title: Radiation-induced c-Jun activation depends on MEK1-ERK1/2 signaling pathway in microglial cells.
abstract: Radiation-induced normal brain injury is associated with acute and/or chronic inflammatory responses, and has been a major concern in radiotherapy. Recent studies suggest that microglial activation is a potential contributor to chronic inflammatory responses following irradiation; however, the molecular mechanism underlying the response of microglia to radiation is poorly understood. c-Jun, a component of AP-1 transcription factors, potentially regulates neural cell death and neuroinflammation. We observed a rapid increase in phosphorylation of N-terminal c-Jun (on serine 63 and 73) and MAPK kinases ERK1/2, but not JNKs, in irradiated murine microglial BV2 cells. Radiation-induced c-Jun phosphorylation is dependent on the canonical MEK-ERK signaling pathway and required for both ERK1 and ERK2 function. ERK1/2 directly interact with c-Jun in vitro and in cells; meanwhile, the JNK binding domain on c-Jun is not required for its interaction with ERK kinases. Radiation-induced reactive oxygen species (ROS) potentially contribute to c-Jun phosphorylation through activating the ERK pathway. Radiation stimulates c-Jun transcriptional activity and upregulates c-Jun-regulated proinflammatory genes, such as tumor necrosis factor-α, interleukin-1β, and cyclooxygenase-2. Pharmacologic blockade of the ERK signaling pathway interferes with c-Jun activity and inhibits radiation-stimulated expression of c-Jun target genes. Overall, our study reveals that the MEK-ERK1/2 signaling pathway, but not the JNK pathway, contributes to the c-Jun-dependent microglial inflammatory response following irradiation.
authors.affiliation: Department of Radiation Oncology and Brain Tumor Center of Excellence, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Deng
authors.forename: Guangchao
authors.initials: G
authors.lastname: Sui
authors.forename: Paulo Mottin
authors.initials: PM
authors.lastname: Rosa
authors.forename: Weiling
authors.initials: W
authors.lastname: Zhao
mesh_terms: D000818:Animals; D001483:Base Sequence; D001930:Brain Injuries / Q000201:enzymology / Q000209:etiology; D002070:Butadienes / Q000494:pharmacology; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D004789:Enzyme Activation / Q000528:radiation effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000201:enzymology / Q000209:etiology; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000528:radiation effects; D051379:Mice; D017628:Microglia / Q000201:enzymology* / Q000528:radiation effects*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011833:Radiation Injuries, Experimental / Q000201:enzymology / Q000209:etiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D002070:Butadienes; D017931:DNA Primers; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; C113580:U 0126; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases