Hyperoxia induces Egr-1 expression through activation of extracellular signal-regulated kinase 1/2 pathway.
Early growth response gene (Egr-1) is a stress response gene activated by various forms of stress and growth factor signaling. We report that supraphysiologic concentrations of O(2) (hyperoxia) induced Egr-1 mRNA and protein expression in cultured alveolar epithelial cells, as well as in mouse lung in vivo. The contribution of the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK), p38 MAPK and PI3-kinase pathways to the activation of Egr-1 in response to hyperoxia was examined. Exposure to hyperoxia resulted in a rapid phosphorylation of ERK 1/2 kinases in mouse alveolar epithelial cells LA4. MEK inhibitor PD98059, but not inhibitors of p38 MAPK or PI3-kinase pathway, prevented Egr-1 induction by hyperoxia. The signaling cascade preceding Egr-1 activation was traced to epidermal growth factor receptor (EGFR) signaling. Hyperoxia is used as supplemental therapy in some diseases and typically results in elevated levels of reactive oxygen intermediates (ROI) in many lung cell types, the organ that receives highest O(2) exposure. Our results support a pathway for the hyperoxia response that involves EGF receptor, MEK/ERK pathway, and other unknown signaling components leading to Egr-1 induction. This forms a foundation for analysis of detailed mechanisms underlying Egr-1 activation during hyperoxia and understanding its consequences for regulating cell response to oxygen toxicity.
Jones
Nicole
N
Department of Anatomy, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Agani
Faton H
FH
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051766:Early Growth Response Protein 1; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D018496:Hyperoxia / Q000201:enzymology / Q000378:metabolism*; D017874:Immediate-Early Proteins; D008168:Lung / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D017874:Immediate-Early Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases