Mechanistic Studies of the Nrf2-Keap1 Signaling Pathway
Top Cited Papers
Open Access
- 1 January 2006
- journal article
- review article
- Published by Taylor & Francis Ltd in Drug Metabolism Reviews
- Vol. 38 (4), 769-789
- https://doi.org/10.1080/03602530600971974
Abstract
Since eukaryotic cells constantly encounter various environmental insults, they have evolved defense mechanisms to cope with toxicant- and carcinogen-induced oxidative stress or electrophiles. One of the most important cellular defense mechanisms against oxidative stress or electrophiles is mediated by the transcription factor Nrf2. Under the basal condition, Nrf2-dependent transcription is repressed by a negative regulator Keap1. When cells are exposed to oxidative stress, electrophiles, or chemopreventive agents, Nrf2 escapes Keap1-mediated repression and activates antioxidant responsive element (ARE)-dependent gene expression to maintain cellular redox homeostasis. Beyond its antioxidant function, Nrf2 has recently been recognized as a key factor regulating an array of genes that defend cells against the deleterious effects of environmental insults. Since this Nrf2-dependent cellular defense response is able to protect multi-organs or multi-tissues, activation of Nrf2 has been implicated in conferring protection against many human diseases, including cancer, neurodegenerative diseases, cardiovascular diseases, acute and chronic lung injury, autoimmune diseases, and inflammation. Therefore, understanding of Nrf2 regulation is crucial in the development of drugs for therapeutic intervention. This review will discuss recent progress in the field of the Nrf2-Keap1 signaling pathway, with emphasis on the mechanistic studies of Nrf2 regulation by Keap1, oxidative stress, or chemopreventive compounds.Keywords
This publication has 71 references indexed in Scilit:
- Gene expression profiling of NRF2-mediated protection against oxidative injuryFree Radical Biology & Medicine, 2005
- The Keap1-BTB Protein Is an Adaptor That Bridges Nrf2 to a Cul3-Based E3 Ligase: Oxidative Stress Sensing by a Cul3-Keap1 LigaseMolecular and Cellular Biology, 2004
- The transcription factor NRF2 protects against pulmonary fibrosisThe FASEB Journal, 2004
- Nrf2 Transcription Factor, a Novel Target of Keratinocyte Growth Factor Action Which Regulates Gene Expression and Inflammation in the Healing Skin WoundMolecular and Cellular Biology, 2002
- Loss of the Nrf2 transcription factor causes a marked reduction in constitutive and inducible expression of the glutathione S-transferase Gsta1, Gsta2, Gstm1, Gstm2, Gstm3 and Gstm4 genes in the livers of male and female miceBiochemical Journal, 2002
- Role of NRF2 in Protection Against Hyperoxic Lung Injury in MiceAmerican Journal of Respiratory Cell and Molecular Biology, 2002
- Accelerated DNA Adduct Formation in the Lung of the Nrf2 Knockout Mouse Exposed to Diesel ExhaustToxicology and Applied Pharmacology, 2001
- An important function of Nrf2 in combating oxidative stress: Detoxification of acetaminophenProceedings of the National Academy of Sciences of the United States of America, 2001
- Targeted disruption of the ubiquitous CNC-bZIP transcription factor, Nrf-1, results in anemia and embryonic lethality in miceThe EMBO Journal, 1998
- NRF2, a member of the NFE2 family of transcription factors, is not essential for murine erythropoiesis, growth, and developmentProceedings of the National Academy of Sciences of the United States of America, 1996