Amino Acid Limitation Induces Expression of CHOP, a CCAAT/Enhancer Binding Protein-related Gene, at Both Transcriptional and Post-transcriptional Levels*
Abstract
In mammals, plasma concentrations of amino acids are affected by nutritional or pathological conditions. Here we examined the role of amino acid limitation in regulating the expression of CHOP, a CCAAT/enhancer binding protein (C/EBP)-related gene. CHOP protein is capable of interacting with other C/EBPs to modify their DNA binding activities and may function as a negative regulator of these transcription factors. Our data show that leucine limitation in human cell lines leads to induction of CHOPmRNA and protein in a dose-dependent manner.CHOP mRNA induction is rapidly reversed by leucine replenishment. Elevated mRNA levels result from both an increase in the rate of CHOP transcription and an increase in theCHOP mRNA stability. Using a transient expression assay, we show that a promoter fragment, when linked to a reporter gene, is sufficient to mediate the regulation of CHOPexpression by leucine starvation in HeLa cells. In addition, we found that decreasing amino acid concentration by itself can induceCHOP expression independently of a cellular stress due to protein synthesis inhibition. Moreover, CHOP expression is induced at leucine concentrations in the range of those observed in blood of protein-restricted animals suggesting that amino acids can participate, in concert with hormones, in the regulation of gene expression.
Footnotes
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↵* This work was supported in part by grants from the Institut National de la Recherche Agronomique and the Fondation pour la Recherche Médicale.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵§ Supported by a fellowship from the Société de Secours des Amis des Sciences.
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↵¶ Recipient of a French Ministère de l’Eduction Nationale et de l’Enscignment Supirieur (MENESR) pre-doctoral scholarship.
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↵** Supported by National Institutes of Health Grants DK47119 and ES08681 and is a Leukemia Society of America Stephen Birnbaum Scholar.
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↵‡ To whom correspondence should be addressed. Tel.: 33 4 73 62 45 62; Fax: 33 4 73 62 45 70; E-mail: fpierre{at}clermont.inra.fr.
- Received February 11, 1997.
- Revision received March 31, 1997.
