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Article ; Online: Selective HIF-1 Regulation under Nonhypoxic Conditions by the p42/p44 MAP Kinase Inhibitor PD184161.

Jalouli, Maroua / Mokas, Sophie / Turgeon, Catherine A / Lamalice, Laurent / Richard, Darren E

2017 Volume 92, Issue 5, Page(s) 510–518

Abstract: Hypoxia-inducible factor-1 (HIF-1) is a key gene regulator for cellular adaptation to low oxygen. In addition to hypoxia, several nonhypoxic stimuli, including hormones and growth factors, are essential for cell-specific HIF-1 regulation. Our studies ... ...

Abstract	Hypoxia-inducible factor-1 (HIF-1) is a key gene regulator for cellular adaptation to low oxygen. In addition to hypoxia, several nonhypoxic stimuli, including hormones and growth factors, are essential for cell-specific HIF-1 regulation. Our studies have highlighted angiotensin II (AngII), a vasoactive hormone, as a potent HIF-1 activator in vascular smooth muscle cells (VSMC). AngII increases HIF-1 transcriptional activity by modulating specific signaling pathways. In VSMC, p42/p44 mitogen-activated protein kinase (MAPK) pathway activation is essential for HIF-1-mediated transcription during AngII treatment. The present study shows that PD184161, a potent MEK1/2 inhibitor, is an HIF-1 blocker in Ang II-treated VSMC. Unlike PD98059, a widely-used MEK1/2 inhibitor, we found that PD184161 blocked AngII-driven HIF-1
MeSH term(s)	Aniline Compounds/pharmacology ; Animals ; Aorta, Thoracic/drug effects ; Aorta, Thoracic/metabolism ; Benzamides/pharmacology ; Cells, Cultured ; Dose-Response Relationship, Drug ; Hypoxia-Inducible Factor 1/antagonists & inhibitors ; Hypoxia-Inducible Factor 1/physiology ; Mitogen-Activated Protein Kinase 1/antagonists & inhibitors ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/antagonists & inhibitors ; Mitogen-Activated Protein Kinase 3/metabolism ; Protein Kinase Inhibitors/pharmacology ; Rats ; Rats, Wistar
Chemical Substances	2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluoro-5-bromobenzamide ; Aniline Compounds ; Benzamides ; Hypoxia-Inducible Factor 1 ; Protein Kinase Inhibitors ; Mitogen-Activated Protein Kinase 1 (EC 2.7.11.24) ; Mitogen-Activated Protein Kinase 3 (EC 2.7.11.24)
Language	English
Publishing date	2017-08-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	124034-1
ISSN	1521-0111 ; 0026-895X
ISSN (online)	1521-0111
ISSN	0026-895X
DOI	10.1124/mol.117.108654
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Article ; Online: Hypoxia-inducible factor-1 plays a role in phosphate-induced vascular smooth muscle cell calcification.

Mokas, Sophie / Larivière, Richard / Lamalice, Laurent / Gobeil, Stéphane / Cornfield, David N / Agharazii, Mohsen / Richard, Darren E

Kidney international

2016 Volume 90, Issue 3, Page(s) 598–609

Abstract: Medial vascular calcification is a common complication of chronic kidney disease (CKD). Although elevated inorganic phosphate stimulates vascular smooth muscle cell (VSMC) osteogenic transdifferentiation and calcification, the mechanisms involved in ... ...

Abstract	Medial vascular calcification is a common complication of chronic kidney disease (CKD). Although elevated inorganic phosphate stimulates vascular smooth muscle cell (VSMC) osteogenic transdifferentiation and calcification, the mechanisms involved in their calcification during CKD are not fully defined. Because hypoxic gene activation is linked to CKD and stimulates bone cell osteogenic differentiation, we used in vivo and in vitro rodent models to define the role of hypoxic signaling during elevated inorganic phosphate-induced VSMC calcification. Cell mineralization studies showed that elevated inorganic phosphate rapidly induced VSMC calcification. Hypoxia strongly enhanced elevated inorganic phosphate-induced VSMC calcification and osteogenic transdifferentiation, as seen by osteogenic marker expression. Hypoxia-inducible factor-1 (HIF-1), the key hypoxic transcription factor, was essential for enhanced VSMC calcification. Targeting HIF-1 expression in murine VSMC blocked calcification in hypoxia with elevated inorganic phosphate while HIF-1 activators, including clinically used FG-4592/Roxadustat, recreated a procalcifying environment. Elevated inorganic phosphate rapidly activated HIF-1, even in normal oxygenation; an effect mediated by HIF-1α subunit stabilization. Thus, hypoxia synergizes with elevated inorganic phosphate to enhance VSMC osteogenic transdifferentiation. Our work identifies HIF-1 as an early CKD-related pathological event, prospective marker, and potential target against vascular calcification in CKD-relevant conditions.
MeSH term(s)	Animals ; Biomarkers/metabolism ; Cell Transdifferentiation ; Cells, Cultured ; Disease Models, Animal ; Glycine/analogs & derivatives ; Glycine/pharmacology ; Humans ; Hypoxia/metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Immunohistochemistry ; Isoquinolines/pharmacology ; Male ; Muscle, Smooth, Vascular/cytology ; Muscle, Smooth, Vascular/metabolism ; Muscle, Smooth, Vascular/pathology ; Phosphates/metabolism ; Rats ; Rats, Wistar ; Renal Insufficiency, Chronic/complications ; Renal Insufficiency, Chronic/metabolism ; Signal Transduction ; Vascular Calcification/etiology ; Vascular Calcification/metabolism ; Vascular Stiffness
Chemical Substances	Biomarkers ; Hif1a protein, rat ; Hypoxia-Inducible Factor 1, alpha Subunit ; Isoquinolines ; Phosphates ; Glycine (TE7660XO1C) ; roxadustat (X3O30D9YMX)
Language	English
Publishing date	2016-07-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	120573-0
ISSN	1523-1755 ; 0085-2538
ISSN (online)	1523-1755
ISSN	0085-2538
DOI	10.1016/j.kint.2016.05.020
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Article ; Online: Endothelial cell migration during angiogenesis.

Lamalice, Laurent / Le Boeuf, Fabrice / Huot, Jacques

Circulation research

2007 Volume 100, Issue 6, Page(s) 782–794

Abstract: Endothelial cell migration is essential to angiogenesis. This motile process is directionally regulated by chemotactic, haptotactic, and mechanotactic stimuli and further involves degradation of the extracellular matrix to enable progression of the ... ...

Abstract	Endothelial cell migration is essential to angiogenesis. This motile process is directionally regulated by chemotactic, haptotactic, and mechanotactic stimuli and further involves degradation of the extracellular matrix to enable progression of the migrating cells. It requires the activation of several signaling pathways that converge on cytoskeletal remodeling. Then, it follows a series of events in which the endothelial cells extend, contract, and throw their rear toward the front and progress forward. The aim of this review is to give an integrative view of the signaling mechanisms that govern endothelial cell migration in the context of angiogenesis.
MeSH term(s)	Actins/metabolism ; Angiopoietins/physiology ; Animals ; Cell Movement/physiology ; Cytoskeleton/metabolism ; Endothelial Cells/cytology ; Endothelial Cells/physiology ; Extracellular Matrix/metabolism ; Humans ; Neovascularization, Physiologic/physiology ; Pericytes/physiology ; Signal Transduction/physiology
Chemical Substances	Actins ; Angiopoietins
Language	English
Publishing date	2007-03-30
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	80100-8
ISSN	1524-4571 ; 0009-7330 ; 0931-6876
ISSN (online)	1524-4571
ISSN	0009-7330 ; 0931-6876
DOI	10.1161/01.RES.0000259593.07661.1e
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Article: Phosphorylation of Tyr1214 within VEGFR-2 triggers the recruitment of Nck and activation of Fyn leading to SAPK2/p38 activation and endothelial cell migration in response to VEGF.

Lamalice, Laurent / Houle, François / Huot, Jacques

The Journal of biological chemistry

2006 Volume 281, Issue 45, Page(s) 34009–34020

Abstract: VEGFR-2 is the major receptor that regulates the different functions of VEGF in adults. We have previously reported that following VEGF treatment of endothelial cells, VEGFR-2 is phosphorylated on Tyr1214 upstream of the Cdc42-SAPK2/p38-MAPKAP K2 pathway. ...

Abstract	VEGFR-2 is the major receptor that regulates the different functions of VEGF in adults. We have previously reported that following VEGF treatment of endothelial cells, VEGFR-2 is phosphorylated on Tyr1214 upstream of the Cdc42-SAPK2/p38-MAPKAP K2 pathway. However, little is known of the earliest molecular events that compose the SAPK2/p38 pathway following VEGFR-2 activation. In this study, we address this question using HA-tagged constructs of either wild-type VEGFR-2 or Y1214F VEGFR-2 mutant in immunoprecipitation assays. We show that the Src family kinase member Fyn, but not c-Src itself, is recruited to VEGFR-2 and is activated in a p-Tyr1214-dependent manner. We also report that the SH2 domain-containing adapter molecule Nck, but not Grb2, is recruited to VEGFR-2 in a p-Tyr1214-dependent manner and that it associates with Fyn. Moreover, PAK-2 is phosphorylated in a Fyn-dependent manner. Using chemical and genetic inhibitors, we show that Fyn activity is required for SAPK2/p38 but not for FAK activation in response to VEGF. In contrast, c-Src permits activation of FAK, but not that of SAPK2/p38. In addition, Fyn is required for stress fiber formation and endothelial cell migration. We propose a model in which Fyn forms a molecular complex with Nck and PAK-2 and suggest that this complex assembles in a p-Tyr1214-dependent manner within VEGFR-2 following VEGF treatment. In turn, this triggers the activation of the SAPK2/p38 MAP kinase module, and promotes stress fiber formation and endothelial cell migration.
MeSH term(s)	Actins/metabolism ; Adaptor Proteins, Signal Transducing ; Animals ; Cell Movement ; Cells, Cultured ; Endothelium, Vascular/cytology ; Endothelium, Vascular/drug effects ; Endothelium, Vascular/metabolism ; Enzyme Activation ; Fluorescent Antibody Technique ; Humans ; Immunoprecipitation ; Mice ; Mitogen-Activated Protein Kinase 11/metabolism ; NIH 3T3 Cells ; Oncogene Proteins/metabolism ; Phosphorylation ; Proto-Oncogene Proteins c-fyn/metabolism ; Tyrosine/metabolism ; Umbilical Veins ; Vascular Endothelial Growth Factor A/pharmacology ; Vascular Endothelial Growth Factor Receptor-2/metabolism ; src-Family Kinases
Chemical Substances	Actins ; Adaptor Proteins, Signal Transducing ; Nck protein ; Oncogene Proteins ; VEGFA protein, human ; Vascular Endothelial Growth Factor A ; Tyrosine (42HK56048U) ; Vascular Endothelial Growth Factor Receptor-2 (EC 2.7.10.1) ; FYN protein, human (EC 2.7.10.2) ; Proto-Oncogene Proteins c-fyn (EC 2.7.10.2) ; src-Family Kinases (EC 2.7.10.2) ; Mitogen-Activated Protein Kinase 11 (EC 2.7.11.24)
Language	English
Publishing date	2006-09-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M603928200
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Article: Phosphorylation of Tyr¹²¹⁴ within VEGFR-2 Triggers the Recruitment of Nck and Activation of Fyn Leading to SAPK2/p38 Activation and Endothelial Cell Migration in Response to VEGF

Lamalice, Laurent / Houle, François / Huot, Jacques

Journal of biological chemistry. 2006 Nov. 10, v. 281, no. 45

2006

Abstract: VEGFR-2 is the major receptor that regulates the different functions of VEGF in adults. We have previously reported that following VEGF treatment of endothelial cells, VEGFR-2 is phosphorylated on Tyr¹²¹⁴ upstream of the Cdc42-SAPK2/p38-MAPKAP K2 pathway. ...

Abstract	VEGFR-2 is the major receptor that regulates the different functions of VEGF in adults. We have previously reported that following VEGF treatment of endothelial cells, VEGFR-2 is phosphorylated on Tyr¹²¹⁴ upstream of the Cdc42-SAPK2/p38-MAPKAP K2 pathway. However, little is known of the earliest molecular events that compose the SAPK2/p38 pathway following VEGFR-2 activation. In this study, we address this question using HA-tagged constructs of either wild-type VEGFR-2 or Y1214F VEGFR-2 mutant in immunoprecipitation assays. We show that the Src family kinase member Fyn, but not c-Src itself, is recruited to VEGFR-2 and is activated in a p~Tyr¹²¹⁴-dependent manner. We also report that the SH2 domain-containing adapter molecule Nck, but not Grb2, is recruited to VEGFR-2 in ap~Tyr¹²¹⁴-dependent manner and that it associates with Fyn. Moreover, PAK-2 is phosphorylated in a Fyn-dependent manner. Using chemical and genetic inhibitors, we show that Fyn activity is required for SAPK2/p38 but not for FAK activation in response to VEGF. In contrast, c-Src permits activation of FAK, but not that of SAPK2/p38. In addition, Fyn is required for stress fiber formation and endothelial cell migration. We propose a model in which Fyn forms a molecular complex with Nck and PAK-2 and suggest that this complex assembles in a p~Tyr¹²¹⁴-dependent manner within VEGFR-2 following VEGF treatment. In turn, this triggers the activation of the SAPK2/p38 MAP kinase module, and promotes stress fiber formation and endothelial cell migration.
Language	English
Dates of publication	2006-1110
Size	p. 34009-34020.
Publishing place	American Society for Biochemistry and Molecular Biology
Document type	Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
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Article ; Online: The prolyl isomerase Pin1 regulates hypoxia-inducible transcription factor (HIF) activity.

Jalouli, Maroua / Déry, Marc-André C / Lafleur, Véronique N / Lamalice, Laurent / Zhou, Xiao Zhen / Lu, Kun Ping / Richard, Darren E

Cellular signalling

2014 Volume 26, Issue 8, Page(s) 1649–1656

Abstract: Hypoxia-inducible transcription factor-1 (HIF-1) plays a decisive role in cell survival and adaptation to hypoxic stress by controlling the expression of genes involved in oxygen homeostasis. HIF-1 activity is fine-tuned through specific post- ... ...

Abstract	Hypoxia-inducible transcription factor-1 (HIF-1) plays a decisive role in cell survival and adaptation to hypoxic stress by controlling the expression of genes involved in oxygen homeostasis. HIF-1 activity is fine-tuned through specific post-translational modifications of its essential HIF-1α subunit. Among these modifications, phosphorylation is important for HIF-1 transcriptional activity. Studies have shown that the mitogen-activated protein kinases, p42/p44 MAPKs, directly phosphorylate HIF-1α and increase HIF-1-mediated transcription. Pin1, a peptidyl-prolyl cis/trans isomerase, targets a number of proteins containing a phosphorylated Ser/Thr-Pro motif. Pin1 isomerization causes a change in target protein conformation which can modify their activity. Here, we identify Pin1 as an important HIF-1α partner. Immunoprecipitation and pull-down studies show that Pin1 interacts with HIF-1α. We demonstrate that the interaction between Pin1 and HIF-1α is regulated through p42/p44 MAPK pathway activation. By performing proteolysis studies, our results indicate that Pin1 catalytic activity generates a conformational change in HIF-1α. Finally, our work shows that Pin1 is required for gene-specific HIF-1 transcriptional activity. Our results indicate that the prolyl isomerase Pin1 regulates HIF-1 transcriptional activity by interacting with HIF-1α and promoting conformational changes in a p42/p44 MAPK phosphorylation-dependent manner.
MeSH term(s)	Animals ; Cell Line ; HEK293 Cells ; HeLa Cells ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Mice ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/metabolism ; NIMA-Interacting Peptidylprolyl Isomerase ; Peptidylprolyl Isomerase/antagonists & inhibitors ; Peptidylprolyl Isomerase/genetics ; Peptidylprolyl Isomerase/metabolism ; Phosphorylation ; Protein Interaction Domains and Motifs ; RNA Interference ; RNA, Small Interfering/metabolism ; Transcription, Genetic
Chemical Substances	Hypoxia-Inducible Factor 1, alpha Subunit ; NIMA-Interacting Peptidylprolyl Isomerase ; RNA, Small Interfering ; Mitogen-Activated Protein Kinase 1 (EC 2.7.11.24) ; Mitogen-Activated Protein Kinase 3 (EC 2.7.11.24) ; PIN1 protein, human (EC 5.2.1.8) ; Peptidylprolyl Isomerase (EC 5.2.1.8) ; Pin1 protein, mouse (EC 5.2.1.8)
Language	English
Publishing date	2014-04-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1002702-6
ISSN	1873-3913 ; 0898-6568
ISSN (online)	1873-3913
ISSN	0898-6568
DOI	10.1016/j.cellsig.2014.04.005
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Article: Phosphorylation of tyrosine 1214 on VEGFR2 is required for VEGF-induced activation of Cdc42 upstream of SAPK2/p38.

