PMID- 19668370
OWN - NLM
STAT- MEDLINE
DCOM- 20100119
LR  - 20220309
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 4
IP  - 8
DP  - 2009 Aug 11
TI  - Phosphorylation of Nrf2 at multiple sites by MAP kinases has a limited 
      contribution in modulating the Nrf2-dependent antioxidant response.
PG  - e6588
LID - 10.1371/journal.pone.0006588 [doi]
LID - e6588
AB  - The bZIP transcription factor Nrf2 has emerged as a pivotal regulator of 
      intracellular redox homeostasis by controlling the expression of many endogenous 
      antioxidants and phase II detoxification enzymes. Upon oxidative stress, Nrf2 is 
      induced at protein levels through redox-sensitive modifications on cysteine 
      residues of Keap1, a component of the E3 ubiquitin ligase that targets Nrf2 for 
      ubiquitin-dependent degradation. The mitogen activated protein kinases (MAPKs) 
      have previously been proposed to regulate Nrf2 in response to oxidative stress. 
      However, the exact role of MAPKs and the underlying molecular mechanism remain 
      poorly defined. Here we report the first evidence that Nrf2 is phosphorylated in 
      vivo by MAPKs. We have identified multiple serine/threonine residues as major 
      targets of MAPK-mediated phosphorylation. Combined alanine substitution on those 
      residues leads to a moderate decrease in the transcriptional activity of Nrf2, 
      most likely due to a slight reduction in its nuclear accumulation. More 
      importantly, Nrf2 protein stability, primarily controlled by Keap1, is not 
      altered by Nrf2 phosphorylation in vivo. These data indicate that direct 
      phosphorylation of Nrf2 by MAPKs has limited contribution in modulating Nrf2 
      activity. We suggest that MAPKs regulate the Nrf2 signaling pathway mainly 
      through indirect mechanisms.
FAU - Sun, Zheng
AU  - Sun Z
AD  - Department of Pharmacology & Toxicology, College of Pharmacy, University of 
      Arizona, Tucson, AZ, USA.
FAU - Huang, Zheping
AU  - Huang Z
FAU - Zhang, Donna D
AU  - Zhang DD
LA  - eng
GR  - P30 ES006694/ES/NIEHS NIH HHS/United States
GR  - R01 ES015010/ES/NIEHS NIH HHS/United States
GR  - ES006694/ES/NIEHS NIH HHS/United States
GR  - 1 R01 ES015010/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20090811
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Antioxidants)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NFE2L2 protein, human)
RN  - 0 (Nfe2l2 protein, mouse)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Antioxidants/*metabolism
MH  - Cell Line
MH  - Humans
MH  - Mass Spectrometry
MH  - Mice
MH  - Mitogen-Activated Protein Kinases/*metabolism
MH  - Molecular Sequence Data
MH  - NF-E2-Related Factor 2/chemistry/*metabolism
MH  - Phosphorylation
MH  - Reverse Transcriptase Polymerase Chain Reaction
PMC - PMC2719090
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2009/08/12 09:00
MHDA- 2010/01/20 06:00
PMCR- 2009/08/11
CRDT- 2009/08/12 09:00
PHST- 2009/04/14 00:00 [received]
PHST- 2009/07/10 00:00 [accepted]
PHST- 2009/08/12 09:00 [entrez]
PHST- 2009/08/12 09:00 [pubmed]
PHST- 2010/01/20 06:00 [medline]
PHST- 2009/08/11 00:00 [pmc-release]
AID - 09-PONE-RA-09753R1 [pii]
AID - 10.1371/journal.pone.0006588 [doi]
PST - epublish
SO  - PLoS One. 2009 Aug 11;4(8):e6588. doi: 10.1371/journal.pone.0006588.