title: Regulation of the VHL/HIF-1 pathway by DJ-1.
abstract: DJ-1 (PARK7) is a gene linked to autosomal recessive Parkinson disease (PD). We showed previously that DJ-1 loss sensitizes neurons in models of PD and stroke. However, the biochemical mechanisms underlying this protective role are not completely clear. Here, we identify Von Hippel Lindau (VHL) protein as a critical DJ-1-interacting protein. We provide evidence that DJ-1 negatively regulates VHL ubiquitination activity of the α-subunit of hypoxia-inducible factor-1 (HIF-1α) by inhibiting HIF-VHL interaction. Consistent with this observation, DJ-1 deficiency leads to lowered HIF-1α levels in models of both hypoxia and oxidative stress, two stresses known to stabilize HIF-1α. We also demonstrate that HIF-1α accumulation rescues DJ-1-deficient neurons against 1-methyl-4-phenylpyridinium-induced toxicity. Interestingly, lymphoblast cells extracted from DJ-1-related PD patients show impaired HIF-1α stabilization when compared with normal individuals, indicating that the DJ-1-VHL link may also be relevant to a human context. Together, our findings delineate a model by which DJ-1 mediates neuronal survival by regulation of the VHL-HIF-1α pathway.
authors.affiliation: Department of Cellular and Molecular Medicine.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Parsanejad
authors.affiliation: Department of Cellular and Molecular Medicine.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Cellular and Molecular Medicine.
authors.forename: Dianbo
authors.initials: D
authors.lastname: Qu
authors.affiliation: Department of Cellular and Molecular Medicine, Department of Ophthalmology, Queen's University, Kingston, Ontario K7L 5G2, Canada.
authors.forename: Isabella
authors.initials: I
authors.lastname: Irrcher
authors.affiliation: Department of Cellular and Molecular Medicine.
authors.forename: Maxime W C
authors.initials: MW
authors.lastname: Rousseaux
authors.affiliation: Department of Cellular and Molecular Medicine.
authors.forename: Hossein
authors.initials: H
authors.lastname: Aleyasin
authors.affiliation: Department of Cellular and Molecular Medicine.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Kamkar
authors.affiliation: Department of Cellular and Molecular Medicine.
authors.forename: Steve
authors.initials: S
authors.lastname: Callaghan
authors.affiliation: Department of Cellular and Molecular Medicine.
authors.forename: Ruth S
authors.initials: RS
authors.lastname: Slack
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Toronto, Ontario M5G 2C1, Canada, and.
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.affiliation: Department of Cellular and Molecular Medicine.
authors.forename: Stephen
authors.initials: S
authors.lastname: Lee
authors.affiliation: Institute of Systems Biology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
authors.forename: Daniel
authors.identifier: http://orcid.org/0000-0002-5373-7546
authors.initials: D
authors.lastname: Figeys
authors.affiliation: Department of Cellular and Molecular Medicine, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735, Korea dpark@uottawa.ca.
authors.forename: David S
authors.initials: DS
authors.lastname: Park
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009447:Neuroblastoma / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009498:Neurotoxins / Q000494:pharmacology; D015513:Oncogene Proteins / Q000172:deficiency / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D010300:Parkinson Disease / Q000473:pathology; D054464:Peroxiredoxins; D000071617:Protein Deglycase DJ-1; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009498:Neurotoxins; D015513:Oncogene Proteins; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D054464:Peroxiredoxins; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1
keywords: DJ-1; Parkinson's disease; oxidative stress