Regulation of the VHL/HIF-1 pathway by DJ-1.
Identifieur interne : 000947 ( Main/Exploration ); précédent : 000946; suivant : 000948Regulation of the VHL/HIF-1 pathway by DJ-1.
Auteurs : Mohammad Parsanejad ; Yi Zhang ; Dianbo Qu ; Isabella Irrcher [Canada] ; Maxime W C. Rousseaux ; Hossein Aleyasin ; Fatemeh Kamkar ; Steve Callaghan ; Ruth S. Slack ; Tak W. Mak ; Stephen Lee ; Daniel Figeys [Canada] ; David S. Park [Canada]Source :
- The Journal of neuroscience : the official journal of the Society for Neuroscience [ 1529-2401 ] ; 2014.
English descriptors
- KwdEn :
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (pharmacology), Animals, Cells, Cultured, Embryo, Mammalian, Female, Gene Expression Regulation (drug effects), Gene Expression Regulation (genetics), Humans, Hypoxia-Inducible Factor 1, alpha Subunit (genetics), Hypoxia-Inducible Factor 1, alpha Subunit (metabolism), Male, Mice, Mice, Knockout, Neuroblastoma (pathology), Neurons (drug effects), Neurons (metabolism), Neurotoxins (pharmacology), Oncogene Proteins (deficiency), Oncogene Proteins (metabolism), Oxidative Stress (drug effects), Oxidative Stress (genetics), Parkinson Disease (pathology), Peroxiredoxins, Protein Deglycase DJ-1, Signal Transduction (drug effects), Signal Transduction (physiology), Time Factors, Von Hippel-Lindau Tumor Suppressor Protein (genetics), Von Hippel-Lindau Tumor Suppressor Protein (metabolism).
- MESH :
- chemical , deficiency : Oncogene Proteins.
- chemical , genetics : Hypoxia-Inducible Factor 1, alpha Subunit, Von Hippel-Lindau Tumor Suppressor Protein.
- chemical , metabolism : Hypoxia-Inducible Factor 1, alpha Subunit, Oncogene Proteins, Von Hippel-Lindau Tumor Suppressor Protein.
- chemical , pharmacology : 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Neurotoxins.
- drug effects : Gene Expression Regulation, Neurons, Oxidative Stress, Signal Transduction.
- genetics : Gene Expression Regulation, Oxidative Stress.
- metabolism : Neurons.
- pathology : Neuroblastoma, Parkinson Disease.
- physiology : Signal Transduction.
- Animals, Cells, Cultured, Embryo, Mammalian, Female, Humans, Male, Mice, Mice, Knockout, Peroxiredoxins, Protein Deglycase DJ-1, Time Factors.
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.
DOI: 10.1523/JNEUROSCI.1244-13.2014
PubMed: 24899725
Affiliations:
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Mak</name><affiliation><nlm:affiliation>The Campbell Family Institute for Breast Cancer Research, Toronto, Ontario M5G 2C1, Canada, and.</nlm:affiliation><wicri:noCountry code="subField">and</wicri:noCountry></affiliation></author><author><name sortKey="Lee, Stephen" sort="Lee, Stephen" uniqKey="Lee S" first="Stephen" last="Lee">Stephen Lee</name><affiliation><nlm:affiliation>Department of Cellular and Molecular Medicine.</nlm:affiliation><wicri:noCountry code="no comma">Department of Cellular and Molecular Medicine.</wicri:noCountry></affiliation></author><author><name sortKey="Figeys, Daniel" sort="Figeys, Daniel" uniqKey="Figeys D" first="Daniel" last="Figeys">Daniel Figeys</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Systems Biology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Institute of Systems Biology, University of Ottawa, Ottawa, Ontario K1H 8M5</wicri:regionArea><wicri:noRegion>Ontario K1H 8M5</wicri:noRegion></affiliation></author><author><name sortKey="Park, David S" sort="Park, David S" uniqKey="Park D" first="David S" last="Park">David S. Park</name><affiliation wicri:level="1"><nlm:affiliation>Department of Cellular and Molecular Medicine, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735, Korea dpark@uottawa.ca.