PMID- 34848742
OWN - NLM
STAT- MEDLINE
DCOM- 20220124
LR  - 20220124
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 11
IP  - 1
DP  - 2021 Nov 30
TI  - Endogenous regulation of the Akt pathway by the aryl hydrocarbon receptor (AhR) 
      in lung fibroblasts.
PG  - 23189
LID - 10.1038/s41598-021-02339-3 [doi]
LID - 23189
AB  - The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor 
      known to mediate toxic responses to dioxin. However, the role of the AhR in the 
      regulation of cellular physiology has only recently been appreciated, including 
      its ability to control cell cycle progression and apoptosis by unknown 
      mechanisms. We hypothesized that the AhR enhances the activation of the AKT 
      serine/threonine kinase (Akt) pathway to promote cell survival. Utilizing AhR 
      knock-out (Ahr(-/-)) and wild-type (Ahr(+/+)) mouse lung fibroblasts (MLFs), we 
      found that Ahr(-/-) MLFs have significantly higher basal Akt phosphorylation but 
      that AhR did not affect Akt phosphorylation in MLFs exposed to growth factors or 
      AhR ligands. Basal Akt phosphorylation was dependent on PI3K but was unaffected 
      by changes in intracellular glutathione (GSH) or p85alpha. There was no significant 
      decrease in cell viability in Ahr(-/-) MLFs treated with LY294002-a PI3K 
      inhibitor-although LY294002 did attenuate MTT reduction, indicating an affect on 
      mitochondrial function. Using a mass spectrometry (MS)-based approach, we 
      identified several proteins that were differentially phosphorylated in the 
      Ahr(-/-) MLFs compared to control cells, including proteins involved in the 
      regulation of extracellular matrix (ECM), focal adhesion, cytoskeleton remodeling 
      and mitochondrial function. In conclusion, Ahr ablation increased basal Akt 
      phosphorylation in MLFs. Our results indicate that AhR may modulate the 
      phosphorylation of a variety of novel proteins not previously identified as AhR 
      targets, findings that help advance our understanding of the endogenous functions 
      of AhR.
CI  - (c) 2021. The Author(s).
FAU - Shi, Fangyi
AU  - Shi F
AD  - Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
AD  - Department of Pathology, McGill University, Montreal, QC, Canada.
FAU - Aloufi, Noof
AU  - Aloufi N
AD  - Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
AD  - Department of Pathology, McGill University, Montreal, QC, Canada.
FAU - Traboulsi, Hussein
AU  - Traboulsi H
AD  - Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
AD  - Department of Medicine, McGill University, Montreal, QC, Canada.
FAU - Trempe, Jean-Francois
AU  - Trempe JF
AD  - Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
AD  - Department of Pharmacology & Therapeutics, McGill University, Montreal, QC, 
      Canada.
FAU - Eidelman, David H
AU  - Eidelman DH
AD  - Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
AD  - Department of Medicine, McGill University, Montreal, QC, Canada.
FAU - Baglole, Carolyn J
AU  - Baglole CJ
AD  - Research Institute of the McGill University Health Centre, Montreal, QC, Canada. 
      Carolyn.baglole@mcgill.ca.
AD  - Department of Pathology, McGill University, Montreal, QC, Canada. 
      Carolyn.baglole@mcgill.ca.
AD  - Department of Medicine, McGill University, Montreal, QC, Canada. 
      Carolyn.baglole@mcgill.ca.
AD  - Department of Pharmacology & Therapeutics, McGill University, Montreal, QC, 
      Canada. Carolyn.baglole@mcgill.ca.
LA  - eng
GR  - PJT-168836/CIHR/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20211130
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Receptors, Aryl Hydrocarbon)
RN  - 0 (Smoke)
RN  - 0 (Tetrazolium Salts)
RN  - 0 (Thiazoles)
RN  - EC 2.7.11.1 (Akt1 protein, mouse)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EUY85H477I (thiazolyl blue)
SB  - IM
MH  - Animals
MH  - Cell Survival
MH  - Cells, Cultured
MH  - Cytoskeleton
MH  - Fibroblasts/metabolism
MH  - *Gene Expression Regulation
MH  - Homeostasis
MH  - Intercellular Signaling Peptides and Proteins
MH  - Lung/*metabolism
MH  - Mass Spectrometry
MH  - Mice
MH  - Phosphorylation
MH  - Proteomics/methods
MH  - Proto-Oncogene Proteins c-akt/*biosynthesis
MH  - Receptors, Aryl Hydrocarbon/*metabolism
MH  - Smoke
MH  - Tetrazolium Salts/pharmacology
MH  - Thiazoles/pharmacology
MH  - Tobacco Products
PMC - PMC8632926
COIS- The authors declare no competing interests.
EDAT- 2021/12/02 06:00
MHDA- 2022/01/27 06:00
PMCR- 2021/11/30
CRDT- 2021/12/01 06:17
PHST- 2021/03/17 00:00 [received]
PHST- 2021/11/08 00:00 [accepted]
PHST- 2021/12/01 06:17 [entrez]
PHST- 2021/12/02 06:00 [pubmed]
PHST- 2022/01/27 06:00 [medline]
PHST- 2021/11/30 00:00 [pmc-release]
AID - 10.1038/s41598-021-02339-3 [pii]
AID - 2339 [pii]
AID - 10.1038/s41598-021-02339-3 [doi]
PST - epublish
SO  - Sci Rep. 2021 Nov 30;11(1):23189. doi: 10.1038/s41598-021-02339-3.