title: Lipopolysaccharide downregulates the expression of p53 through activation of MDM2 and enhances activation of nuclear factor-kappa B.
abstract: The effect of lipopolysaccharide (LPS) on the expression of p53 protein in RAW 264.7 macrophage cells was examined. LPS downregulated the expression of p53 protein 4-24 h after the stimulation. LPS-induced p53 inhibition was restored with pharmacological inhibitors of c-jun N-terminal kinase (JNK) and phosphatidylinositol 3-kinase (PI3K). It was also restored by inhibitors of MDM2 activation and proteasome. LPS-induced p53 inhibition corresponded to activation of MDM2. LPS-induced MDM2 activation was prevented by inhibitors of JNK and PI3K. The expression of p65 NF-κB at a late stage after LPS stimulation was downregulated in the presence of a MDM2 inhibitor. Nutlin-3 as a MDM2 inhibitor reduced LPS-induced production of nitric oxide but not tumor necrosis factor-α. Administration of LPS into mice downregulated the in vivo expression of p53 in the livers. Taken together, LPS was suggested to downregulate the expression of p53 via activation of MDM2 and enhance the activation of NF-κB at a late stage.
authors.affiliation: Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Nagakute, Aichi 480-1195, Japan; Departments of Anatomy, Mongolian National University of Medical Sciences, Ulaanbaatar 210648, Mongolia. Electronic address: zayamgl@aichi-med-u.ac.jp.
authors.forename: Erdenezaya
authors.initials: E
authors.lastname: Odkhuu
authors.affiliation: Oncology, Mongolian National University of Medical Sciences, Ulaanbaatar 210648, Mongolia.
authors.forename: Adilsaikhan
authors.initials: A
authors.lastname: Mendjargal
authors.affiliation: Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Nagakute, Aichi 480-1195, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Koide
authors.affiliation: Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Nagakute, Aichi 480-1195, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Naiki
authors.affiliation: Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Nagakute, Aichi 480-1195, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Komatsu
authors.affiliation: Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Nagakute, Aichi 480-1195, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yokochi
mesh_terms: D000818:Animals; D002460:Cell Line; D007093:Imidazoles / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology* / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D007093:Imidazoles; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D009569:Nitric Oxide; C482205:nutlin 3; D051736:Proto-Oncogene Proteins c-mdm2; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: Lipopolysaccharide; MDM2; NF-κB; Nutlin-3; P53