AAR and ERSR pathways
Although amino acid limitation increases CHOP expression by post-transcriptional mechanisms (Bruhat et al., 1997; Abcouwer et al., 1999), there is also clear evidence for transcriptional control of the CHOP gene by either amino acid or glucose starvation (Price and Calderwood, 1992; Jousse et al., 1999). Glucose starvation of eukaryotic cells results in aberrant accumulation of glycoproteins in the endoplasmic reticulum (ER) that causes the ERSR, also known in yeast as the unfolded protein response (UPR) (Kaufman, 1999; Pahl, 1999; Patil and Walter, 2001). The ERSR signal transduction pathway culminates in increased transcription of a number of genes, many of which are involved in protein processing and trafficking within the ER. The prototypical example would be the ER resident chaperone GRP78. It is important to note that amino acid deprivation (i.e. the AAR pathway) does not induce ERSR-activated genes such as GRP78 (Barbosa-Tessmann et al., 1999a), presumably because mere slowing of protein synthesis does not result in a significant accumulation of misfolded proteins within the ER. The target genes for the ERSR pathway in mammalian cells contain one or more copies of a highly conserved cis-element (ER stress element, ERSE) for which the consensus sequence is 5'-CCAAT-N9-CCACG-3' (Yoshida etal, 1998; Roy and Lee,
- The human CHOP promoter contains two ERSE sequences (CHOP-ERSE1 and CHOP-ERSE2), which are orientated in opposite directions (Yoshida et al., 2000). Mutational analysis documented that CHOP-ERSE2 is nonfunctional, but that CHOP-ERSE1 (nucleotides —93 to —75) mediates activation of the gene by ER stress, which is the basis for induction of the gene following glucose deprivation (Yoshida et al.,
- Jousse et al. (1999) used deletion analysis of the human CHOP promoter to provide evidence that the cis-element necessary for activation of transcription by the ERSR pathway was different from that responsible for increased transcription following amino acid deprivation and subsequent activation of the AAR pathway. Their deletion analysis was consistent with the identification of the ERSE sequence by Yoshida et al. (2000), and, as discussed below, the amino acid response element (AARE) in the CHOP gene was later shown to reside at nucleotides —302 to —310 (Bruhat et al., 2000; Fafournoux et al., 2000). Therefore, activation of the CHOP gene by the AAR pathway is mediated by a different set of genomic elements from those responsible for activation by glucose limitation via the ERSR pathway. The use of two independent genomic elements to respond to either amino acid or glucose limitation contrasts with the transcriptional control mechanisms functional within the human asparagine synthetase promoter, as described below.
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