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Processing and proliferative effects of human progastrin in transgenic mice.
Open accessAbstract
Incompletely processed gastrins have been postulated to play a role in growth of the gastrointestinal tract, but few studies have examined the effects of progastrin on mucosal proliferation in vivo. Human gastrin gene expression and progastrin processing were therefore studied in transgenic mice containing a human gastrin (hGAS) minigene, and compared to processing in mice bearing an insulin gastrin (INS-GAS) transgene that overexpresses amidated gastrin. Progastrin processing was studied using region-specific antisera and radioimmunoassays, biosynthetic labeling, immunoprecipitation, and HPLC. Proliferative effects due to overexpression of processed and unprocessed gastrin in INS-GAS and hGAS mice, respectively, were determined using routine histology and BrdU incorporation. The pancreatic islets of INS-GAS mice were able to produce carboxyamidated G-17, resulting in a twofold elevation of serum amidated gastrin, marked thickening of the oxyntic mucosa, and an increased BrdU labeling index (LI) of the gastric body. In contrast, livers of adult hGAS mice expressed abundant human gastrin mRNA and human progastrin but were unable to process this peptide to the mature amidated form, resulting in markedly elevated serum progastrin levels and normal amidated gastrin levels. Nevertheless, there was a marked increase in the BrdU labeling index of the colon in hGAS mice (LI 7.46+/-1.90%), as well as in INS-GAS mice (LI 6.16+/-1.17%), compared to age-matched, wild type control mice (LI 4.01+/-0.98%, P < 0.05). These studies suggest that incompletely processed gastrin precursors may contribute to colonic mucosal proliferation in vivo.
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Cites
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Cited by
Freedberg, D. E., Kim, L. S., & Yang, Y.-X. (2017) · Gastroenterology · doi:10.1053/j.gastro.2017.01.031 · Cited by 891
Lundell, L., Vieth, M., Gibson, F., Nagy, P., & Kahrilas, P. J. (2015) · Alimentary Pharmacology & Therapeutics · doi:10.1111/apt.13324 · Cited by 258
Proton Pump Inhibitor Use and Risk of Colorectal Cancer: A Population-Based, Case–Control Study
Robertson, D. J., Larsson, H., Friis, S., Pedersen, L., Baron, J. A., & Sørensen, H. T. (2007) · Gastroenterology · doi:10.1053/j.gastro.2007.06.014 · Cited by 139
Chronic Proton Pump Inhibitor Therapy and the Risk of Colorectal Cancer
Yang, Y., Hennessy, S., Propert, K., Hwang, W., Sedarat, A., & Lewis, J. D. (2007) · Gastroenterology · doi:10.1053/j.gastro.2007.06.022 · Cited by 125
Proton Pump Inhibitors and the Risk of Colorectal Cancer
van Soest, E. M., van Rossum, L. G. M., Dieleman, J. P., van Oijen, M. G. H., Siersema, P. D., Sturkenboom, M. C. J. M., & Kuipers, E. J. (2008) · The American Journal of Gastroenterology · doi:10.1111/j.1572-0241.2007.01665.x · Cited by 80
Metadata
- Authors
- Wang, T. C., Koh, T. J., Varro, A., Cahill, R. J., Dangler, C. A., Fox, J. G., & Dockray, G. J.
- Venue
- Journal of Clinical Investigation
- Published
- 1996-10-15
- Volume
- 98
- Issue
- 8
- Pages
- 1918-1929
- ISSN
- 0021-9738 (ISSN-L)
- OpenAlex
- W2075021269
- Cited by
- 300
- References
- 25
- FWCI
- 4.30
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Wang, T. C., Koh, T. J., Varro, A., Cahill, R. J., Dangler, C. A., Fox, J. G., & Dockray, G. J. (1996). Processing and proliferative effects of human progastrin in transgenic mice. Journal of Clinical Investigation. https://doi.org/10.1172/jci118993
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