title: Oxidized DJ-1 inhibits p53 by sequestering p53 from promoters in a DNA-binding affinity-dependent manner.
abstract: DJ-1 is an oncogene and the causative gene for familial Parkinson's disease. Although the oxidative status of DJ-1 at cysteine 106 (C106) is thought to affect all of the activities of DJ-1 and excess oxidation leads to the onset of various diseases, the precise molecular mechanisms underlying the effects of oxidation of DJ-1 on protein-protein interactions of DJ-1 remain unclear. In this study, we found that DJ-1 bound to the DNA-binding region of p53 in a manner dependent on the oxidation of C106. Of the p53 target genes, the expression level and promoter activity of the DUSP1 gene, but not those of the p21 gene, were increased in H(2)O(2)-treated DJ-1(-/-) cells and were decreased in wild-type DJ-1- but not C106S DJ-1-transfected H1299 cells through sequestration of p53 from the DUSP1 promoter by DJ-1. DUSP1 downregulated by oxidized DJ-1 activated extracellular signal-regulated kinase (ERK) and decreased apoptosis. The DUSP1 and p21 promoters harbor nonconsensus and consensus p53 recognition sequences, respectively, which have low affinity and high affinity for p53. However, DJ-1 inhibited p21 promoter activity exhibited by p53 mutants harboring low DNA-binding affinity but not by wild-type p53. These results indicate that DJ-1 inhibits the expression of p53 target genes and depend on p53 DNA-binding affinity and oxidation of DJ-1 C106.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo, Japan.
authors.forename: Izumi
authors.initials: I
authors.lastname: Kato
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maita
authors.forename: Kazuko
authors.initials: K
authors.lastname: Takahashi-Niki
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Saito
authors.forename: Noriko
authors.initials: N
authors.lastname: Noguchi
authors.forename: Sanae M M
authors.initials: SM
authors.lastname: Iguchi-Ariga
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Ariga
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003545:Cysteine / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D006861:Hydrogen Peroxide; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000235:genetics / Q000503:physiopathology; D011401:Promoter Regions, Genetic; D000071617:Protein Deglycase DJ-1; D060888:Real-Time Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D006861:Hydrogen Peroxide; D048049:Extracellular Signal-Regulated MAP Kinases; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D003545:Cysteine