P53 gene mutation increases progastrin dependent colonic proliferation and colon cancer formation in mice.

Abstract

Transgenic mice overexpressing human progastrin (hGAS) show colonic crypt hyper-proliferation and elevated susceptibility to colon carcinogenesis. We aimed to investigate effects of p53 mutation on colon carcinogenesis in hGAS mice. We show that introducing a p53 gene mutation further increases progastrin dependent BrdU labeling and results in markedly elevated number of aberrant crypt foci (ACF) and colonic tumors. We demonstrate that hGAS/Lgr5-GFP mice have higher number of Lgr5+ colonic stem cells per crypt when compared to Lgr5-GFP mice indicating that progastrin changes crypt biology through increased stem cell numbers and additional p53 mutation leads to more aggressive phenotype in this murine colon cancer model.

• Authors: Vigneshwaran Ramanathan, Guangchun Jin, Christoph Benedikt Westphalen, Ashley Whelan, Alexander Dubeykovskiy, Shigeo Takaishi, Timothy C Wang
• Journal: Cancer investigation (Cancer Invest) Vol. 30 Issue 4 Pg. 275-86 (May 2012) ISSN: 1532-4192 [Electronic] England
• PMID: 22480191 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Carcinogens
• Gastrins
• Protein Precursors
• Tumor Suppressor Protein p53
• big gastrin
• Azoxymethane

Topics

• Aberrant Crypt Foci (chemically induced, genetics, metabolism)
• Animals
• Azoxymethane (toxicity)
• Carcinogens (toxicity)
• Cell Proliferation
• Cell Transformation, Neoplastic (genetics)
• Colonic Neoplasms (chemically induced, genetics, metabolism)
• Disease Models, Animal
• Female
• Gastrins (metabolism)
• Humans
• Immunohistochemistry
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Mutation
• Protein Precursors (metabolism)
• Tumor Suppressor Protein p53 (genetics)