Structural organization of the microsomal glutathione S-Transferase gene (MGST1) on chromosome 12p13.1-13.2 - Identification of the correct promoter region and demonstration of transcriptional regulation in response to oxidative stress

The structure and regulation of the microsomal glutathione S-transferase ge ne (MGST1) are considerably more complex than originally perceived to be. T he MGST1 gene has two alternative first exons and is located in the 12p13.1 -13.2 region. Two other potential first exons were determined to be nonfunc tional. The region between the functional first exons cannot direct transcr iption. Thus, one common promoter element directing transcription exists, a nd RNA splicing occurs such that only one of the first exons (containing on ly untranslated mRNA) is incorporated into each mRNA species with common do wnstream exons, MGST1 expression and regulation are therefore similar to th ose of other hepatic xenobiotic handling enzymes, which also produce mRNA s pecies differing only in the 5'-untranslated regions to yield identical pro teins. MGST1 was previously considered a "housekeeping" gene, as non-oxidan t inducers had little effect on activity. However, the promoter region imme diately upstream of the dominant first exon transcriptionally responds to o xidative stress. In this respect, MGST1 is similar to glutathione peroxidas es that also transcriptionally respond to oxidative stress. The discovery t hat MGST1 utilizes alternative first exon splicing eliminates a problem wit h the first description of MGST1 cDNA in that it appeared that MGST1 expres sion was in violation of the ribosomal scanning model. The identification t hat the first exon originally noted is in fact a minor alternative first ex on far downstream of the primary first exon eliminates this conundrum.