Pathway-specific tumor suppression. Reduction of p27 accelerates gastrointestinal tumorigenesis in Apc mutant mice, but not in Smad3 mutant mice.
Expression of the cyclin-dependent kinase inhibitor p27(Kip1) (p27) is frequently reduced in human colorectal cancer, and this correlates with poor patient prognosis. To clarify the role of p27 in gastrointestinal (GI) cancer, we measured p27 expression, as well as the effect of germline deletion of p27, in 3 different mouse models of GI neoplasia. p27 expression was frequently reduced in GI tumors arising in 1,2-dimethylhydrazine (DMH) treated mice, and in Apc mutant Min/+ mice, but not in GI tumors arising in Smad3 mutant mice. Germline deletion of p27 resulted in accelerated tumor development and increased tumor cell proliferation in both DMH treated and Min/+ mice, but not in Smad3 mutant mice. p27 deficiency also led to increased adenoma to adenocarcinoma progression. These results indicate that reduction of p27 cooperates with mutations in Apc but not in Smad3 during GI tumorigenesis. Thus, tumor suppression by p27 is contingent on the specific oncogenic pathway that drives tumor development.
Philipp-Staheli
Jeannette
J
Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 90109, USA.
Kim
Kyung-Hoon
KH
Payne
Shannon R
SR
Gurley
Kay E
KE
Liggitt
Denny
D
Longton
Gary
G
Kemp
Christopher J
CJ
D019813:1,2-Dimethylhydrazine; D000230:Adenocarcinoma / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D000236:Adenoma / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics*; D005770:Gastrointestinal Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D019656:Loss of Heterozygosity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D044786:S-Phase Kinase-Associated Proteins; D015398:Signal Transduction; D051785:Smad Proteins; D015534:Trans-Activators / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*; D051176:beta Catenin
D025601:Adenomatous Polyposis Coli Protein; C495267:CTNNB1 protein, mouse; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D044786:S-Phase Kinase-Associated Proteins; D051785:Smad Proteins; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; D050760:Cyclin-Dependent Kinase Inhibitor p27; D019813:1,2-Dimethylhydrazine