Altered tumor biology and tumorigenesis in irradiated and chemical carcinogen-treated single and combined connexin32/p27Kip1-deficient mice.
Connexin32 knockout mice (Cx32-KO) exhibit increased chemical and radiation-induced liver and lung tumorigenesis. This increased tumor incidence is associated with altered tumor biology including enhanced tumor progression and an increased percent of MAPK-active tumors. Likewise, mice lacking the tumor suppressor/cell cycle regulator p27Kip1 exhibit increased tumorigenesis in a variety of tissues following chemical and radiation induction. Interestingly, in a double-deficient mouse model (DKO), additional loss of p27Kip1 in a Cx32-KO background results in attenuation of liver and lung tumorigenesis as well as MAPK activation profiles, suggesting pathway interaction. While these mouse strains exhibit altered liver and lung tumor susceptibility following both chemical (DEN) and radiation (X-ray) induction protocols, comparisons of the resulting tumor incidence, multiplicity, tumor progression, and MAPK activation in response to these two distinct carcinogens underscores the separate influence of each individual gene on both tumor formation and activation of specific oncogenic pathways. Furthermore, these studies demonstrate that different carcinogens interact disparately with Cx32/p27Kip1 genotypic backgrounds in situ resulting in varied tumorigenic response.
Molecular Diagnostics Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Timothy J
TJ
King
Paul D
PD
Lampe
D000818:Animals; D017630:Connexins / Q000172:deficiency / Q000235:genetics*; D019938:Cyclin D1 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000172:deficiency / Q000235:genetics*; D004052:Diethylnitrosamine; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D008175:Lung Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009381:Neoplasms, Radiation-Induced / Q000378:metabolism / Q000473:pathology*; D051176:beta Catenin / Q000378:metabolism; D000097002:Gap Junction beta-1 Protein
D017630:Connexins; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004052:Diethylnitrosamine; D020928:Mitogen-Activated Protein Kinases; D051176:beta Catenin; D000097002:Gap Junction beta-1 Protein