Role of connexin32 and beta-catenin in tumor promotion in mouse liver.
Tumor promoters are nonmutagenic chemicals that increase the probability of cancer by accelerating the clonal expansion of cells transformed during tumor initiation. The molecular mechanisms underlying this process are only partly understood but interference with signaling pathways regulating cell division and/or cell death is likely to be important. Ras- and beta-Catenin-dependent signaling is important for both of these processes and ras and beta-catenin genes are known mutational targets in mouse hepatocarcinogenesis. About 80% of liver tumors generated in mice by a promotional regimen including phenobarbital (PB) as tumor promoter and N-nitrosodiethylamine (DEN) as initiator showed beta-catenin mutations whereas Ha-ras mutations were not detected. By contrast, tumors from mice treated with DEN alone showed a approximately 30% Ha-ras mutation prevalence but no beta-catenin mutations. This result suggests that PB-mediated promotion in mouse liver consists in a positive selection for hepatocytes harboring mutations in beta-catenin. The gap junction protein connexin 32 (Cx32) was also found to be involved in tumor promotion by PB because Cx32 gene knockout mice were almost entirely resistent to the promotional effects of the barbiturate. The link between beta-catenin-signaling and Cx32-dependent gap junctional intercellular communication, if existent, remains obscure.
Schwarz
Michael
M
Institut für Pharmakologie und Toxikologie, Universität Tübingen, Tübingen, Germany. michael.schwarz@uni-tuebingen.de
Wanke
Ines
I
Wulbrand
Ulrich
U
Moennikes
Oliver
O
Buchmann
Albrecht
A
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D003043:Cocarcinogenesis; D017630:Connexins / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000235:genetics*; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D015534:Trans-Activators / Q000235:genetics*; D051176:beta Catenin; D000097002:Gap Junction beta-1 Protein
D002273:Carcinogens; D017630:Connexins; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin; D000097002:Gap Junction beta-1 Protein; C495267:CTNNB1 protein, mouse