Cellular mechanisms of redox cell signalling: role of cysteine modification in controlling antioxidant defences in response to electrophilic lipid oxidation products.
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-Delta12,14-prostaglandin J2. On exposure to 15-deoxy-Delta12,14-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-A(2t)-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.
Levonen
Anna-Liisa
AL
Department of Pathology, Center for Free Radical Biology, University of Alabama at Birmingham, Biomedical Research Building II, 901 19th Str. S., Birmingham, AL 35294, USA.
Landar
Aimee
A
Ramachandran
Anup
A
Ceaser
Erin K
EK
Dickinson
Dale A
DA
Zanoni
Giuseppe
G
Morrow
Jason D
JD
Darley-Usmar
Victor M
VM
D000447:Aldehydes / Q000737:chemistry / Q000494:pharmacology; D000975:Antioxidants / Q000378:metabolism*; D001483:Base Sequence; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D003545:Cysteine / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005721:Glutamate-Cysteine Ligase / Q000096:biosynthesis / Q000235:genetics; D005978:Glutathione / Q000096:biosynthesis; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D051267:NF-E2-Related Factor 2; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D011454:Prostaglandins A / Q000737:chemistry / Q000494:pharmacology; D020218:Response Elements; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D015533:Transcriptional Activation
C097240:15-deoxy-delta(12,14)-prostaglandin J2; C117466:8-isoprostaglandin A2; D000447:Aldehydes; D000975:Antioxidants; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D011454:Prostaglandins A; D015534:Trans-Activators; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; C027576:4-hydroxy-2-nonenal; D003545:Cysteine; D015230:Prostaglandin D2