title: DJ-1 induces thioredoxin 1 expression through the Nrf2 pathway.
abstract: DJ-1, which is linked to recessively inherited Parkinson's disease when mutated, is a multi-functional protein with anti-oxidant and transcription regulatory activities. However, the mechanism(s) through which DJ-1 and the genes it regulates provide neuroprotection is not fully understood. Here, we show that wild-type DJ-1 induces the expression of thioredoxin 1 (Trx1), a protein disulfide oxidoreductase, whereas pathogenic mutant isoforms L166P and M26I cannot. Conversely, DJ-1 knockdown in SH-SY5Y cells and DJ-1 knockout in mice result in significant decrease in Trx1 protein and mRNA expression levels. The importance of Trx1 in the cytoprotective function of DJ-1 is confirmed using a pharmacological inhibitor of Trx reductase, 1-chloro-2,4-dinitrobenzene, and Trx1 siRNA. Both approaches result in partial loss of DJ-1-mediated protection. Additionally, knockdown of Trx1 significantly abrogates DJ-1-dependent, hydrogen peroxide-induced activation of the pro-survival factor AKT. Promoter analysis of the human Trx1 gene identified an antioxidant response element (ARE) that is required for DJ-1-dependent induction of Trx1 expression. The transcription factor Nuclear factor erythroid-2 related factor 2 (Nrf2), which is a critical inducer of ARE-mediated expression, is regulated by DJ-1. Overexpression of DJ-1 results in increased Nrf2 protein levels, promotes its translocation into the nucleus and enhances its recruitment onto the ARE site in the Trx1 promoter. Further, Nrf2 knockdown abolishes DJ-1-mediated Trx1 induction and cytoprotection against hydrogen peroxide, indicating the critical role of Nrf2 in carrying out the protective functions of DJ-1 against oxidative stress. These findings provide a new mechanism to support the antioxidant function of DJ-1 by increasing Trx1 expression via Nrf2-mediated transcriptional induction.
authors.affiliation: Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
authors.forename: Joo-Young
authors.initials: JY
authors.lastname: Im
authors.forename: Kang-Woo
authors.initials: KW
authors.lastname: Lee
authors.forename: Jong-Min
authors.initials: JM
authors.lastname: Woo
authors.forename: Eunsung
authors.initials: E
authors.lastname: Junn
authors.forename: M Maral
authors.initials: MM
authors.lastname: Mouradian
mesh_terms: D000818:Animals; D000975:Antioxidants; D045744:Cell Line, Tumor; D019610:Cytoprotection; D004137:Dinitrochlorobenzene / Q000494:pharmacology; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000071617:Protein Deglycase DJ-1; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D020218:Response Elements; D015398:Signal Transduction; D013879:Thioredoxins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000975:Antioxidants; D004137:Dinitrochlorobenzene; D047908:Intracellular Signaling Peptides and Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D015513:Oncogene Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D013879:Thioredoxins; D006861:Hydrogen Peroxide; D051057:Proto-Oncogene Proteins c-akt; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1