TCDD-dependent downregulation of γ-catenin in rat liver epithelial cells (WB-F344)

✍ Scribed by Cornelia Dietrich; Dagmar Faust; Matthias Moskwa; Anja Kunz; Karl-Walter Bock; Franz Oesch

• Publisher: John Wiley and Sons
• Year: 2002
• Tongue: French
• Weight: 306 KB
• Volume: 103
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.10830

✦ Synopsis

Abstract

TCDD (2,3,7,8‐tetrachlorodibenzo‐p‐dioxin) is the most potent tumor promoter ever tested in rodents. Although it is known that most of the effects of TCDD are mediated by binding to the aryl hydrocarbon receptor (AHR), the mechanisms leading to tumor promotion still remain to be elucidated. Loss of contact‐inhibition is a characteristic hallmark in tumorigenesis. In WB‐F344 cells, TCDD induces a release from contact‐inhibition manifested by a 2‐ to 3‐fold increase in DNA‐synthesis and the emergence of foci when TCDD (1 nM) is given to confluent cells. We focussed our interest on potential cell membrane proteins mediating contact‐inhibition in WB‐F344 cells, namely E‐cadherin, α,‐ β,‐ and γ‐catenin (plakoglobin). Using indirect immunofluorescence, E‐cadherin, α‐, β‐ and γ‐catenin were detected at cell adhesion sites in untreated, confluent cells. After TCDD‐exposure, γ‐catenin was exclusively localized in the cytoplasm whereas localization of E‐cadherin, α‐ and β‐catenin remained unaffected. Cytoplasmic γ‐catenin could be extracted by Triton X‐100 treatment, demonstrating that γ‐catenin was no longer bound to the actin cytoskeleton. Western blot analysis showed downregulation of γ‐catenin protein levels. This effect was not blocked by pre‐incubation with the selective proteasome inhibitor MG‐132, indicating that proteolytical degradation of γ‐catenin by the proteasome system was not increased by TCDD. Because mRNA‐levels of γ‐catenin were markedly diminished after TCDD‐exposure, we conclude that transcriptional downregulation or destabilization of the mRNA contributes to the decrease in γ‐catenin protein levels in response to TCDD. Because γ‐catenin is considered to be a tumor suppressor, our findings might give more insight into the tumor promoting actions of TCDD. © 2002 Wiley‐Liss, Inc.