PMID- 31107893
OWN - NLM
STAT- MEDLINE
DCOM- 20200123
LR  - 20200309
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 14
IP  - 5
DP  - 2019
TI  - Activation of NRF2 by dexamethasone in ataxia telangiectasia cells involves KEAP1 
      inhibition but not the inhibition of p38.
PG  - e0216668
LID - 10.1371/journal.pone.0216668 [doi]
LID - e0216668
AB  - Oxidative stress has been shown to play a crucial role in the pathophysiology of 
      the neurodegenerative disease Ataxia Telangiectasia. We have recently 
      demonstrated that Dexamethasone treatment is able to counteract the oxidative 
      state by promoting nuclear factor erythroid 2-related factor 2 (NRF2) nuclear 
      accumulation. However, substantial gaps remain in our knowledge of the underlying 
      molecular mechanism(s) according to which Dexamethasone acts as an NRF2 inducer. 
      Herein we investigate the possible effects of the drug on the main NRF2 
      activation pathways by initially focusing on key kinases known to differently 
      affect NRF2 activation. Neither AKT nor ERK1/2, known to be NRF2-activating 
      kinases, were found to be activated upon Dexamethasone treatment, thus excluding 
      their involvement in the transcription factor nuclear shift. Likewise, GSK3 
      inactivating kinase was not inhibited, thus ruling out its role in NRF2 
      activation. On the other hand, p38 MAPK, another NRF2-inhibitory kinase, was 
      indeed switched-off in Ataxia Telangiectasia cells by Dexamethasone-mediated 
      induction of DUSP1 phosphatase, and therefore it appeared that it might account 
      for NRF2 triggering. However, this mechanism was excluded by the use of a 
      selective p38 inhibitor, which failed to cause a significant NRF2 nuclear shift 
      and target gene induction. Finally, dexamethasone effects on the classical 
      oxidative pathway orchestrated by KEAP1 were addressed. Dexamethasone was found 
      to decrease the expression of the inhibitor KEAP1 at both mRNA and protein levels 
      and to induce the shift from the reduced to the oxidized form of KEAP1, thus 
      favouring NRF2 translocation into the nucleus. Furthermore, preliminary data 
      revealed very low levels of the negative regulator Fyn in Ataxia Telangiectasia 
      cells, which might account for the prolonged NRF2-activated gene expression.
FAU - Biagiotti, Sara
AU  - Biagiotti S
AUID- ORCID: 0000-0001-9554-7858
AD  - Department of Biomolecular Sciences, University of Urbino, Urbino, Italy.
FAU - Bianchi, Marzia
AU  - Bianchi M
AD  - Department of Biomolecular Sciences, University of Urbino, Urbino, Italy.
FAU - Rossi, Luigia
AU  - Rossi L
AD  - Department of Biomolecular Sciences, University of Urbino, Urbino, Italy.
FAU - Chessa, Luciana
AU  - Chessa L
AD  - Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, 
      Italy.
FAU - Magnani, Mauro
AU  - Magnani M
AD  - Department of Biomolecular Sciences, University of Urbino, Urbino, Italy.
LA  - eng
PT  - Journal Article
DEP - 20190520
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Antioxidants)
RN  - 0 (KEAP1 protein, human)
RN  - 0 (Kelch-Like ECH-Associated Protein 1)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NFE2L2 protein, human)
RN  - 0 (Reactive Oxygen Species)
RN  - 7S5I7G3JQL (Dexamethasone)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Antioxidants/metabolism
MH  - Ataxia Telangiectasia/genetics/*metabolism
MH  - Cell Line
MH  - Dexamethasone/pharmacology
MH  - Humans
MH  - Kelch-Like ECH-Associated Protein 1/antagonists & inhibitors/genetics/*metabolism
MH  - NF-E2-Related Factor 2/genetics/*metabolism
MH  - Neurodegenerative Diseases/genetics
MH  - Oxidation-Reduction
MH  - Oxidative Stress
MH  - Reactive Oxygen Species/metabolism
MH  - p38 Mitogen-Activated Protein Kinases/metabolism/physiology
PMC - PMC6527213
COIS- The authors have declared that no competing interests exist.
EDAT- 2019/05/21 06:00
MHDA- 2020/01/24 06:00
PMCR- 2019/05/20
CRDT- 2019/05/21 06:00
PHST- 2019/01/11 00:00 [received]
PHST- 2019/04/26 00:00 [accepted]
PHST- 2019/05/21 06:00 [entrez]
PHST- 2019/05/21 06:00 [pubmed]
PHST- 2020/01/24 06:00 [medline]
PHST- 2019/05/20 00:00 [pmc-release]
AID - PONE-D-19-00993 [pii]
AID - 10.1371/journal.pone.0216668 [doi]
PST - epublish
SO  - PLoS One. 2019 May 20;14(5):e0216668. doi: 10.1371/journal.pone.0216668. 
      eCollection 2019.