Abstract
Electrophiles and reactive oxygen species have been implicated in the pathogenesis of many diseases. Transcription factor Nrf2 was recently identified as a general regulator of one defense mechanism against such havoc. Nrf2 regulates the inducible expression of a group of detoxication enzymes, such as glutathione S-transferase and NAD(P)H:quinone oxidoreductase, via antioxidant response elements. Using peritoneal macrophages from Nrf2-deficient mice, we show here that Nrf2 also controls the expression of a group of electrophile- and oxidative stress-inducible proteins and activities, which includes heme oxygenase-1, A170, peroxiredoxin MSP23, and cystine membrane transport (system x(c)(-)) activity. The response to electrophilic and reactive oxygen species-producing agents was profoundly impaired in Nrf2-deficient cells. The lack of induction of system x(c)(-) activity resulted in the minimum level of intracellular glutathione, and Nrf2-deficient cells were more sensitive to toxic electrophiles. Several stress agents induced the DNA binding activity of Nrf2 in the nucleus without increasing its mRNA level. Thus Nrf2 regulates a wide-ranging metabolic response to oxidative stress.
Highlights
Oxidative stress conditions or enhanced production of reactive oxygen species (ROS)1 result from a variety of stimuli including ionizing radiation, exposure to xenobiotics, inflammation, and phagocytosis [1]
We recently demonstrated that transcription factor Nrf2 (6 – 8) is essential for the coordinated transcriptional activation of genes encoding the drug-metabolizing enzymes, such as glutathione S-transferase (GST) and NQO1, via antioxidant-responsive element (ARE)/electrophile-responsive element (EpRE) [9]
To test whether the electrophilic induction of this group of genes shares a common regulatory mechanism with that of the drug-metabolizing enzymes, we examined their expression in Nrf2-deficient macrophages
Summary
Oxidative stress conditions or enhanced production of reactive oxygen species (ROS)1 result from a variety of stimuli including ionizing radiation, exposure to xenobiotics, inflammation, and phagocytosis [1]. Treatment of mammalian cells with electrophilic agents usually provokes cellular responses, including transcriptional activation of genes encoding proteins that partake in the defense against oxidative stress. A number of defense proteins and activities in murine peritoneal macrophages are markedly induced upon exposure to electrophilic agents or other oxidative stresses.
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