Reference : Role of ERK and calcium in the hypoxia-induced activation of HIF-1.
Scientific journals : Article
Human health sciences : Oncology
Life sciences : Biochemistry, biophysics & molecular biology
Role of ERK and calcium in the hypoxia-induced activation of HIF-1.
Mottet, Denis mailto [Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Labo de recherche sur les métastases >]
Michel, Gaetan [> > > >]
Renard, Patricia [> > > >]
Ninane, Noelle [> > > >]
Raes, Martine [> > > >]
Michiels, Carine [> > > >]
Journal of Cellular Physiology
Wiley Liss, Inc.
Yes (verified by ORBi)
New York
[en] Animals ; Calcium/metabolism ; Calcium Signaling/physiology ; Calmodulin/antagonists & inhibitors/metabolism ; Cell Hypoxia/physiology ; Cells, Cultured ; Chelating Agents/pharmacology ; DNA-Binding Proteins/drug effects/metabolism ; Dose-Response Relationship, Drug ; Drug Interactions/physiology ; Endothelial Growth Factors/metabolism ; Enzyme Inhibitors/pharmacology ; Eukaryotic Cells/metabolism ; Humans ; Hypoxia-Inducible Factor 1 ; Hypoxia-Inducible Factor 1, alpha Subunit ; Intercellular Signaling Peptides and Proteins/metabolism ; Ionomycin/pharmacology ; Ionophores/pharmacology ; Lymphokines/metabolism ; Mitogen-Activated Protein Kinases/metabolism ; Nuclear Proteins/metabolism ; Transcription Factors ; Transcription, Genetic/physiology ; Vascular Endothelial Growth Factor A ; Vascular Endothelial Growth Factors
[en] Oxygen-dependent regulation of HIF-1 activity occurs at multiple levels in vivo. The mechanisms regulating HIF-1alpha protein expression have been most extensively analyzed but the ones modulating HIF-1 transcriptional activity remain unclear. Changes in the phosphorylation and/or redox status of HIF-1alpha certainly play a role. Here, we show that ionomycin could activate HIF-1 transcriptional activity in a way that was additive to the effect of hypoxia without affecting HIF-1alpha protein level. In addition, a calmodulin dominant negative mutant and W7, a calmodulin antagonist, as well as BAPTA, an intracellular calcium chelator, inhibited the hypoxia-induced HIF-1 activation. These results indicate that elevated calcium in hypoxia could participate in HIF-1 activation. Furthermore, ERK but not JNK phosphorylation was evidenced in both conditions, ionomycin and hypoxia. PD98059, an inhibitor of the ERK pathway as well as a ERK1 dominant negative mutant also blocked HIF-1 activation by hypoxia and by ionomycin. A MEKK1 (a kinase upstream of JNK) dominant negative mutant had no effect. In addition, BAPTA, calmidazolium, a calmodulin antagonist and PD98059 inhibited VEGF secretion by hypoxic HepG2. All together, these results suggest that calcium and calmodulin would act upstream of ERK in the hypoxia signal transduction pathway.
Fonds de la Recherche Scientifique (Communauté française de Belgique) - F.R.S.-FNRS ; Fonds pour Recherche dans l'Industrie et l'Agriculture, Belgique ; Service public fédéral de Programmation Politique scientifique
Copyright 2002 Wiley-Liss, Inc.

File(s) associated to this reference

Fulltext file(s):

Restricted access
J Cell Physiology 2002.pdfPublisher postprint705.73 kBRequest copy

Bookmark and Share SFX Query

All documents in ORBi are protected by a user license.