[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.
Mottet, Denis ; 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
Language :
English
Title :
Role of ERK and calcium in the hypoxia-induced activation of HIF-1.
Publication date :
2003
Journal title :
Journal of Cellular Physiology
ISSN :
0021-9541
eISSN :
1097-4652
Publisher :
Wiley Liss, Inc., New York, United States - New York
Volume :
194
Issue :
1
Pages :
30-44
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
F.R.S.-FNRS - Fonds de la Recherche Scientifique Fonds pour Recherche dans l'Industrie et l'Agriculture, Belgique BELSPO - SPP Politique scientifique - Service Public Fédéral de Programmation Politique scientifique
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