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J. Biol. Chem., Vol. 279, Issue 49, 50829-50839, December 3, 2004

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Amino Acid Deprivation Induces the Transcription Rate of the Human Asparagine Synthetase Gene through a Timed Program of Expression and Promoter Binding of Nutrient-responsive Basic Region/Leucine Zipper Transcription Factors as Well as Localized Histone Acetylation^*

Hong Chen, Yuan-Xiang Pan, Elizabeth E. Dudenhausen, and Michael S. Kilberg

From the Department of Biochemistry and Molecular Biology, Genetics Institute, and Shands Cancer Center, University of Florida College of Medicine, Gainesville, Florida 32610

Expression of human asparagine synthetase (ASNS), which catalyzes asparagine and glutamate biosynthesis, is transcriptionally induced following amino acid deprivation. Previous overexpression and electrophoresis mobility shift analysis showed the involvement of the transcription factors ATF4, C/EBP, and ATF3-FL through the nutrient-sensing response element-1 (NSRE-1) within the ASNS promoter. Amino acid deprivation caused an elevated mRNA level for ATF4, C/EBP, and ATF3-FL, and the present study established that the nuclear protein content for ATF4 and ATF3-FL were increased during amino acid limitation, whereas C/EBP-LIP declined slightly. The total amount of C/EBP-LAP protein was unchanged, but changes in the distribution among multiple C/EBP-LAP forms were observed. Overexpression studies established that ATF4, ATF3-FL, and C/EBP-LAP could coordinately modulate the transcription from the human ASNS promoter. Chromatin immunoprecipitation demonstrated that amino acid deprivation increased ATF3-FL, ATF4, and C/EBP binding to the ASNS promoter and enhanced promoter association of RNA polymerase II, TATA-binding protein, and TFIIB of the general transcription machinery. A time course revealed a markedly different temporal order of interaction between these transcription factors and the ASNS promoter. During the initial 2 h, there was a 20-fold increase in ATF4 binding and a rapid increase in histone H3 and H4 acetylation, which closely paralleled the increased transcription rate of the ASNS gene, whereas the increase in ATF3-FL and C/EBP binding was considerably slower and more closely correlated with the decline in transcription rate between 2 and 6 h. The data suggest that ATF3-FL and C/EBP act as transcriptional suppressors for the ASNS gene to counterbalance the transcription rate activated by ATF4 following amino acid deprivation.

Received for publication, August 10, 2004 , and in revised form, September 21, 2004.

^* This research was supported by Grant DK-52064 (to M. S. K.) from the NIDDK, the National Institutes of Health and by The Leukemia Research Foundation (to H. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, University of Florida College of Medicine, Box 100245, JHMHC, Gainesville, FL 32610-0245. Tel.: 352-392-2711; Fax: 352-392-6511; E-mail: mkilberg{at}ufl.edu.

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