The molecular mechanisms through which oxidized lipids and their electrophilic decomposition products mediate redox cell signalling is not well understood and may involve direct modification of signal-transduction proteins or the secondary production of reactive oxygen or nitrogen species in the cell. Critical in the adaptation of cells to oxidative stress, including exposure to subtoxic concentrations of oxidized lipids, is the transcriptional regulation of antioxidant enzymes, many of which are controlled by antioxidant-responsive elements (AREs), also known as electrophile-responsive elements. The central regulator of the ARE response is the transcription factor Nrf2 (NF-E2-related factor 2), which on stimulation dissociates from its cytoplasmic inhibitor Keap1, translocates to the nucleus and transactivates ARE-dependent genes. We hypothesized that electrophilic lipids are capable of activating ARE through thiol modification of Keap1 and we have tested this concept in an intact cell system using induction of glutathione synthesis by the cyclopentenone prostaglandin, 15-deoxy-Δ12,14-prostaglandin J2. On exposure to 15-deoxy-Δ12,14-prostaglandin J2, the dissociation of Nrf2 from Keap1 occurred and this was dependent on the modification of thiols in Keap1. This mechanism appears to encompass other electrophilic lipids, since 15-A2t-isoprostane and the lipid aldehyde 4-hydroxynonenal were also shown to modify Keap1 and activate ARE. We propose that activation of ARE through this mechanism will have a major impact on inflammatory situations such as atherosclerosis, in which both enzymic as well as non-enzymic formation of electrophilic lipid oxidation products are increased.
Skip Nav Destination
Article navigation
Research Article|
March 01 2004
Cellular mechanisms of redox cell signalling: role of cysteine modification in controlling antioxidant defences in response to electrophilic lipid oxidation products
Anna-Liisa LEVONEN;
Anna-Liisa LEVONEN
*Department of Pathology, Center for Free Radical Biology, University of Alabama at Birmingham, Biomedical Research Building II, 901 19th Str. S., Birmingham, AL 35294, U.S.A.
Search for other works by this author on:
Aimee LANDAR;
Aimee LANDAR
*Department of Pathology, Center for Free Radical Biology, University of Alabama at Birmingham, Biomedical Research Building II, 901 19th Str. S., Birmingham, AL 35294, U.S.A.
Search for other works by this author on:
Anup RAMACHANDRAN;
Anup RAMACHANDRAN
*Department of Pathology, Center for Free Radical Biology, University of Alabama at Birmingham, Biomedical Research Building II, 901 19th Str. S., Birmingham, AL 35294, U.S.A.
Search for other works by this author on:
Erin K. CEASER;
Erin K. CEASER
*Department of Pathology, Center for Free Radical Biology, University of Alabama at Birmingham, Biomedical Research Building II, 901 19th Str. S., Birmingham, AL 35294, U.S.A.
Search for other works by this author on:
Dale A. DICKINSON;
Dale A. DICKINSON
†Department of Environmental Health Sciences, University of Alabama at Birmingham, Birmingham, AL 35294-0022, U.S.A.
Search for other works by this author on:
Giuseppe ZANONI;
Giuseppe ZANONI
‡Dipartimento di Chimica Organica, Università di Pavia, Pavia 27100, Italy
Search for other works by this author on:
Jason D. MORROW;
Jason D. MORROW
§Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-6602, U.S.A.
Search for other works by this author on:
Victor M. DARLEY-USMAR
Victor M. DARLEY-USMAR
1
*Department of Pathology, Center for Free Radical Biology, University of Alabama at Birmingham, Biomedical Research Building II, 901 19th Str. S., Birmingham, AL 35294, U.S.A.
1To whom correspondence should be addressed (e-mail darley@path.uab.edu).
Search for other works by this author on:
Publisher: Portland Press Ltd
Received:
July 11 2003
Revision Received:
October 20 2003
Accepted:
November 17 2003
Accepted Manuscript online:
November 17 2003
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2004
2004
Biochem J (2004) 378 (2): 373–382.
Article history
Received:
July 11 2003
Revision Received:
October 20 2003
Accepted:
November 17 2003
Accepted Manuscript online:
November 17 2003
Citation
Anna-Liisa LEVONEN, Aimee LANDAR, Anup RAMACHANDRAN, Erin K. CEASER, Dale A. DICKINSON, Giuseppe ZANONI, Jason D. MORROW, Victor M. DARLEY-USMAR; Cellular mechanisms of redox cell signalling: role of cysteine modification in controlling antioxidant defences in response to electrophilic lipid oxidation products. Biochem J 1 March 2004; 378 (2): 373–382. doi: https://doi.org/10.1042/bj20031049
Download citation file:
Sign in
Don't already have an account? Register
Sign in to your personal account
You could not be signed in. Please check your email address / username and password and try again.
Captcha Validation Error. Please try again.