Complex nutrient sensing by the AS gene

Barbosa-Tessmann et al. (1999a) demonstrated that the human AS gene is also induced by glucose starvation and that this induction is mediated via the ERSR (UPR) pathway (Barbosa-Tessmann et al., 1999b). An increase in AS mRNA content in human hepatoma HepG2 cells was detectable following glucose starvation for 8 h, and reached a maximum by 12 h. Elevated AS protein expression following glucose deprivation was also documented (Barbosa-Tessmann et al., 1999a). To confirm that the induction of AS transcription following glucose limitation was the result of the ERSR pathway, other recognized activators for the pathway such as the protein glycosylation inhibitor tunicamycin and the proline analogue, azetidine-2-carboxylate (Aze), were shown to be activators (Barbosa-Tessmann etal., 1999b). These results documented that the human AS is a target gene for the ERSR pathway and that the gene represents a link between amino acid metabolism and the ERSR pathway. The exact metabolic function of increased asparagine biosynthesis during ER stress has not been determined.

The ERSR pathway induces the AS gene by a transcriptional mechanism. Barbosa-Tessmann et al. (1999b) showed that expression of a reporter gene was significantly enhanced by glucose starvation when it was driven by the human AS promoter. Deletion analysis indicated that the ciselements responsible for the ERSR control of the AS gene were located within nucleotides —111 to —34 of the AS promoter, but the known mammalian ERSE consensus sequence (5'-CCAAT-N9-CCACG-3'), present in all other ERSR-inducible genes previously identified, was not present. Barbosa-Tessmann et al. (2000) went on to demonstrate that activation of AS gene transcription by starvation for either amino acids (AAR pathway) or glucose (ERSR pathway) is mediated through a common and unique set of genomic elements within the AS proximal promoter.

0 0

Post a comment