in starved and
unstarved conditions. Using ATF-2-deficient mouse embryonic
fibroblasts and an ATF-2-dominant negative mutant, we demonstrate that
expression of this transcription factor is essential for the
transcriptional activation of CHOP by leucine starvation.
Altogether, these results suggest that ATF-2 may be a member
of a cascade of molecular events by which the cellular
concentration of amino acids can regulate mammalian gene expression.
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Amino Acids Control Mammalian Gene Transcription: Activating
Transcription Factor 2 Is Essential for the Amino Acid
Responsiveness of the CHOP Promoter
*
Corresponding author. Mailing address: U.R. 238 de
Nutrition Cellulaire et Moléculaire, INRA de Theix, 63122 Saint
Genès Champanelle, France. Phone: 33 4 73 62 45 62. Fax: 33 4 73 62 45 70. E-mail: fpierre{at}clermont.inra.fr.
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