title: JNK1, but not JNK2, is required for COX-2 induction by nickel compounds.
abstract: Activation of the signaling pathways leading to gene expression regulation is critical in the carcinogenic effects of nickel exposure. In the present study, we found nickel exposure could induce cyclooxygenase-2 (COX-2) expression at transcriptional and protein levels in both human bronchoepithelial cells (Beas-2B) and murine embryonic fibroblasts (MEFs). We further provided direct evidence for the specific involvement of the JNK1 signaling pathway in the COX-2 induction using specific gene knockout approaches. Our results demonstrated that COX-2 induction by nickel was impaired in JNK1(-/-) MEFs, but not in JNK2(-/-) MEFs. Moreover, re-constitutional expression of JNK1 restored COX-2 induction, confirming the specific requirement of JNK1 in COX-2 induction. Further investigation revealed that JNK1 mediated the nickel-induced COX-2 expression in a c-Jun/AP-1-dependent manner. Ectopic expression of TAM67, a c-Jun dominant negative mutant, also suppressed the COX-2 induction. Our results demonstrate that the JNK1/c-Jun/AP-1 pathway, but not the JNK2 pathway, plays a critical role in nickel-induced COX-2 expression.
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA.
authors.forename: Dongyun
authors.initials: D
authors.lastname: Zhang
authors.forename: Jingxia
authors.initials: J
authors.lastname: Li
authors.forename: Kangjian
authors.initials: K
authors.lastname: Wu
authors.forename: Weiming
authors.initials: W
authors.lastname: Ouyang
authors.forename: Jin
authors.initials: J
authors.lastname: Ding
authors.forename: Zheng-gang
authors.initials: ZG
authors.lastname: Liu
authors.forename: Max
authors.initials: M
authors.lastname: Costa
authors.forename: Chuanshu
authors.initials: C
authors.lastname: Huang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D006720:Homozygote; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis*; D051379:Mice; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000502:physiology*; D048056:Mitogen-Activated Protein Kinase 9 / Q000235:genetics / Q000502:physiology*; D009532:Nickel / Q000633:toxicity*; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000201:enzymology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D008565:Membrane Proteins; C022838:nickel chloride; D009532:Nickel; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8; C017558:nickel sulfide