Alternative titles; symbols
HGNC Approved Gene Symbol: GAST
Cytogenetic location: 17q21.2 Genomic coordinates (GRCh38) : 17:41,712,331-41,715,969 (from NCBI)
The 17- and 34-residue amidated gastrin peptides (G17 and G34, respectively) are processed from a common preprogastrin and are major gastrointestinal hormones that regulate gastric acid secretion, gastric motility, and growth of the gastrointestinal mucosa. In addition, progastrin and intermediate peptides in gastrin biosynthesis have their own biologic activities (Kariya et al., 1986, Bishop et al., 1998).
Using a probe encoding the C-terminal tetrapeptide of human gastrin to screen a pancreatic tumor cDNA library, Boel et al. (1983) cloned a cDNA encoding full-length preprogastrin. The deduced 101-amino acid protein has a calculated molecular mass of 11.4 kD. Preprogastrin has an N-terminal leader sequence and hormone processing sites at dibasic motifs arg57-arg58 and lys74-lys75 for cleavage by a trypsin-like protease (see PRSS1, 276000). Cleavage at these sites would yield G34 (amino acids 59-92) and G17 (amino acids 76-92). A gly-arg-arg sequence (residues 93-95) may also function as a peptide amidation signal.
Kato et al. (1983) independently cloned human GAST from gastric antrum mRNA. They stated that arg94-arg95 may represent a third site for progastrin processing. Grabowska et al. (2008) determined that the transcript identified by Kato et al. (1983) initiates within intron 1 via an internal ribosome entry site (IRES). RT-PCR detected the alternative transcript in all gastrointestinal cancer cell lines examined, including pancreatic, colonic, gastric, and esophageal cell lines.
Friis-Hansen et al. (1996) reported that the mouse gastrin gene encodes a deduced prepropolypeptide of 101 amino acids. The sequence of gastrin-34 is 76% identical to human gastrin-34.
Bishop et al. (1998) stated that progastrin functions as a growth factor but not as a secretagogue, and cleavage of progastrin at arg94-arg95 determines progastrin processing into the small amidated gastrin secretagogues. Using a hamster insulinoma cell line transfected with rat preprogastrin cDNA, Bishop et al. (1998) showed that phosphorylation of progastrin at the conserved ser96 by a casein kinase-like enzyme (see CSNK1A1, 600505) delayed the cleavage of progastrin at arg94-arg95, which in turn delayed progastrin processing at lys74-lys75. Phosphorylation of ser96 was calcium-dependent, and depletion of calcium stores reduced ser96 phosphorylation and increased progastrin processing at arg94-arg95. Bishop et al. (1998) concluded that calcium availability and phosphorylation regulates the ratio of the progastrin growth factor to gastrin secretagogues.
Using a bicistronic reporter, Grabowska et al. (2008) demonstrated that gastrin IRES was functional and required the presence of a promoter. IRES-dependent, but not cap-dependent, expression of the bicistronic reporter was upregulated following exposure of human colon carcinoma and pancreatic adenocarcinoma cell lines to genotoxic stress or hypoxia. Grabowska et al. (2008) concluded that utilization of the IRES in the gastrin gene allows continued expression of gastrin peptides when normal translational mechanisms are inactive, such as in hypoxia.
In addition to stimulating acid secretion, gastrin triggers tissue response to damage, infection, and inflammation in cells expressing gastrin receptor (CCKBR; 118445) and, indirectly, in nearby cells via a paracrine mechanism. Almeida-Vega et al. (2009) stated that the direct effect of gastrin on CCKBR-expressing cells involves PKC (see 176960), RAS (HRAS; 190020), RAF (see 164760), MAP kinase (see 176948), RHOA (165390), NF-kappa-B (see 164011), CREB (CREB1; 123810), and AP1 (see 165160) signaling pathways. Using the parental AGS human gastric cancer cell line that lacks CCKBR expression and AGS cells expressing CCKBR, Almeida-Vega et al. (2009) examined gastrin-mediated paracrine signaling. They found that gastrin directly induced upregulation of the antiapoptotic regulator PAI2 (SERPINB2; 173390) in CCKBR-positive cells. CCKBR-positive cells also released IL8 (146930) and prostaglandin E2 into the culture medium in response to gastrin, which resulted in elevated PAI2 expression in cocultured CCKBR-negative cells. IL8 signaling in CCKBR-negative cells upregulated PAI2 via binding of the ASC1 complex (see TRIP4; 604501) to the PAI2 promoter. Prostaglandin E2 independently upregulated PAI2 via RHOA-dependent signaling that induced binding of MAZ (600999) to the PAI2 promoter. Electrophoretic mobility shift assays and chromatin immunoprecipitation analysis revealed that MAZ and the p50 subunit of the ASC1 complex (ASCC1; 614215) bound directly to sites in the PAI2 promoter. Mutation of the putative MAZ site in the PAI2 promoter reduced responses to RHOA. Knockdown of the p50 or p65 (TRIP4) subunits of the ASC1 complex via small interfering RNA significantly reduced PAI2 upregulation in response to gastrin.
