Deficiency in the gap junction protein connexin32 alters p27Kip1 tumor suppression and MAPK activation in a tissue-specific manner.
Connexin32 knockout mice (Cx32-KO) exhibit increased chemical- and radiation-induced liver and lung tumor formation with many lung tumors demonstrating decreased levels of the tumor suppressor p27KIP1. To determine if p27 deficiency alters Cx32-influenced tumorigenesis, we have generated a Cx32/p27 double-deficient mouse strain (DKO) and show here that exposure of these mice to X-ray radiation resulted in an increase or decrease in tumorigenesis depending on the tissue. Several tissues were highly sensitive to loss of p27 tumor suppressor function (intestine, adrenal, pituitary) resulting in an increased overall tumor burden in DKO mice compared to both wild-type (P<0.005) and Cx32-KO mice (P=0.066). However, additional deletion of p27 in a Cx32-KO background resulted in a statistically significant decrease in the liver tumor incidence suggesting that Cx32 and p27 pathways mechanistically interact. Immunohistochemical analysis revealed an increased percentage of Cx32-KO liver and lung tumors harboring active mitogen-activated protein kinase (Erk1, Erk2) pathways in contrast to lower percentages of activated wild-type (P<0.005) and DKO tumors (P=0.027). Increased MAPK activation in liver tumors did not correlate with Ha-ras codon-61 mutation status. This study demonstrates that tissues dependent on Cx32 tumor suppression, such as the liver and lung, exhibit altered tumorigenesis and tumor biology (MAPK pathway activation) related to p27 status.
King
Timothy J
TJ
Cancer Prevention Research Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. tking@fhcrc.org
Gurley
Kay E
KE
Prunty
Joann
J
Shin
Jung-Lim
JL
Kemp
Christopher J
CJ
Lampe
Paul D
PD
D000236:Adenoma / Q000209:etiology; D000818:Animals; D018797:Cell Cycle Proteins / Q000502:physiology*; D017630:Connexins / Q000172:deficiency / Q000502:physiology*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003598:Cytoskeletal Proteins / Q000235:genetics; D004789:Enzyme Activation; D005260:Female; D011905:Genes, ras; D008114:Liver Neoplasms, Experimental / Q000209:etiology; D008175:Lung Neoplasms / Q000209:etiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009369:Neoplasms / Q000209:etiology*; D009381:Neoplasms, Radiation-Induced / Q000209:etiology; D009928:Organ Specificity; D010911:Pituitary Neoplasms / Q000209:etiology; D015534:Trans-Activators / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000502:physiology*; D015430:Weight Gain; D051176:beta Catenin; D000097002:Gap Junction beta-1 Protein
D018797:Cell Cycle Proteins; D017630:Connexins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003598:Cytoskeletal Proteins; D020928:Mitogen-Activated Protein Kinases; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; D000097002:Gap Junction beta-1 Protein; C495267:CTNNB1 protein, mouse; C493961:Cdkn1b protein, mouse