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PMID: 19538984 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Review

Nrf2 signaling and cell survival.

Toxicology and applied pharmacology ·Vol. 244 ·No. 1 ·2010-04-01 ·Pages 37-42

Niture SK, Kaspar JW, Shen J, Jaiswal AK

Abstract

Nrf2:INrf2 acts as a sensor for oxidative/electrophilic stress. INrf2 serves as an adaptor to link Nrf2 to the ubiquitin ligase Cul3-Rbx1 complex that ubiquitinate and degrade Nrf2. Under basal conditions, cytosolic INrf2/Cul3-Rbx1 is constantly degrading Nrf2. When a cell encounters stress Nrf2 dissociates from the INrf2 and translocates into the nucleus. Oxidative/electrophilic stress induced modification of INrf2Cysteine151 and/or protein kinase C (PKC)-mediated phosphorylation of Nrf2Serine40 controls Nrf2 release from INrf2 followed by stabilization and nuclear translocation of Nrf2. Nrf2 binds to the antioxidant response element (ARE) and activates a myriad of genes that protect cells against oxidative/electrophilic stress and neoplasia. A delayed response of oxidative/electrophilic stress activates GSK-3beta that phosphorylates Fyn at unknown threonine residue(s). Phosphorylated Fyn translocates to the nucleus and phosphorylates Nrf2Tyrosine568 that leads to nuclear export and degradation of Nrf2. Prothymosin-alpha mediated nuclear translocation of INrf2 also degrades nuclear Nrf2. The degradation of Nrf2 both in cytosol and nuclear compartments rapidly brings down its levels to normal resulting in suppression of Nrf2 downstream gene expression. An auto-regulatory loop between Nrf2 and INrf2 controls their cellular abundance. Nrf2 regulates INrf2 by controlling its transcription, and INrf2 controls Nrf2 by degrading it. In conclusion, switching on and off of Nrf2 combined with promoting an auto-regulatory loop between them regulates activation/deactivation of defensive genes leading to protection of cells against adverse effects of oxidative and electrophilic stress and promote cell survival.

MeSH Terms
Active Transport, Cell Nucleus Adaptor Proteins, Signal Transducing/metabolism Amino Acid Sequence Animals Antioxidants/metabolism Binding Sites Cell Survival Cytoskeletal Proteins/metabolism Drug Resistance Homeostasis Humans Intracellular Signaling Peptides and Proteins/metabolism Kelch-Like ECH-Associated Protein 1 Molecular Sequence Data NF-E2-Related Factor 2/metabolism Neoplasms/metabolism,prevention & control Oxidative Stress Phosphorylation Response Elements Signal Transduction
Chemicals
Adaptor Proteins, Signal Transducing Antioxidants Cytoskeletal Proteins Intracellular Signaling Peptides and Proteins KEAP1 protein, human Keap1 protein, mouse Kelch-Like ECH-Associated Protein 1 NF-E2-Related Factor 2
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Niture Suryakant K
Department of Pharmacology, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201, USA.
Kaspar James W
Shen Jun
Jaiswal Anil K
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Article Info
Journal
Toxicology and applied pharmacology
Abbr.
Toxicol Appl Pharmacol
ISSN
1096-0333
DOI
10.1016/j.taap.2009.06.009
Published
2010-04-01
Epub
2009-00-16
Pages
37-42
Language
English
Region
United States
NLM ID
0416575
PMCID
PMC2837794
Subset
IM
Grants
NIEHS NIH HHS · R01 ES012265 · United States
NIEHS NIH HHS · R01 ES012265-06 · United States
NIGMS NIH HHS · R01 GM047466 · United States
NIGMS NIH HHS · R01 GM047466-19 · United States
External Links
PubMed source DOI: 10.1016/j.taap.2009.06.009 PMC Full Text View journal details
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