Journal Article

Radiation-Induced c-Jun Activation Depends on MEK1-ERK1/2 Signaling Pathway in Microglial Cells

Rosa, Paulo Mottin, Deng, Zhiyong, Zhao, Weiling, Sui, Guangchao

2012

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Activation / Activator protein 1 / Animals / Apoptosis / Base Sequence / Biology / Brain / Brain cancer / Brain injuries / Brain Injuries - enzymology / Brain Injuries - etiology / Brain injury / Butadienes - pharmacology / c-Jun protein / Cell death / Cell Line / Cyclooxygenase-2 / Cytokines / Deoxyribonucleic acid / DNA / DNA binding proteins / DNA Primers - genetics / Enzyme Activation - radiation effects / Extracellular signal-regulated kinase / Extracellular Signal-Regulated MAP Kinases - genetics / Extracellular Signal-Regulated MAP Kinases - metabolism / Fibroblasts / Gene expression / Genes / Genetic research / Head injuries / Inflammation / Inflammation - enzymology / Inflammation - etiology / Inflammatory response / Interleukin / Interleukins / Ionizing radiation / Irradiation / JNK Mitogen-Activated Protein Kinases - genetics / JNK Mitogen-Activated Protein Kinases - metabolism / Kinases / MAP kinase / MAP Kinase Signaling System - drug effects / MAP Kinase Signaling System - radiation effects / Medicine / Metabolic pathways / Mice / Microglia / Microglia - enzymology / Microglia - radiation effects / Microglial cells / Neurogenesis / Nitric oxide / Nitriles - pharmacology / Oncology / Oxidative stress / Oxygen / Pharmacology / Phosphorylation / Phosphotransferases / Protein Kinase Inhibitors - pharmacology / Proteins / Radiation / Radiation effects / Radiation injuries / Radiation Injuries, Experimental - enzymology / Radiation Injuries, Experimental - etiology / Radiation therapy / Radiotherapy / Reactive oxygen species / Reactive Oxygen Species - metabolism / Recombinant Fusion Proteins - genetics / Recombinant Fusion Proteins - metabolism / Rodents / Serine / Signal transduction / Signaling / Smooth muscle / TNF inhibitors / Transcription (Genetics) / Transcription factors / Transcription, Genetic / Traumatic brain injury / Tumor necrosis factor-TNF / Tumor necrosis factor-α