Up-Regulation of Neuronal Nitric Oxide Synthase Expression by Cobalt Chloride Through a HIF-1α Mechanism in Neuroblastoma Cells.
Nitric oxide (NO) plays a dual role in response to neural hypoxia. NO is synthesized by three isoforms of nitric oxide synthase (NOS), among which the neuronal NOS (nNOS) is predominant in the nervous system. Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that is induced under hypoxic conditions, but its correlation with nNOS remains unclear. In the present study, we aimed at clarifying the regulation pattern of the nNOS expression in response to cobalt chloride (CoCl2), a widely used chemical mimic of hypoxia, and the role of HIF-1α in this process in neuroblastoma cells. We found CoCl2 evidently increased the nNOS expression and NO production in human neuroblastoma SK-N-SH cells, but the effect of CoCl2 on NO was partially abrogated by 7-nitroindazole, a selective inhibitor for nNOS. Importantly, we identified a hypoxia response element (HRE) within the nNOS promoter, to which HIF-1α may bind, and CoCl2 greatly enhanced the HIF-1α expression and its binding to the HRE. Meanwhile, we demonstrated that this HRE was functionally important for the activation of the nNOS transcription, and CoCl2 increased the transcriptional activity of the nNOS promoter through this HRE. Taken together, our study shows that CoCl2 may induce the nNOS expression and NO production through a HIF-1α mechanism in neuroblastoma cells, which may provide a potential target for the treatment of neurological hypoxic disorders caused by NO dysregulation.
['Li|Guangyu|G|', 'Zhao|Yanyan|Y|', 'Li|Yinghui|Y|', 'Lu|Jingyu|J|']
D015687:Cell Hypoxia D045744:Cell Line, Tumor D047369:Chromatin Immunoprecipitation D003035:Cobalt D015972:Gene Expression Regulation, Neoplastic D017930:Genes, Reporter D006801:Humans D051795:Hypoxia-Inducible Factor 1, alpha Subunit D016297:Mutagenesis, Site-Directed D009363:Neoplasm Proteins D009447:Neuroblastoma D009569:Nitric Oxide D052248:Nitric Oxide Synthase Type I D011401:Promoter Regions, Genetic D012333:RNA, Messenger D012334:RNA, Neoplasm D020218:Response Elements D014158:Transcription, Genetic D014162:Transfection D015854:Up-Regulation
HIF-1α Hypoxia nNOS Nervous system