</nlm:affiliation><country wicri:rule="url">Canada</country><wicri:regionArea>Department of Cellular and Molecular Medicine, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735</wicri:regionArea><wicri:noRegion>Busan 609-735</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2014">2014</date><idno type="RBID">pubmed:24899725</idno><idno type="pmid">24899725</idno><idno type="doi">10.1523/JNEUROSCI.1244-13.2014</idno><idno type="wicri:Area/PubMed/Corpus">000733</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000733</idno><idno type="wicri:Area/PubMed/Curation">000733</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000733</idno><idno type="wicri:Area/PubMed/Checkpoint">000733</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000733</idno><idno type="wicri:Area/Ncbi/Merge">001784</idno><idno type="wicri:Area/Ncbi/Curation">001784</idno><idno type="wicri:Area/Ncbi/Checkpoint">001784</idno><idno type="wicri:Area/Main/Merge">000949</idno><idno type="wicri:Area/Main/Curation">000947</idno><idno type="wicri:Area/Main/Exploration">000947</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Regulation of the VHL/HIF-1 pathway by DJ-1.</title><author><name sortKey="Parsanejad, Mohammad" sort="Parsanejad, Mohammad" uniqKey="Parsanejad M" first="Mohammad" last="Parsanejad">Mohammad Parsanejad</name><affiliation><nlm:affiliation>Department of Cellular and Molecular Medicine.</nlm:affiliation><wicri:noCountry code="no comma">Department of Cellular and Molecular Medicine.</wicri:noCountry></affiliation></author><author><name sortKey="Zhang, Yi" sort="Zhang, Yi" uniqKey="Zhang Y" first="Yi" last="Zhang">Yi Zhang</name><affiliation><nlm:affiliation>Department of Cellular and Molecular Medicine.</nlm:affiliation><wicri:noCountry code="no comma">Department of Cellular and Molecular Medicine.</wicri:noCountry></affiliation></author><author><name sortKey="Qu, Dianbo" sort="Qu, Dianbo" uniqKey="Qu D" first="Dianbo" last="Qu">Dianbo Qu</name><affiliation><nlm:affiliation>Department of Cellular and Molecular Medicine.</nlm:affiliation><wicri:noCountry code="no comma">Department of Cellular and Molecular Medicine.</wicri:noCountry></affiliation></author><author><name sortKey="Irrcher, Isabella" sort="Irrcher, Isabella" uniqKey="Irrcher I" first="Isabella" last="Irrcher">Isabella Irrcher</name><affiliation wicri:level="1"><nlm:affiliation>Department of Cellular and Molecular Medicine, Department of Ophthalmology, Queen's University, Kingston, Ontario K7L 5G2, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Cellular and Molecular Medicine, Department of Ophthalmology, Queen's University, Kingston, Ontario K7L 5G2</wicri:regionArea><wicri:noRegion>Ontario K7L 5G2</wicri:noRegion></affiliation></author><author><name sortKey="Rousseaux, Maxime W C" sort="Rousseaux, Maxime W C" uniqKey="Rousseaux M" first="Maxime W C" last="Rousseaux">Maxime W C. Rousseaux</name><affiliation><nlm:affiliation>Department of Cellular and Molecular Medicine.</nlm:affiliation><wicri:noCountry code="no comma">Department of Cellular and Molecular Medicine.</wicri:noCountry></affiliation></author><author><name sortKey="Aleyasin, Hossein" sort="Aleyasin, Hossein" uniqKey="Aleyasin H" first="Hossein" last="Aleyasin">Hossein Aleyasin</name><affiliation><nlm:affiliation>Department of Cellular and Molecular Medicine.</nlm:affiliation><wicri:noCountry code="no comma">Department of Cellular and Molecular Medicine.</wicri:noCountry></affiliation></author><author><name sortKey="Kamkar, Fatemeh" sort="Kamkar, Fatemeh" uniqKey="Kamkar F" first="Fatemeh" last="Kamkar">Fatemeh Kamkar</name><affiliation><nlm:affiliation>Department of Cellular and Molecular Medicine.</nlm:affiliation><wicri:noCountry code="no comma">Department of Cellular and Molecular Medicine.</wicri:noCountry></affiliation></author><author><name sortKey="Callaghan, Steve" sort="Callaghan, Steve" uniqKey="Callaghan S" first="Steve" last="Callaghan">Steve Callaghan</name><affiliation><nlm:affiliation>Department of Cellular and Molecular Medicine.</nlm:affiliation><wicri:noCountry code="no comma">Department of Cellular and Molecular Medicine.</wicri:noCountry></affiliation></author><author><name sortKey="Slack, Ruth S" sort="Slack, Ruth S" uniqKey="Slack R" first="Ruth S" last="Slack">Ruth S. Slack</name><affiliation><nlm:affiliation>Department of Cellular and Molecular Medicine.</nlm:affiliation><wicri:noCountry code="no comma">Department of Cellular and Molecular Medicine.</wicri:noCountry></affiliation></author><author><name sortKey="Mak, Tak W" sort="Mak, Tak W" uniqKey="Mak T" first="Tak W" last="Mak">Tak W. Mak</name><affiliation><nlm:affiliation>The Campbell Family Institute for Breast Cancer Research, Toronto, Ontario M5G 2C1, Canada, and.</nlm:affiliation><wicri:noCountry code="subField">and</wicri:noCountry></affiliation></author><author><name sortKey="Lee, Stephen" sort="Lee, Stephen" uniqKey="Lee S" first="Stephen" last="Lee">Stephen Lee</name><affiliation><nlm:affiliation>Department of Cellular and Molecular Medicine.</nlm:affiliation><wicri:noCountry code="no comma">Department of Cellular and Molecular Medicine.</wicri:noCountry></affiliation></author><author><name sortKey="Figeys, Daniel" sort="Figeys, Daniel" uniqKey="Figeys D" first="Daniel" last="Figeys">Daniel Figeys</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Systems Biology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Institute of Systems Biology, University of Ottawa, Ottawa, Ontario K1H 8M5</wicri:regionArea><wicri:noRegion>Ontario K1H 8M5</wicri:noRegion></affiliation></author><author><name sortKey="Park, David S" sort="Park, David S" uniqKey="Park D" first="David S" last="Park">David S. Park</name><affiliation wicri:level="1"><nlm:affiliation>Department of Cellular and Molecular Medicine, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735, Korea dpark@uottawa.ca.</nlm:affiliation><country wicri:rule="url">Canada</country><wicri:regionArea>Department of Cellular and Molecular Medicine, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735</wicri:regionArea><wicri:noRegion>Busan 609-735</wicri:noRegion></affiliation></author></analytic><series><title level="j">The Journal of neuroscience : the official journal of the Society for Neuroscience</title><idno type="eISSN">1529-2401</idno><imprint><date when="2014" type="published">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (pharmacology)</term><term>Animals</term><term>Cells, Cultured</term><term>Embryo, Mammalian</term><term>Female</term><term>Gene Expression Regulation (drug effects)</term><term>Gene Expression Regulation (genetics)</term><term>Humans</term><term>Hypoxia-Inducible Factor 1, alpha Subunit (genetics)</term><term>Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)</term><term>Male</term><term>Mice</term><term>Mice, Knockout</term><term>Neuroblastoma (pathology)</term><term>Neurons (drug effects)</term><term>Neurons (metabolism)</term><term>Neurotoxins (pharmacology)</term><term>Oncogene Proteins (deficiency)</term><term>Oncogene Proteins (metabolism)</term><term>Oxidative Stress (drug effects)</term><term>Oxidative Stress (genetics)</term><term>Parkinson Disease (pathology)</term><term>Peroxiredoxins</term><term>Protein Deglycase DJ-1</term><term>Signal Transduction (drug effects)</term><term>Signal Transduction (physiology)</term><term>Time Factors</term><term>Von Hippel-Lindau Tumor Suppressor Protein (genetics)</term><term>Von Hippel-Lindau Tumor Suppressor Protein (metabolism)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="deficiency" xml:lang="en"><term>Oncogene Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Hypoxia-Inducible Factor 1, alpha Subunit</term><term>Von Hippel-Lindau Tumor Suppressor Protein</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Hypoxia-Inducible Factor 1, alpha Subunit</term><term>Oncogene Proteins</term><term>Von Hippel-Lindau Tumor Suppressor Protein</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine</term><term>Neurotoxins</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Gene Expression Regulation</term><term>Neurons</term><term>Oxidative Stress</term><term>Signal Transduction</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Gene Expression Regulation</term><term>Oxidative Stress</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Neurons</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Neuroblastoma</term><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Signal Transduction</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Cells, Cultured</term><term>Embryo, Mammalian</term><term>Female</term><term>Humans</term><term>Male</term><term>Mice</term><term>Mice, Knockout</term><term>Peroxiredoxins</term><term>Protein Deglycase DJ-1</term><term>Time Factors</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><affiliations><list><country><li>Canada</li></country></list><tree><noCountry><name sortKey="Aleyasin, Hossein" sort="Aleyasin, Hossein" uniqKey="Aleyasin H" first="Hossein" last="Aleyasin">Hossein Aleyasin</name><name sortKey="Callaghan, Steve" sort="Callaghan, Steve" uniqKey="Callaghan S" first="Steve" last="Callaghan">Steve Callaghan</name><name sortKey="Kamkar, Fatemeh" sort="Kamkar, Fatemeh" uniqKey="Kamkar F" first="Fatemeh" last="Kamkar">Fatemeh Kamkar</name><name sortKey="Lee, Stephen" sort="Lee, Stephen" uniqKey="Lee S" first="Stephen" last="Lee">Stephen Lee</name><name sortKey="Mak, Tak W" sort="Mak, Tak W" uniqKey="Mak T" first="Tak W" last="Mak">Tak W. Mak</name><name sortKey="Parsanejad, Mohammad" sort="Parsanejad, Mohammad" uniqKey="Parsanejad M" first="Mohammad" last="Parsanejad">Mohammad Parsanejad</name><name sortKey="Qu, Dianbo" sort="Qu, Dianbo" uniqKey="Qu D" first="Dianbo" last="Qu">Dianbo Qu</name><name sortKey="Rousseaux, Maxime W C" sort="Rousseaux, Maxime W C" uniqKey="Rousseaux M" first="Maxime W C" last="Rousseaux">Maxime W C. Rousseaux</name><name sortKey="Slack, Ruth S" sort="Slack, Ruth S" uniqKey="Slack R" first="Ruth S" last="Slack">Ruth S. Slack</name><name sortKey="Zhang, Yi" sort="Zhang, Yi" uniqKey="Zhang Y" first="Yi" last="Zhang">Yi Zhang</name></noCountry><country name="Canada"><noRegion><name sortKey="Irrcher, Isabella" sort="Irrcher, Isabella" uniqKey="Irrcher I" first="Isabella" last="Irrcher">Isabella Irrcher</name></noRegion><name sortKey="Figeys, Daniel" sort="Figeys, Daniel" uniqKey="Figeys D" first="Daniel" last="Figeys">Daniel Figeys</name><name sortKey="Park, David S" sort="Park, David S" uniqKey="Park D" first="David S" last="Park">David S. Park</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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