Role of ERK and calcium in the hypoxia-induced activation of HIF-1

✍ Scribed by Denis Mottet; Gaetan Michel; Patricia Renard; Noelle Ninane; Martine Raes; Carine Michiels

• Publisher: John Wiley and Sons
• Year: 2002
• Tongue: English
• Weight: 706 KB
• Volume: 194
• Category: Article
• ISSN: 0021-9541
• DOI: 10.1002/jcp.10176

✦ Synopsis

Abstract

Oxygen‐dependent regulation of HIF‐1 activity occurs at multiple levels in vivo. The mechanisms regulating HIF‐1α 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‐1α 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‐1α 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. © 2002 Wiley‐Liss, Inc.