Copper activation of NF-kappaB signaling in HepG2 cells.
Copper is a persistent environmental contaminant, and exposure to elevated levels of this transition metal can result in a variety of pathologies. Copper affects the transcription of multiple defense and repair genes to protect against metal-induced pathologies. HepG2 cells were treated with copper under multiple conditions and microarray analyses were previously performed to better understand the mechanisms by which copper affects the transcription of stress-responsive genes. Analysis of the microarray data indicated that copper modulates multiple signal transduction pathways, including those mediated by NF-kappaB. Luciferase assays, quantitative reverse transcription real-time PCR, and chemical inhibition in HepG2 cells validated the microarray results and confirmed that NF-kappaB was activated by stress-inducible concentrations of copper. In addition, two novel NF-kappaB-regulated genes, SRXN1 (sulfiredoxin 1 homolog) and ZFAND2A (zinc-finger, AN1-type domain 2A), were identified. Our results indicate that the activation of NF-kappaB may be important for survival under elevated concentrations of copper.
McElwee
Matthew K
MK
Laboratory of Molecular Toxicology, National Institute of Environmental Health Sciences, NIH, DHHS, Box 12233, MD E1-05, 111 T. W. Alexander Drive, Research Triangle Park, NC 27709, USA.
Song
Min Ok
MO
Freedman
Jonathan H
JH
D045744:Cell Line, Tumor; D019295:Computational Biology; D003300:Copper / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D053263:Gene Regulatory Networks; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors; D016328:NF-kappa B / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051996:Transcription Factor RelA / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D003300:Copper; D006861:Hydrogen Peroxide; D051550:I-kappa B Kinase