title: Activation of NF-kappaB via a Src-dependent Ras-MAPK-pp90rsk pathway is required for Pseudomonas aeruginosa-induced mucin overproduction in epithelial cells.
abstract: Cystic fibrosis (CF) is an autosomal recessive disorder, the most common lethal genetic disease in Caucasians. Respiratory disease is the major cause of morbidity and mortality. Indeed, 95% of CF patients die of respiratory failure. Pseudomonas aeruginosa, an opportunistic pathogen, chronically infects the lungs of over 85% of CF patients. It is ineradicable by antibiotics and responsible for airway mucus overproduction that contributes to airway obstruction and death. The molecular mechanisms underlying this pathology are unknown. Here we show that P. aeruginosa activates a c-Src-Ras-MEK1/2-MAPK-pp90rsk signaling pathway that leads to activation of nuclear factor NF-kappaB (p65/p50). Activated NF-kappaB binds to a kappaB site in the 5'-flanking region of the MUC2 gene and activates MUC2 mucin transcription. These studies bring new insight into bacterial-epithelial interactions and more specifically into the molecular pathogenesis of cystic fibrosis. Understanding these signaling and gene regulatory mechanisms opens up new therapeutic targets for cystic fibrosis.
authors.affiliation: Department of Anatomy, Program in Biomedical Sciences, and Cardiovascular Research Institute, University of California, San Francisco, CA 94143, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Li
authors.forename: W
authors.initials: W
authors.lastname: Feng
authors.forename: M
authors.initials: M
authors.lastname: Gallup
authors.forename: J H
authors.initials: JH
authors.lastname: Kim
authors.forename: J
authors.initials: J
authors.lastname: Gum
authors.forename: Y
authors.initials: Y
authors.lastname: Kim
authors.forename: C
authors.initials: C
authors.lastname: Basbaum
mesh_terms: D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002478:Cells, Cultured; D003550:Cystic Fibrosis / Q000378:metabolism / Q000382:microbiology; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology*; D017930:Genes, Reporter; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics; D008954:Models, Biological; D009077:Mucins / Q000096:biosynthesis* / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011552:Pseudomonas Infections / Q000378:metabolism*; D011550:Pseudomonas aeruginosa; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D008070:Lipopolysaccharides; D009077:Mucins; D016328:NF-kappa B; D008156:Luciferases; D019893:Ribosomal Protein S6 Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases