Structure of the 5′ sequences of the human γ‐glutamyltransferase gene

Abstract

In humans, five distinct mRNAs code for gamma-glutamyltransferase (GGT). Their coding regions are identical and their 5' untranslated regions exhibit both common and type-specific sequences. To elucidate the mecanisms that generate these different mRNAs, we cloned and determined the structure of the 5' region of the human GGT gene. The common regions of the 5' UTR are encoded by five exons, localized within a 2.4-kb region of the genomic DNA. Three of them are separated only by intron-donor or intron-acceptor sites at their boundaries. Alternative splicing of these exons may determine the unique pattern of the different GGT mRNA 5' UTRs in a tissue-specific manner. In addition, we have isolated a genomic fragment containing the most distal 5' sequences of the major GGT mRNA in HepG2 cells. Primer extension analysis revealed one major transcription initiation site while 5' RACE indicated that one more distal initiation site could be present. In the putative promoter sequence neither classical TATA or CAAT boxes were found. However, sites for AP1, AP2, CREB, GRE and SP1 transcription factors were identified. Chimeric plasmids, containing this genomic region fused to the luciferase gene, were transiently expressed in three cell lines of different origin: HeLa cells, ovarian carcinoma A2780 cells and V79 lung fibroblasts. The significant promoter activities obtained indicate a transcription start within this region. However, differences in the level of expression were found between the different cell lines used. These data suggest that the human GGT gene employs regulatory sequences and alternative splicing, and gene expression may therefore be regulated in tissue specific and cell-type-specific manners.

TNFα increases activity of γ‐glutamyl transpeptidase in cultured rat astroglial cells

“…For example, AP‐1 mediates the transcription of the collagenase gene in TNFα stimulated cells (Brenner et al, 1989). In addition, potential binding sites for transcription factors such as AP‐1 for the human γGT gene have been identified (Visvikis et al, 2001). Activation of AP‐1 is thus likely to participate also in upregulation of astroglial γGT expression by TNFα.…”

Gamma-Glutamyl Transpeptidase

“…The transcriptional regulation of GGT in humans is tissue-specific with multiple mRNAs encoding the same open reading frame but differing in their 5′ untranslated region (Daubeuf et al, 2001; Visvikis et al, 2001). The human GGT promoter contains binding sites for AP1, AP2, CREB, GRE, NF-κB and two Sp1 binding sites (Visvikis, et al, 2001)(Reuter et al, 2009).…”

“…The human GGT promoter contains binding sites for AP1, AP2, CREB, GRE, NF-κB and two Sp1 binding sites (Visvikis, et al, 2001)(Reuter et al, 2009). The 5′untranslated region of human GGT also contains multiple steroid modulatory elements (Diederich, Wellman, Visvikis, Puga, & Siest, 1993).…”