Lamalice, Laurent / Houle, François / Jourdan, Guillaume / Huot, Jacques

Oncogene

2004 Volume 23, Issue 2, Page(s) 434–445

Abstract: Activation of the tyrosine kinase receptor vascular endothelial growth factor receptor 2 (VEGFR2) by VEGF leads to the activation of stress-activated protein kinase (SAPK)2/p38 and then to actin polymerization and reorganization into stress fibers in ... ...

Abstract	Activation of the tyrosine kinase receptor vascular endothelial growth factor receptor 2 (VEGFR2) by VEGF leads to the activation of stress-activated protein kinase (SAPK)2/p38 and then to actin polymerization and reorganization into stress fibers in endothelial cells. In turn, this triggers endothelial cell migration. Yet, nothing is known about the molecular mechanisms that couple VEGFR2 to SAPK2/p38. Here, we found that VEGF increased by twofold the activity of the small GTPase Cdc42 and that the expression of two different constitutively active forms of Cdc42 (Cdc42 V12 and Cdc42 L61) led to a marked increase in the formation of stress fibers that was sensitive to SAPK2/p38 inhibition by SB203580. Moreover, the expression of a dominant-negative form of Cdc42 (Cdc42 N17) inhibited the activation of SAPK2/p38 and of its direct target MAP kinase-activated protein kinase 2. These results indicate that Cdc42 is upstream of SAPK2/p38 in response to the activation of VEGFR2 by VEGF. In contrast, we found that neither RhoA nor Rac was involved in the SAPK2/p38-mediated actin reorganization induced by VEGF. Using a site-specific mutant of the major autophosphorylation site Y1214 on VEGFR2, we found that the mutant Y1214F inhibited the activation of both Cdc42 and SAPK2/p38 in response to VEGF. We conclude that phosphorylation of Y1214 on VEGFR2 is required to trigger the sequential activation of Cdc42 and SAPK2/p38 and to drive the SAPK2/p38-mediated actin remodeling in stress fibers in endothelial cells exposed to VEGF.
MeSH term(s)	Actins/metabolism ; Cells, Cultured ; Enzyme Activation/drug effects ; Humans ; Mitogen-Activated Protein Kinases/metabolism ; Models, Biological ; Phosphorylation/drug effects ; Phosphotyrosine/metabolism ; Signal Transduction/drug effects ; Stress Fibers/metabolism ; Vascular Endothelial Growth Factor A/pharmacology ; Vascular Endothelial Growth Factor Receptor-2/metabolism ; cdc42 GTP-Binding Protein/metabolism ; p38 Mitogen-Activated Protein Kinases ; rac1 GTP-Binding Protein/metabolism ; rhoA GTP-Binding Protein/metabolism
Chemical Substances	Actins ; Vascular Endothelial Growth Factor A ; Phosphotyrosine (21820-51-9) ; Vascular Endothelial Growth Factor Receptor-2 (EC 2.7.10.1) ; Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; p38 Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; cdc42 GTP-Binding Protein (EC 3.6.5.2) ; rac1 GTP-Binding Protein (EC 3.6.5.2) ; rhoA GTP-Binding Protein (EC 3.6.5.2)
Language	English
Publishing date	2004-01-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639046-8
ISSN	1476-5594 ; 0950-9232
ISSN (online)	1476-5594
ISSN	0950-9232
DOI	10.1038/sj.onc.1207034
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Article ; Online: The Werner syndrome gene product (WRN): a repressor of hypoxia-inducible factor-1 activity.

