Genes for gastric proton pump and their transcriptional regulation

Abstract

The highly differentiated gastric parietal cell has a characteristic morphology and plays a specialized role in the hydrochloric acid secretion into the stomach lumen. The major enzyme in this system is an ATP-driven proton pump, the H+/K(+)-ATPase, which is responsible for proton translocation across the apical plasma membrane. The primary structures of the catalytic alpha and glycosylated beta subunits, and their transmembrane topology are similar to those of the corresponding subunits of Na+/K(+)-ATPase, suggesting that the reaction mechanism of both ATPases would be essentially the same if not identical. Most of the positions of introns in the H+/K(+)-ATPase subunit gene. These findings suggest that the alpha and beta subunit genes, respectively, of the two ATPases were derived from the common ancestors. We found that a DNA sequence motif, (G/C)PuPu(G/C)NGAT(A/T)PuPy, was located in the upstream regions of both alpha and beta subunit genes from human and rat. This motif may be a binding site for a positive transcriptional regulator that functions specifically in the parietal cells. cDNA cloning and in situ hybridization demonstrated that novel zinc finger proteins (GATA-GT1 and GATA-GT2) are present in the gastric parietal cells. These proteins bind to the (G/C)PuPu(G/C)NGAT(A/T)PuPy motif. Furthermore, they activate the transcription of the reporter gene with the 5'-upstream region of the alpha or beta subunit gene. These results suggest that gastric GATA DNA-binding proteins play important roles in transcriptional activation of H+/K(+)-ATPase genes in the parietal cells.