Cadmium blocks receptor-mediated Jak/STAT signaling in neurons by oxidative stress.
Cadmium is an environmental contaminant producing numerous pathological effects including neurological disorders. The mechanisms through which cadmium produces neurotoxicities are not completely known. We found that divalent cadmium (CdCl2) inhibited ciliary neurotrophic factor (CNTF)-mediated Jak1 and Jak2 tyrosine kinase signaling in human BE(2)-C neuroblastoma cells. CdCl2 concentrations as low as 0.1 microM and for times as brief as 2 h significantly reduced CNTF-induced tyrosine phosphorylation of both STAT1 and STAT3, the principle substrates of Jak kinases in neurons. The phosphorylation of STAT1 by interferon-gamma was also inhibited by CdCl2. However, activation of the fibroblast growth factor receptor tyrosine kinase was not inhibited by CdCl2. Jak/STAT signaling was inhibited by CdCl2 selectively in cultures of chick retina neurons and neuroblastoma cells, whereas signaling in the nonneuronal cells HepG2 and chick skeletal myotubes was not affected. Results using dichlorofluorescein indicated CdCl2 increased cellular oxidative stress, and all of these effects of CdCl2 were protected against by pretreatment with antioxidants. Neuronal inhibition of Jak kinase by CdCl2-induced oxidative stress is a new mechanism of cadmium action which may directly produce neurotoxic symptoms as well as implicate cadmium and related metals as environmental factors in the etiology of neurodegenerative diseases.
Monroe
Richard K
RK
Program in Neurosciences, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, 102 Farber Hall, Buffalo, NY 14214-3000, USA.
Halvorsen
Stanley W
SW
D021581:Active Transport, Cell Nucleus; D017209:Apoptosis / Q000187:drug effects; D002104:Cadmium / Q000494:pharmacology*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D053613:Janus Kinase 1 / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D020801:Receptor, Ciliary Neurotrophic Factor / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
D016207:Cytokines; D020801:Receptor, Ciliary Neurotrophic Factor; D050791:STAT Transcription Factors; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D002104:Cadmium; D053613:Janus Kinase 1; D053614:Janus Kinase 2