Labbé, Adam / Lafleur, Véronique N / Patten, David A / Robitaille, Geneviève A / Garand, Chantal / Lamalice, Laurent / Lebel, Michel / Richard, Darren E

Experimental cell research

2012 Volume 318, Issue 14, Page(s) 1620–1632

Abstract: Werner syndrome (WS) is a rare autosomal disease characterized by the premature onset of several age-associated pathologies. The protein defective in WS patients (WRN) is a helicase/exonuclease involved in DNA repair, replication, transcription and ... ...

Abstract	Werner syndrome (WS) is a rare autosomal disease characterized by the premature onset of several age-associated pathologies. The protein defective in WS patients (WRN) is a helicase/exonuclease involved in DNA repair, replication, transcription and telomere maintenance. Hypoxia-inducible factor-1 (HIF-1) is a decisive element for the transcriptional regulation of genes essential for adaptation to low oxygen conditions. HIF-1 is also implicated in the molecular mechanisms of ageing. Here, we show that the cellular depletion of WRN protein (by siRNA targeting) leads to increased HIF-1 complex stabilization and activation. HIF-1 activation in the absence of WRN involves the generation of mitochondrial reactive oxygen species (mtROS) since SkQ1, a mitochondrial-targeted antioxidant, and stigmatellin, an inhibitor of mitochondrial complex III, blocked increased HIF-1 levels. Ascorbate, an essential co-factor involved in HIF-1 stability, was decreased in WRN-depleted cells. Interestingly, expression levels of GLUT1, a known dehydroascorbic acid transporter, were also decreased in WRN-depleted cells. Ascorbate supplementation of WRN-depleted cells led to a dose-dependent inhibition of HIF-1 activation. These results indicate that WRN protein regulates HIF-1 activation by affecting mitochondrial ROS production and intracellular ascorbate levels. This work provides a novel mechanistic link between HIF-1 activity and different age-associated pathologies.
MeSH term(s)	Cells, Cultured ; Exodeoxyribonucleases/genetics ; Exodeoxyribonucleases/metabolism ; HeLa Cells ; Humans ; Intracellular Signaling Peptides and Proteins ; Mitochondria/metabolism ; Mitochondrial Proteins ; Neoplasm Proteins/metabolism ; Reactive Oxygen Species/metabolism ; RecQ Helicases/genetics ; RecQ Helicases/metabolism ; Werner Syndrome/genetics ; Werner Syndrome Helicase
Chemical Substances	HIGD1A protein, human ; Intracellular Signaling Peptides and Proteins ; Mitochondrial Proteins ; Neoplasm Proteins ; Reactive Oxygen Species ; Exodeoxyribonucleases (EC 3.1.-) ; RecQ Helicases (EC 3.6.4.12) ; WRN protein, human (EC 3.6.4.12) ; Werner Syndrome Helicase (EC 3.6.4.12)
Language	English
Publishing date	2012-05-31
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1493-x
ISSN	1090-2422 ; 0014-4827
ISSN (online)	1090-2422
ISSN	0014-4827
DOI	10.1016/j.yexcr.2012.04.010
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Article: The Werner syndrome gene product (WRN): a repressor of hypoxia-inducible factor-1 activity

Labbé, Adam / Lafleur, Véronique N / Patten, David A / Robitaille, Geneviève A / Garand, Chantal / Lamalice, Laurent / Lebel, Michel / Richard, Darren E