Wiborg et al. (1984) and Ito et al. (1984) determined that the GAST gene contains 3 exons and spans about 4.3 kb. The first exon is noncoding and the first intron is almost 3.5 kb long. The 5-prime flanking region contains a TATAA box and a CAT-like box.
Kariya et al. (1986) identified 5 Alu sequences in the first intron of the GAST gene, which account for nearly 50% of the intron's total length. The 5-prime flanking region contains 3 additional Alu sequences, and another Alu sequence immediately follows exon 3.
In panels of human-rodent somatic cell hybrids, Lund et al. (1985, 1986) used the probe to map the gene to 17q. Fukushige et al. (1986) confirmed the assignment to chromosome 17 by chromosome sorting combined with velocity sedimentation and Southern hybridization.
Flejter et al. (1993) demonstrated that a tetranucleotide repeat polymorphism at D17S846 was located on the same cosmid clone as the GAS gene within a 40-kb interval; the clone that demonstrated the tetranucleotide repeat polymorphism was mapped to 7q12-q21 by fluorescence in situ hybridization. Flejter et al. (1993) used multicolor fluorescence in situ hybridization with Alu-PCR-amplified YAC clone DNA to determine the order of the GAS locus in relation to others on 17q. They demonstrated that GAS is distal to TOP2 (126430) and proximal to EPB3 (109270); both TOP2 and EPB3 had previously been mapped to 17q21-q22.
By family linkage studies using multiple DNA markers, Anderson et al. (1993) positioned GAS just distal to KRT10 (148080), which had been mapped to 17q21-q22, and proximal to EDH17B (109684).
Friis-Hansen et al. (1996) mapped the mouse gastrin gene to the distal region of chromosome 11.
Both gastrin I and gastrin II (of normal sequence) are excreted in excess by pancreatic tumors in the Zollinger-Ellison syndrome (Gregory et al., 1969). See 131100.
Almeida-Vega, S., Catlow, K., Kenny, S., Dimaline, R., Varro, A. Gastrin activates paracrine networks leading to induction of PAI-2 via MAZ and ASC-1. Am. J. Physiol. Gastrointest. Liver Physiol. 296: G414-G423, 2009. [PubMed: 19074642] [Full Text: https://doi.org/10.1152/ajpgi.90340.2008]
Anderson, L. A., Friedman, L., Osborne-Lawrence, S., Lynch, E., Weissenbach, J., Bowcock, A., King, M.-C. High-density genetic map of the BRCA1 region of chromosome 17q12-q21. Genomics 17: 618-623, 1993. [PubMed: 8244378] [Full Text: https://doi.org/10.1006/geno.1993.1381]
Bentley, P. H., Kenner, G. W., Sheppard, R. C. Structure of human gastrins I and II. Nature 209: 583-585, 1966. [PubMed: 5921183] [Full Text: https://doi.org/10.1038/209583b0]
Bishop, L., Dimaline, R., Blackmore, C., Deavall, D., Dockray, G. J., Varro, A. Modulation of the cleavage of the gastrin precursor by prohormone phosphorylation. Gastroenterology 115: 1154-1162, 1998. [PubMed: 9797370] [Full Text: https://doi.org/10.1016/s0016-5085(98)70086-1]
Boel, E., Vuust, J., Norris, F., Norris, K., Wind, A., Rehfeld, J. F., Marcker, K. A. Molecular cloning of human gastrin cDNA: evidence for evolution of gastrin by gene duplication. Proc. Nat. Acad. Sci. 80: 2866-2869, 1983. [PubMed: 6574456] [Full Text: https://doi.org/10.1073/pnas.80.10.2866]
Flejter, W. L., Barcroft, C. L., Guo, S.-W., Lynch, E. D., Boehnke, M., Chandrasekharappa, S., Hayes, S., Collins, F. S., Weber, B. L., Glover, T. W. Multicolor FISH mapping with Alu-PCR-amplified YAC clone DNA determines the order of markers in the BRCA1 region on chromosome 17q12-q21. Genomics 17: 624-631, 1993. [PubMed: 8244379] [Full Text: https://doi.org/10.1006/geno.1993.1382]
Flejter, W. L., Kukowska-Latallo, J. F., Kiousis, S., Chandrasekharappa, S. C., King, S. E., Chamberlain, J. S. Tetranucleotide repeat polymorphism at D17S846 maps within 40 kb of GAS at 17q12-q22. Hum. Molec. Genet. 2: 1080 only, 1993. [PubMed: 8364555] [Full Text: https://doi.org/10.1093/hmg/2.7.1080]
Friis-Hansen, L., Rourke, I. J., Bundgaard, J. R., Rehfeld, J. F., Samuelson, L. C. Molecular structure and genetic mapping of the mouse gastrin gene. FEBS Lett. 386: 128-132, 1996. [PubMed: 8647266] [Full Text: https://doi.org/10.1016/0014-5793(96)00430-9]
Fukushige, S., Murotsu, T., Matsubara, K. Chromosomal assignment of human genes for gastrin, thyrotropin (TSH)-beta subunit and C-erb-2 by chromosome sorting combined with velocity sedimentation and southern hybridization. Biochem. Biophys. Res. Commun. 134: 477-483, 1986. [PubMed: 3511905] [Full Text: https://doi.org/10.1016/s0006-291x(86)80445-4]
Grabowska, A. M., Berry, C. A., Hughes, J., Bushell, M., Willis, A. E., Watson, S. A. A gastrin transcript expressed in gastrointestinal cancer cells contains an internal ribosome entry site. Brit. J. Cancer 98: 1696-1703, 2008. [PubMed: 18392051] [Full Text: https://doi.org/10.1038/sj.bjc.6604326]
Gregory, R. A., Tracy, H. J., Agarwal, K. L., Grossman, M. I. Amino acid constitution of two gastrins isolated from Zollinger-Ellison tumor tissue. Gut 10: 603-608, 1969. [PubMed: 5822140] [Full Text: https://doi.org/10.1136/gut.10.8.603]
Ito, R., Sato, K., Helmer, T., Jay, G., Agarwal, K. Structural analysis of the gene encoding human gastrin: the large intron contains an Alu sequence. Proc. Nat. Acad. Sci. 81: 4662-4666, 1984. [PubMed: 6087340] [Full Text: https://doi.org/10.1073/pnas.81.15.4662]
Kariya, Y., Kato, K., Hayashizaki, Y., Himeno, S., Tarui, S., Matsubara, K. Expression of human gastrin gene in normal and gastrinoma tissues. Gene 50: 345-352, 1986. [PubMed: 3034736] [Full Text: https://doi.org/10.1016/0378-1119(86)90338-0]
Kato, K., Himeno, S., Takahashi, Y., Wakabayashi, T., Tarui, S., Matsubara, K. Molecular cloning of human gastrin precursor cDNA. Gene 26: 53-57, 1983. [PubMed: 6689486] [Full Text: https://doi.org/10.1016/0378-1119(83)90035-5]
Lund, T., Geurts van Kessel, A. H. M., Huan, S., Dixon, J. E. The genes for human gastrin and cholecystokinin are located on different chromosomes. Hum. Genet. 73: 77-80, 1986. [PubMed: 3011648] [Full Text: https://doi.org/10.1007/BF00292669]
Lund, T., Geurts van Kessel, A. H. M., Westerveld, A. The human gastrin gene is located at human chromosome 17. (Abstract) Cytogenet. Cell Genet. 40: 683 only, 1985.
Wiborg, O., Berglund, L., Boel, E., Norris, F., Norris, K., Rehfeld, J. F., Marcker, K. A., Vuust, J. Structure of a human gastrin gene. Proc. Nat. Acad. Sci. 81: 1067-1069, 1984. [PubMed: 6322186] [Full Text: https://doi.org/10.1073/pnas.81.4.1067]