Activation of metallothionein transcription by 4-hydroxynonenal.
Metallothioneins (MTs) protect cells from oxidative damage by scavenging reactive oxygen species (ROS). Concurrent with protecting cells from ROS-mediated damage, MT transcription is induced by ROS. ROS activate transcription by affecting several signal transduction pathways, many of which have been implicated in regulating MT transcription. ROS-activated intracellular signaling is mediated by the stable lipid peroxide 4-hydroxynonenal (HNE). After determining the level of sensitivity of Hepa 1-6 cells to HNE, MT-1 mRNA expression was shown to be induced in a concentration and time-dependent manner after HNE exposure. Finally, using MT-based reporters, HNE was found to induce MT transcription via both antioxidant response and metal response elements. Thus, ROS may activate MT transcription by generating HNE that in turn affects signaling pathways that regulate MT transcription via the transcription factors AP-1 and MTF-1.
Laboratory of Molecular Toxicology, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA.
Elena K
EK
Braithwaite
Michael D
MD
Mattie
Jonathan H
JH
Freedman
D000447:Aldehydes / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D008054:Lipid Peroxides / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008668:Metallothionein / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D008670:Metals / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics*; D000097809:Transcription Factor MTF-1
D000447:Aldehydes; D000975:Antioxidants; D004268:DNA-Binding Proteins; D008054:Lipid Peroxides; D008668:Metallothionein; D008670:Metals; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D000097809:Transcription Factor MTF-1; C027576:4-hydroxy-2-nonenal