Experimental cell research. 2012 Aug. 15, v. 318, no. 14

2012

Abstract	Werner syndrome (WS) is a rare autosomal disease characterized by the premature onset of several age-associated pathologies. The protein defective in WS patients (WRN) is a helicase/exonuclease involved in DNA repair, replication, transcription and telomere maintenance. Hypoxia-inducible factor-1 (HIF-1) is a decisive element for the transcriptional regulation of genes essential for adaptation to low oxygen conditions. HIF-1 is also implicated in the molecular mechanisms of ageing. Here, we show that the cellular depletion of WRN protein (by siRNA targeting) leads to increased HIF-1 complex stabilization and activation. HIF-1 activation in the absence of WRN involves the generation of mitochondrial reactive oxygen species (mtROS) since SkQ1, a mitochondrial-targeted antioxidant, and stigmatellin, an inhibitor of mitochondrial complex III, blocked increased HIF-1 levels. Ascorbate, an essential co-factor involved in HIF-1 stability, was decreased in WRN-depleted cells. Interestingly, expression levels of GLUT1, a known dehydroascorbic acid transporter, were also decreased in WRN-depleted cells. Ascorbate supplementation of WRN-depleted cells led to a dose-dependent inhibition of HIF-1 activation. These results indicate that WRN protein regulates HIF-1 activation by affecting mitochondrial ROS production and intracellular ascorbate levels. This work provides a novel mechanistic link between HIF-1 activity and different age-associated pathologies.
Keywords	DNA repair ; antioxidants ; dehydroascorbic acid ; dose response ; essential genes ; oxygen ; patients ; reactive oxygen species ; small interfering RNA ; telomeres ; transcription (genetics) ; ubiquinol-cytochrome-c reductase
Language	English
Dates of publication	2012-0815
Size	p. 1620-1632.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	1493-x
ISSN	1090-2422 ; 0014-4827
ISSN (online)	1090-2422
ISSN	0014-4827
DOI	10.1016/j.yexcr.2012.04.010
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Article ; Online: Long-term consequences of a prolonged febrile seizure in a dual pathology model.

Gibbs, Steve / Chattopadhyaya, Bidisha / Desgent, Sébastien / Awad, Patricia N / Clerk-Lamalice, Olivier / Levesque, Maxime / Vianna, Rose-Mari / Rébillard, Rose-Marie / Delsemme, Andrée-Anne / Hébert, David / Tremblay, Luc / Lepage, Martin / Descarries, Laurent / Di Cristo, Graziella / Carmant, Lionel

Neurobiology of disease

2011 Volume 43, Issue 2, Page(s) 312–321

Abstract: Clinical evidence suggests that febrile status epilepticus (SE) in children can lead to acute hippocampal injury and subsequent temporal lobe epilepsy. The contribution of febrile SE to the mechanisms underlying temporal lobe epilepsy are however poorly ... ...

Abstract	Clinical evidence suggests that febrile status epilepticus (SE) in children can lead to acute hippocampal injury and subsequent temporal lobe epilepsy. The contribution of febrile SE to the mechanisms underlying temporal lobe epilepsy are however poorly understood. A rat model of temporal lobe epilepsy following hyperthermic SE was previously established in our laboratory, wherein a focal cortical lesion induced at postnatal day 1 (P1), followed by a hyperthermic SE (more than 30 min) at P10, leads to hippocampal atrophy at P22 (dual pathology model) and spontaneous recurrent seizures (SRS) with mild visuospatial memory deficits in adult rats. The goal of this study was to identify the long term electrophysiological, anatomical and molecular changes in this model. Following hyperthermic SE, all cortically lesioned pups developed progressive SRS as adults, characterized by the onset of highly rhythmic activity in the hippocampus. A reduction of hippocampal volume on the side of the lesion preceded the SRS and was associated with a loss of hippocampal neurons, a marked decrease in pyramidal cell spine density, an increase in the hippocampal levels of NMDA receptor NR2A subunit, but no significant change in GABA receptors. These findings suggest that febrile SE in the abnormal brain leads to hippocampal injury that is followed by progressive network reorganization and molecular changes that contribute to the epileptogenesis as well as the observed memory deficits.
MeSH term(s)	Acute Disease ; Animals ; Animals, Newborn ; Disease Models, Animal ; Epilepsy, Temporal Lobe/complications ; Epilepsy, Temporal Lobe/pathology ; Epilepsy, Temporal Lobe/physiopathology ; Female ; Hippocampus/pathology ; Hippocampus/physiopathology ; Male ; Nerve Degeneration/pathology ; Nerve Degeneration/physiopathology ; Rats ; Rats, Sprague-Dawley ; Seizures, Febrile/complications ; Seizures, Febrile/pathology ; Seizures, Febrile/physiopathology ; Time Factors
Language	English
Publishing date	2011-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1211786-9
ISSN	1095-953X ; 0969-9961
ISSN (online)	1095-953X
ISSN	0969-9961
DOI	10.1016/j.nbd.2011.02.013
Database	MEDical Literature Analysis and Retrieval System OnLINE

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