J. Biol. Chem., Vol. 284, Issue 20, 13291-13295, May 15, 2009
The Nrf2-Antioxidant Response Element Signaling Pathway and Its Activation by Oxidative Stress
J. Biol. Chem. Nguyen et al. 284: 13291
Truyen Nguyen and Cecil B. Pickett
TRUYEN NGUYEN
Current Position: Mechanistic and Predictive Toxicology at Schering-Plough Research Institute in Summit, New Jersey
Education: Ph.D. in Toxicology (2006) from Rutgers University in New Jersey
Non-scientific Interests: Travel, woodworking, hockey
I became fascinated with the field of molecular biology when working as a research assistant in the department of Biology at McGill University. I joined the laboratory of Dr. Pickett in 1988 when his group had just identified a novel enhancer now known as the antioxidant response element, or ARE, in the promoter of genes encoding rat glutathione S-transferase A2 and NAD(P)H:quinone oxidoreductase 1. Characterization of the ARE was undertaken at the time by two postdoctoral fellows, Thomas Rushmore and Leonard Favreau, and my responsibility was to assist them in this effort. This has led to our identifying the primary structure as well as the unique biological activities of this enhancer. In later years, we attempted to identify the trans-acting factor using conventional biochemical techniques as well as various cloning strategies, but it remained elusive. Following its cloning by Y. W. Kan’s group while investigating the β-globin locus control region, Nrf2 was eventually identified by M. Yamamoto’s group as the key protein acting through the ARE to activate gene transcription based on studies using knockout mice. Characterization of the Nrf2 protein proved to be difficult in the early days because of a lack of specific reagents for its detection. We were able to raise a fairly specific anti-Nrf2 antibody, and this has facilitated our investigations into the mechanisms involved in the regulation of this transcription factor under homeostatic conditions and in response to oxidative stress. This minireview describes our current understanding of the Nrf2 signaling pathway and its being a potential target for developing therapy against multiple sclerosis, among others.
CECIL B. PICKETT
Current Position: President of Research and Development at Biogen Idec in Cambridge, Massachusetts
Education: Ph.D. in Cell Biology (1976) from University of California, Los Angeles
Non-scientific Interests: Golf, travel, jazz
After completing my postdoctoral fellowship at UCLA in 1978, I accepted a position in the Department of Biochemical Regulation of the Merck Research Laboratories (MRL). My research interest focused on the biosynthesis of membrane proteins, and I established cell free translation and cDNA cloning systems to explore this problem. Shortly after I joined MRL, Anthony Lu moved to MRL to lead the Department of Drug Metabolism and introduced me to the field of drug metabolism. I became interested in the Glutathione S-Transferase (GSTs) drug metabolizing systems, and we collaborated on characterizing this family of enzymes. My laboratory used the cell free translation and cDNA cloning systems I established to clone and sequence several GSTs family members. We also isolated and characterized GSTs genes and determined they were comprised of a multi-gene family. After isolating the structural genes, I explored how xenobiotics transcriptionally activated a specific GST gene (GST-A2) and the NAD(P)H:quinonereductase (NQO1) gene. Using 5’ deletion analysis and various promoter constructs, we identified a unique enhancer in the 5’ flanking region of both genes that conferred inducibility to xenobiotics that redox cycle and oxidants such as hydrogen peroxide. We named this enhancer the Antioxidant Response Element (ARE). Identification of the ARE enabled other laboratories to identify the transcriptional factors, which interacted with the ARE. Work from Yamamoto’s laboratory at the University of Tsukuba in Japan identified Nrf2 as the transcriptional factor that bound to the ARE and triggered transcriptional activation of the GSTA2 gene as well as several other genes which harbor an ARE. My laboratory then demonstrated that xenobiotics, which activated expression of the GSTA2 gene stabilized Nrf2 in the nucleus and that KEAP1, also identified by the Yamamoto laboratory as a cytoplasmic anchor for Nrf2, shuttled into the nucleus to target Nrf2 for proteosomal degradation. It has been extremely rewarding to see the basic science in my laboratory being translated into what may be meaningful therapy for patients with multiple sclerosis.
Read Drs. Nguyen and Pickett's article on page 13291.
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