TITLE

PROGASTRIN STIMULATES MURINE COLONIC MITOSIS AFTER DNA DAMAGE VIA THE CYCLIN D-CDK4 COMPLEX

AUTHOR(S)
Ottewell, P.D.; Watson, A.J.M.; Wang, T.C.; Dockray, G.J.; Pritchard, D.M.
PUB. DATE
April 2003
SOURCE
Gut;Apr2003 Supplement 1, Vol. 52, pA55
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Background and Aims: Transgenic mice which overexpress human progastrin (hGAS) are more susceptible to the induction of colonic aberrant crypt foci and adenomas by the chemical carcinogen azoxymethane than wild-type mice (FVB/N) and mice which overexpress amidated gastrin (INS-GAS). We have previously shown that 4.5h following DNA damage by 8Gy γ-radiation, colonic mitosis persists at significantly higher levels in hGAS compared with FVB/N or INS-GAS mice. We have now investigated the molecular mechanisms responsible for this continued mitosis. Methods: Mice used were 10-12 week old hGAS and FVB/N. 4.5h following 8Gy γ-radiation colonic epithelial ceils were harvested using o modified Weiser technique. Expression of cell cycle regulatory genes were assessed using a GEArray™ pathway specific gene expression profiling system (SuperArray.com). Protein expression of p21[sup WAF1/CIP1] p27[sup KIP1], cdk6, cdk4 and cyclin D1 were analysed by Western blotting. Results: Gene array analysis showed increased abundance of cdk4, cdk6 and cyclin D1 mRNA in hGAS colonic epithelial cells compared to FVB/N 4.5h following 8Gy γ-radiation. Western blots confirmed that the abundance of cdk4 protein was significantly higher in hGAS colonic epithelium compared to FVB/N and did not change following γ-radiation. In FVB/N mice, cyclin D1 protein expression was decreased in colonic epithelial cells 4.5h following 8Gy γ-radiation. However, no change was observed in cyclin D1 protein expression in hGAS colonic epithelial cells after this treatment. No significant differences were observed between hGAS and FVB/N mice in the levels of p27[sup KIP1], p21[sup WAF-1/CIP1] and cdk6 proteins in colonic epithelia. Conclusion: (1) Progastrin overexpression results in increased expression of cdk4 in murine colonic epithelium. (2) The persistent colonic epithelial mitosis found in hGAS mice after γ-radiation is due to continued expression of cyclin D1.
ACCESSION #
9747647

 

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