Cellular signaling crosstalk between Wnt signaling and gap junctions inbenzo[a]pyrene toxicity.
Benzo[a]pyrene
Connexin 43
Gap junction
Toxicity
Wnt
β-catenin
Journal
Cell biology and toxicology
ISSN: 1573-6822
Titre abrégé: Cell Biol Toxicol
Pays: Switzerland
ID NLM: 8506639
Informations de publication
Date de publication:
02 2023
02 2023
Historique:
received:
29
03
2021
accepted:
24
06
2021
medline:
29
3
2023
pubmed:
21
7
2021
entrez:
20
7
2021
Statut:
ppublish
Résumé
Gap junctional intercellular communication (GJIC) is considered a key biological mechanism to maintain homeostasis in cell differentiation and growth. In addition, as another major signaling pathway associated with cell proliferation and differentiation, Wnt/β-catenin signaling appears to trigger several cellular responses against injury. The purpose of the present study was to investigate the effects of a known toxic agent, benzo[a]pyrene (BaP), on the regulation and interaction between GJIC and Wnt/β-catenin signaling. BaP treatment resulted in GJIC inhibition and decreases the major GJIC protein connexin 43 (Cx43) in WB-F344 rat liver epithelial cells. We also found BaP-mediated downregulation of Wnt/β-catenin signaling related to the PI3K-Akt pathway. To identify the relationship between GJIC and Wnt/β-catenin signaling, we treated WB-F344 cells with the Wnt agonist CHIR99021 and found that it inhibited GJIC while causing a significant reduction in Cx43 expression at both the mRNA and protein levels, through the repression of promoter activity. This Wnt agonist-mediated GJIC inhibition was confirmed using a small interfering RNA directed against the Wnt antagonist Dact2, indicating that Wnt/β-catenin signaling negatively regulates GJIC. Despite the inverse correlation between Wnt/β-catenin signaling and Cx43 promoter activation as indicated by downregulation of β-catenin nuclear translocation and upregulation of Cx43 promoter activation involving HNF3β, BaP treatment decreased the Cx43 protein expression, which was associated with protein degradation, possibly through protein kinase C activation. In conclusion, our results revealed the mechanism of BaP-induced inhibition of GJIC and Wnt/β-catenin signaling. More importantly, linking Wnt/β-catenin signaling to Cx protein expression will have profound implications in understanding the relationships among different major signaling pathways associated with cell proliferation and differentiation in toxicity.
Identifiants
pubmed: 34283317
doi: 10.1007/s10565-021-09630-z
pii: 10.1007/s10565-021-09630-z
doi:
Substances chimiques
Connexin 43
0
beta Catenin
0
Phosphatidylinositol 3-Kinases
EC 2.7.1.-
Pyrenes
0
Dact2 protein, rat
0
Nuclear Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
165-182Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature B.V.
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