JNK1, but not JNK2, is required for COX-2 induction by nickel compounds.
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.
Zhang
Dongyun
D
Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA.
Li
Jingxia
J
Wu
Kangjian
K
Ouyang
Weiming
W
Ding
Jin
J
Liu
Zheng-gang
ZG
Costa
Max
M
Huang
Chuanshu
C
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
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