title: 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.affiliation: Department of Medicine, Division of Digestive and Liver Diseases, Columbia University Medical Center, New York 10032, USA.
authors.forename: Vigneshwaran
authors.initials: V
authors.lastname: Ramanathan
authors.forename: Guangchun
authors.initials: G
authors.lastname: Jin
authors.forename: Christoph Benedikt
authors.initials: CB
authors.lastname: Westphalen
authors.forename: Ashley
authors.initials: A
authors.lastname: Whelan
authors.forename: Alexander
authors.initials: A
authors.lastname: Dubeykovskiy
authors.forename: Shigeo
authors.initials: S
authors.lastname: Takaishi
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Wang
mesh_terms: D058739:Aberrant Crypt Foci / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001397:Azoxymethane / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005755:Gastrins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D011498:Protein Precursors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D002273:Carcinogens; D005755:Gastrins; D011498:Protein Precursors; D016159:Tumor Suppressor Protein p53; C013706:big gastrin; D001397:Azoxymethane