Activation of the unfolded protein response pathway induces human asparagine synthetase gene expression

The gene for the amino acid biosynthetic activity asparagine synthetase (AS ) is induced by both amino acid and glucose deprivation of cells. The data reported here document that the human AS gene is induced following activati on of the Unfolded Response Pathway (UPR), also known as the Endoplasmic Re ticulum Stress Response (ERSR) in mammals. Increased AS transcription occur s in response to glucose deprivation, tunicamycin, or azetidine-2-carboxyla te, all known to activate the UPR/ERSR pathway. Previously identified ERSR target genes contain multiple copies of a single highly conserved cis-eleme nt. In contrast, the human AS gene does not contain the ERSR element, as it has been described for other responsive genes. Instead, AS induction requi res an Spl-like sequence, a sequence previously shown to be associated with amino acid control of transcription, and possibly, a third region containi ng no consensus sequences for known transcription factors. Oligonucleotides covering each of these regions form DNA-protein complexes in vitro, and fo r some the amount of these complexes is greater when nuclear extracts from glucose-starved cells are tested. These results document that a wider range of metabolic activities are activated by the UPR/ERSR pathway than previou sly recognized and that genomic elements other than those already described can serve to enhance transcription of specific target genes.