Altered homologous and heterologous gap-junctional intercellular communication in primary human liver tumors associated with aberrant protein localization but not gene mutation of connexin 32

2007 ◽  
Vol 56 (1) ◽  
pp. 87-94 ◽  
Author(s):  
V. Krutovskikh ◽  
G. Mazzoleni ◽  
N. Mironov ◽  
Y. Omori ◽  
A.-M. Aguelon ◽  
...  
Keyword(s):  
Gene Mutation ◽  
Intercellular Communication ◽  
Human Liver ◽  
Liver Tumors ◽  
Protein Localization ◽  
Connexin 32 ◽  
Gap Junctional Intercellular Communication ◽  
Aberrant Protein ◽  
Gap Junctional

Transgenic Disruption of Gap Junctional Intercellular Communication Enhances Early but Not Late Stage Hepatocarcinogenesis in the Rat

2005 ◽  
Vol 33 (6) ◽  
pp. 695-701 ◽  
Author(s):  
Naomi Hokaiwado ◽  
Makoto Asamoto ◽  
Kumiko Ogawa ◽  
Tomoyuki Shirai
Keyword(s):  
Intercellular Communication ◽  
Early Stage ◽  
Intraperitoneal Administration ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Connexin 32 ◽  
Dye Transfer ◽  
Gap Junctional Intercellular Communication ◽  
Transgenic Rats ◽  
Gap Junctional

Much experimental evidence supports the conclusion that loss of gap junctional intercellular communication (GJIC) contributes to carcinogenesis. Transgenic rats featuring a dominant negative mutant of the connexin 32 gene under albumin promoter control (Cx32ΔTg-High and Cx32ΔTg-Low lines, respectively with high and low copy numbers of the transgene) have disrupted GJIC, as demonstrated by scrape dye-transfer assay in vivo as previous report by Asamoto et al. (2004) . In the present study, we investigated the susceptibility of these transgenic rats to a single intraperitoneal administration of diethylnitrosamine (DEN), and found a significant increase in preneoplastic glutathione S-transferase placental form (GST-P) positive lesions in the livers of Cx32ΔTg-High but not Cx32ΔTg-Low rats. However, incidences of adenomas and hepatocellular carcinomas were not elevated at the end of the experiment (52 weeks). In addition, we investigated the promotional effect of phenobarbital (PB) on Cx32ΔTg-High rats pretreated with DEN and found enhanced formation of GST-P positive lesions, in contrast to the lack of promoting effects reported for Cx32 deficient mice. The results indicate that although both high and low expression of the dominant negative connexin 32 mutant gene in our rats is able to inhibit gap junctional capacity, only high expression is effective at enhancing susceptibility to early stage DEN-induced liver carcinogenesis.

Doxorubicin induces EGF receptor-dependent downregulation of gap junctional intercellular communication in rat liver epithelial cells

2005 ◽  
Vol 386 (3) ◽  
pp. 217-223 ◽  
Author(s):  
Kotb Abdelmohsen ◽  
Claudia von Montfort ◽  
Dominik Stuhlmann ◽  
P. Arne Gerber ◽  
Ulrich K.M. Decking ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Rat Liver ◽  
Intercellular Communication ◽  
Connexin 43 ◽  
Egf Receptor ◽  
Gap Junctional Intercellular Communication ◽  
Erk Activation ◽  
Liver Epithelial Cells ◽  
Rat Liver Epithelial Cells ◽  
Gap Junctional

Abstract Exposure of rat liver epithelial cells to doxorubicin, an anthraquinone derivative widely employed in cancer chemotherapy, led to a dose-dependent decrease in gap junctional intercellular communication (GJC). Gap junctions are clusters of inter-cellular channels consisting of connexins, the major connexin in the cells used being connexin-43 (Cx43). Doxorubicin-induced loss of GJC was mediated by activation of extracellular signal-regulated kinase (ERK)-1 and ERK-2, as demonstrated using inhibitors of ERK activation. Furthermore, activation of the epidermal growth factor (EGF) receptor by doxorubicin was responsible for ERK activation and the subsequent attenuation of GJC. Inhibition of GJC, however, was not by direct phosphorylation of Cx43 by ERK-1/2, whereas menadione, a 1,4-naphthoquinone derivative that was previously demonstrated to activate the same EGF receptor-dependent pathway as doxorubicin, resulting in downregulation of GJC, caused strong phos-phorylation of Cx43 at serines 279 and 282. Thus, ERK-dependent downregulation of GJC upon exposure to quinones may occur both by direct phosphorylation of Cx43 and in a phosphorylation-independent manner.

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