The 2,2',4,4',5,5'-hexachlorobiphenyl-enhanced degradation of connexin 43 involves both proteasomal and lysosomal activities
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
18832185
DOI
10.1093/toxsci/kfn202
PII: kfn202
Knihovny.cz E-resources
- MeSH
- Analysis of Variance MeSH
- Cell Membrane drug effects MeSH
- Cell Line MeSH
- Extracellular Signal-Regulated MAP Kinases antagonists & inhibitors metabolism MeSH
- Proteasome Inhibitors MeSH
- Liver metabolism MeSH
- Connexin 43 genetics metabolism MeSH
- Rats MeSH
- Leupeptins pharmacology MeSH
- Lysosomes drug effects metabolism MeSH
- Metabolic Networks and Pathways drug effects MeSH
- Gap Junctions drug effects metabolism MeSH
- Cell Communication drug effects MeSH
- Polychlorinated Biphenyls pharmacology MeSH
- Proteasome Endopeptidase Complex drug effects metabolism MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 2,4,5,2',4',5'-hexachlorobiphenyl MeSH Browser
- Extracellular Signal-Regulated MAP Kinases MeSH
- Proteasome Inhibitors MeSH
- Connexin 43 MeSH
- leupeptin MeSH Browser
- Leupeptins MeSH
- Polychlorinated Biphenyls MeSH
- Proteasome Endopeptidase Complex MeSH
One of the toxic effects of non-dioxin-like polychlorinated biphenyls (NDL-PCBs) is the acute inhibition of gap junctional intercellular communication (GJIC), an event possibly associated with tumor promotion. The model NDL-PCB-2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153)-induces a sustained GJIC inhibition in rat liver epithelial WB-F344 cells. As this effect might be related to deregulation of connexin 43 (Cx43) synthesis, trafficking, or degradation, we investigated the impact of PCB 153 on these events. Although PCB 153 had no effect on Cx43 mRNA levels, it induced a gradual loss of Cx43 protein and significantly decreased the amount of gap junction plaques in plasma membrane. PCB 153 contributed to extracellular signal-regulated kinases 1 and 2 (ERK1/2)-dependent accumulation of hyperphosphorylated Cx43-P3 form, thus indicating that ERK1/2 activation by PCB 153 might contribute to its effects on Cx43 internalization or degradation. Inhibition of either proteasomes or lysosomes with their specific inhibitors largely restored total Cx43 protein levels, thus suggesting that both proteasomes and lysosomes may participate in the PCB 153-enhanced Cx43 internalization and degradation. However, neither the proteasomal nor the lysosomal inhibitors restored normal GJIC or number/size of gap junction plaques. Finally, PCB 153 also interfered with restoration of gap junction plaques following the inhibition of Cx43 transport to plasma membrane. Taken together, multiple modes of action seem to contribute to downregulation of Cx43 in PCB 153-treated rat liver epithelial cells. The enhanced degradation of Cx43, together with persistent inhibition of GJIC, might contribute to tumor-promoting effects of NDL-PCBs.
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