Progastrin stimulates murine colonic epithelial mitosis after DNA damage

Ottewell, Penelope D, Watson, Alastair J M ORCID:, Wang, Timothy C, Varro, Andrea, Dockray, Graham J and Pritchard, D.Mark (2003) Progastrin stimulates murine colonic epithelial mitosis after DNA damage. Gastroenterology, 124 (5). pp. 1348-1357. ISSN 1528-0012

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Background & Aims: Transgenic mice that overexpress progastrin are more susceptible than either wild-type mice or mice that overexpress amidated gastrin to chemical carcinogen-induced colonic adenomas. We have investigated whether alterations in the regulation of apoptosis or mitosis after DNA damage contribute to the effects of progastrin on murine colonic epithelium. Methods: Apoptosis and mitosis were assessed on a cell positional basis in murine intestinal epithelium after γ-irradiation. Mice analyzed were progastrin overexpressing, gastrin overexpressing, gastrin knockout, and their wild-type counterparts. The expression of cell cycle regulators was analyzed by gene array and Western blotting. Results: Apoptosis was induced to similar levels in the small intestinal and colonic crypts of all mice 4.5 hours after 8 Gy γ-radiation. Colonic mitosis was inhibited to almost undetectable levels by 8Gy γ-radiation in wild-type, gastrin-knockout, and gastrin-overexpressing mice. However, significant colonic mitosis persisted in progastrin-overexpressing mice up to 24 hours after 8Gy γ-radiation. Increased levels of cdk4 and cyclin D1 proteins were found in the colonic epithelium of progastrin-overexpressing mice relative to wild-type animals after γ-radiation. Conclusions: After DNA damage by γ-radiation, mice with elevated progastrin exhibit significantly higher levels of colonic mitosis than wild-type or gastrin-overexpressing mice. Persistently elevated cdk4 and cyclin D1 in progastrin overexpressing mice accounts for the capacity of colon cells to continue with the cell cycle after DNA damage.

Item Type: Article
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Groups > Gastroenterology and Gut Biology
Depositing User: Rhiannon Harvey
Date Deposited: 14 Jul 2011 09:46
Last Modified: 20 Aug 2023 00:55
DOI: 10.1016/S0016-5085(03)00288-9

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