Nitric oxide-induced programmed cell death in human neuroblastoma cells is accompanied by the synthesis of Egr-1, a zinc finger transcription factor.
Nitric oxide (NO) is cytotoxic for human SH-SY5Y neuroblastoma cells. While nuclear condensation was visible in cells treated with nitric oxide donors, we observed that the plasma membrane remained intact, indicating that NO induced apoptotic cell death. We analyzed the NO-induced apoptotic signaling cascade in SH-SY5Y cells and observed a striking increase in early growth response (Egr)-1 promoter activity as a result of NO-induced cell death. Likewise, we detected an activation of the transcriptional activation potential of the ternary complex factor Elk1, a key transcriptional regulator of serum response element-driven gene transcription. Egr-1 is a zinc finger transcription factor that couples extracellular signals to long-term responses by altering expression of Egr-1 target genes. The Egr-1 5'-flanking region contains five serum response elements (SRE) that function as genetic elements for stimulus-transcription coupling. Moreover, these SREs are binding sites for Elk1, suggesting that NO activated Egr-1 gene transcription via activation of Elk1. The NO-induced biosynthesis of Egr-1 was confirmed by Western blot analysis and an NO-dependent increase in the transcriptional activation potential of Egr-1 was observed. The fact that NO-induced neuronal cell death is accompanied by the biosynthesis of Egr-1 suggests that Egr-1 may be an integral part of the NO triggered apoptotic signaling cascade.
Cibelli
Giuseppe
G
Department of Medical Biochemistry and Molecular Biology, University of Saarland Medical Center, D-6642 Homburg, Germany.
Policastro
Vincenza
V
Rössler
Oliver G
OG
Thiel
Gerald
G
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000187:drug effects; D051766:Early Growth Response Protein 1; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D017874:Immediate-Early Proteins; D009447:Neuroblastoma; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009603:Nitroso Compounds / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis* / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism*; D016335:Zinc Fingers / Q000187:drug effects / Q000502:physiology*; D050807:ets-Domain Protein Elk-1
D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; C494112:ELK1 protein, human; D051766:Early Growth Response Protein 1; D017874:Immediate-Early Proteins; C093285:NOC 18; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D009569:Nitric Oxide