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Transcriptional regulation of N-acetylglutamate synthase.

Publication ,  Journal Article
Heibel, SK; Lopez, GY; Panglao, M; Sodha, S; Mariño-Ramírez, L; Tuchman, M; Caldovic, L
Published in: PLoS One
2012

The urea cycle converts toxic ammonia to urea within the liver of mammals. At least 6 enzymes are required for ureagenesis, which correlates with dietary protein intake. The transcription of urea cycle genes is, at least in part, regulated by glucocorticoid and glucagon hormone signaling pathways. N-acetylglutamate synthase (NAGS) produces a unique cofactor, N-acetylglutamate (NAG), that is essential for the catalytic function of the first and rate-limiting enzyme of ureagenesis, carbamyl phosphate synthetase 1 (CPS1). However, despite the important role of NAGS in ammonia removal, little is known about the mechanisms of its regulation. We identified two regions of high conservation upstream of the translation start of the NAGS gene. Reporter assays confirmed that these regions represent promoter and enhancer and that the enhancer is tissue specific. Within the promoter, we identified multiple transcription start sites that differed between liver and small intestine. Several transcription factor binding motifs were conserved within the promoter and enhancer regions while a TATA-box motif was absent. DNA-protein pull-down assays and chromatin immunoprecipitation confirmed binding of Sp1 and CREB, but not C/EBP in the promoter and HNF-1 and NF-Y, but not SMAD3 or AP-2 in the enhancer. The functional importance of these motifs was demonstrated by decreased transcription of reporter constructs following mutagenesis of each motif. The presented data strongly suggest that Sp1, CREB, HNF-1, and NF-Y, that are known to be responsive to hormones and diet, regulate NAGS transcription. This provides molecular mechanism of regulation of ureagenesis in response to hormonal and dietary changes.

Duke Scholars

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2012

Volume

7

Issue

2

Start / End Page

e29527

Location

United States

Related Subject Headings

  • Transcription, Genetic
  • Transcription Factor AP-2
  • Species Specificity
  • Sp1 Transcription Factor
  • Smad3 Protein
  • Sequence Homology, Nucleic Acid
  • Sequence Alignment
  • Promoter Regions, Genetic
  • Molecular Sequence Data
  • Mice, Inbred C57BL
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Heibel, S. K., Lopez, G. Y., Panglao, M., Sodha, S., Mariño-Ramírez, L., Tuchman, M., & Caldovic, L. (2012). Transcriptional regulation of N-acetylglutamate synthase. PLoS One, 7(2), e29527. https://doi.org/10.1371/journal.pone.0029527
Heibel, Sandra Kirsch, Giselle Yvette Lopez, Maria Panglao, Sonal Sodha, Leonardo Mariño-Ramírez, Mendel Tuchman, and Ljubica Caldovic. “Transcriptional regulation of N-acetylglutamate synthase.PLoS One 7, no. 2 (2012): e29527. https://doi.org/10.1371/journal.pone.0029527.
Heibel SK, Lopez GY, Panglao M, Sodha S, Mariño-Ramírez L, Tuchman M, et al. Transcriptional regulation of N-acetylglutamate synthase. PLoS One. 2012;7(2):e29527.
Heibel, Sandra Kirsch, et al. “Transcriptional regulation of N-acetylglutamate synthase.PLoS One, vol. 7, no. 2, 2012, p. e29527. Pubmed, doi:10.1371/journal.pone.0029527.
Heibel SK, Lopez GY, Panglao M, Sodha S, Mariño-Ramírez L, Tuchman M, Caldovic L. Transcriptional regulation of N-acetylglutamate synthase. PLoS One. 2012;7(2):e29527.

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2012

Volume

7

Issue

2

Start / End Page

e29527

Location

United States

Related Subject Headings

  • Transcription, Genetic
  • Transcription Factor AP-2
  • Species Specificity
  • Sp1 Transcription Factor
  • Smad3 Protein
  • Sequence Homology, Nucleic Acid
  • Sequence Alignment
  • Promoter Regions, Genetic
  • Molecular Sequence Data
  • Mice, Inbred C57BL