We have found that gastrin is important in the growth of the colon, with gastrin deficiency resulting in decreased colonic proliferation, and over- expression of glycine-extended gastrin resulting in increased colonic proliferation and colonic mucosal hypertrophy. We have further demonstrated that gastrin appears to be a downstream target of the beta- catenin/Tcf-4 signaling pathway that mediates growth of intestinal polyps. Gastrin is also important in the development of the stomach. Gastrin deficiency results in a marked decreased in parietal cell number which can be rescued by short-term infusions of gastrin. With long term infusion however, parietal cell atrophy occurs. We have shown that transgenic mice that overexpress amidated gastrin also have initial hyperplasia, followed by parietal cell atrophy, foveolar hyperplasia, and eventually invasive gastric cancer. At the time when parietal cell atrophy develops, there is an up-regulation of heparin binding epidermal-like growth factor (HB-EGF). We have shown that gastrin can directly up- regulate HB-EGF expression through a PKC-dependent pathway. From these findings we hypothesize that gastrin can directly influence the gastric stem cell to differentiate towards the parietal cell partway, but with time it causes up-regulation of HB-EGF in parietal cells which in a negative feedback loop inhibits differentiation towards parietal cells and promotes differentiation into pit cells.
The aims are to test this hypothesis: 1. Determine the cis-acting regulatory elements involved in gastrin's regulation of the HB-EGF promoter. 2. Determine the role of HB-EGF expression in gastric parietal cells on gastric mucosal differentiation by creating transgenic mice that over-expression HB-EGF in parietal cells.
| Koh, Theodore J; Field, John K; Varro, Andrea et al. (2004) Glycine-extended gastrin promotes the growth of lung cancer. Cancer Res 64:196-201 |
| McLaughlin, John T; Ai, Wandong; Sinclair, Natalie F et al. (2004) PACAP and gastrin regulate the histidine decarboxylase promoter via distinct mechanisms. Am J Physiol Gastrointest Liver Physiol 286:G51-9 |
