Identification of a liver-specific cAMP response element in the human argininosuccinate synthetase gene

Argininosuccinate synthetase (ASS), a key enzyme in the urea cycle, participates in many metabolic processes including arginine biosynthesis and the citrulline–nitric oxide (NO) cycle. Factors like diets, hormones and pro-inflammatory stimuli are known to regulate ASS gene expression primarily at the transcription level. However, little is known about the cis-elements for transcriptional regulation of the ASS gene. In this study, we employed DNase I hypersensitive sites mapping to identify potential regulatory sites of the gene and revealed a site located at 10 kb upstream of the transcription start site which is responsible for liver-specific cAMP induction. Furthermore, a cAMP response element (CRE) highly conserved among mammals was identified and was experimentally verified. Our results show that liver-specific enhancement of ASS gene expression is mediated in part by the cAMP signaling pathway through a distal CRE site.