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

Mottet, Denis; Michel, G.; Renard, Patricia; Ninane, Noëlle; Raes, Martine; Michiels, Carine

doi:10.1002/jcp.10176

Cited by 124 publications

(102 citation statements)

References 55 publications

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“…71 Raf was already identified to play a role in the activation of the ERK MAP Kinase pathway and hence in HIF-1 activation in hypoxic conditions. 72 However, neither DRB nor apigenin affected the hypoxia-induced increase in ERK1/2 phosphorylation (data not shown).…”

Section: Discussionmentioning

confidence: 83%

Role for casein kinase 2 in the regulation of HIF‐1 activity

Mottet

Ruys

Demazy

et al. 2005

Intl Journal of Cancer

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Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor that plays a major role in cellular adaptation to hypoxia. The mechanisms regulating HIF-1 activity occurs at multiple levels in vivo. The HIF-1a subunit is highly sensible to oxygen and is rapidly degraded by the proteasome 26S in normoxia. Activation in hypoxia occurs through a multistep process including inhibition of HIF-1a degradation, but also increase in the transactivation activity of HIF-1. Several data indicate that phosphorylation could play a role in this regulation. In this report, we investigated the role of casein kinase 2 (CK2), an ubiquitous serine/ threonine kinase, in the regulation of HIF-1 activity. Hypoxia was capable of increasing the expression of the b subunit of CK2, of inducing a relocalization of this subunit at the plasma membrane, of inducing nuclear translocation of the a subunit and of increasing CK2 activity. Three inhibitors of this kinase, DRB (5,6-dichloro-1-b-D-ribofuranosyl-benzimidazole), TBB (4,5,6,7-tetrabromotriazole) and apigenin, as well as overexpression of a partial dominant negative mutant of CK2a, were shown to inhibit HIF-1 activity as measured by a reporter assay and through hypoxiainduced VEGF and aldolase expression. This does not occur at the stabilization process since they did not affect HIF-1a protein level. DNA-binding activity was also not inhibited. We conclude that CK2 is an important regulator of HIF-1 transcriptional activity but the mechanism of this regulation remains to be determined. Since HIF-1 plays a major role in tumor angiogenesis and since CK2 has been described to be overexpressed in tumor cells, this new pathway of regulation can be one more way for tumor cells to survive. ' 2005 Wiley-Liss, Inc.Key words: casein kinase 2; HIF-1; neoangiogenesis HIF-1 (hypoxia-inducible factor-1) is a key regulator of cell response to reduced oxygen level. In response to hypoxic conditions, HIF-1 increases the expression of downstream target genes such as erythropoietin (EPO), vascular endothelial growth factor (VEGF) and glycolytic enzymes (aldolase A, enolase-a) and mediates adaptation of cells to decreased oxygen level. 1 The role of HIF-1 in the regulation of tumor growth by hypoxia via the initiation of angiogenesis is certainly the best example of such an adaptive response. 2 Oncogene activation and tumor-suppressor inactivation result in deregulated cellular proliferation. However, most tumors grown larger than 1 mm 3 contain regions of low oxygen tension (hypoxia) due to an imbalance between oxygen supply and consumption. Formation of new blood vessels or ''neoangiogenesis'' is thus essential for further tumor growth. It is also important to allow tumor cell dissemination at distant sites, i.e., metastasis.Several studies using HIF-1 mutant cells have shown that HIF-1 has a profound effect on tumor biology. For example, tumors grown from HIF-1a-defective embryonic stem cells display abnormal vascularity and reduced growth rate. 3 Moreover, HIF-1 is upregulated in a broad r...

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Section: Discussionmentioning

confidence: 83%

Role for casein kinase 2 in the regulation of HIF‐1 activity

Mottet

Ruys

Demazy

et al. 2005

Intl Journal of Cancer

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“…Lowering calcium may not only block PHD activity but also attenuate calpain and both actions may synergize in stabilizing HIF-1␣. However, on the basis of current information one would not assume a simple role of calcium as several reports noticed the involvement of calcium and/or calmodulin in signal transduction pathways, e.g., ERK activation (Mottet et al, 2003;Liu et al, 2004), leading to enhanced HIF-1 transcriptional activity (Yuan et al, 2005). The dual role of calcium is reflected by showing that chelating calcium provoked a transient HIF-1␣ increase by attenuating protein degradation, whereas the calcium ionophore A23187 induced HIF-1␣ mRNA expression at the same time (Liu et al, 2004).…”

Section: Discussionmentioning

confidence: 97%

Calpain Mediates a von Hippel-Lindau Protein–independent Destruction of Hypoxia-inducible Factor-1α

Zhou

Köhl

Herr

et al. 2006

MBoC

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Hypoxia-inducible factor 1 (HIF-1) is controlled through stability regulation of its alpha subunit, which is expressed under hypoxia but degraded under normoxia. Degradation of HIF-1␣ requires association of the von Hippel Lindau protein (pVHL) to provoke ubiquitination followed by proteasomal digestion. Besides hypoxia, nitric oxide (NO) stabilizes HIF-1␣ under normoxia but destabilizes the protein under hypoxia. To understand the role of NO under hypoxia we made use of pVHL-deficient renal carcinoma cells (RCC4) that show a high steady state HIF-1␣ expression under normoxia. Exposing RCC4 cells to hypoxia in combination with the NO donor DETA-NO (2,2-(hydroxynitrosohydrazono) bis-ethanimine), but not hypoxia or DETA-NO alone, decreased HIF-1␣ protein and attenuated HIF-1 transactivation. Mechanistically, we noticed a role of calpain because calpain inhibitors reversed HIF-1␣ degradation. Furthermore, chelating intracellular calcium attenuated HIF-1␣ destruction by hypoxia/DETA-NO, whereas a calcium increase was sufficient to lower the amount of HIF-1␣ even under normoxia. An active role of calpain in lowering HIF-1␣ amount was also evident in pVHL-containing human embryonic kidney cells when the calcium pump inhibitor thapsigargin reduced HIF-1␣ that was stabilized by the prolyl hydroxylase inhibitor dimethyloxalylglycine (DMOG). We conclude that calcium contributes to HIF-1␣ destruction involving the calpain system. INTRODUCTIONThe transcription factor hypoxia-inducible factor-1 (HIF-1) constitutes a central component in coordinating adaptive responses toward low oxygen availability, i.e., hypoxia. HIF-1 is a heterodimer composed of the 120-kDa HIF-1␣ subunit and the 91-94-kDa HIF-1␤ subunit (Semenza and Wang, 1992;Wang and Semenza, 1995). Although HIF-1␤ is constitutively expressed, oxygen facilitates continues destruction of HIF-1␣ via the 26S proteasome. This requires polyubiquitination by an E3-ubiquitin ligase complex that contains the von Hippel Lindau protein (pVHL; Kaelin, 2002;Bruick, 2003;Huang and Bunn, 2003;Pugh and Ratcliffe, 2003;Semenza, 2003). Ubiquitination and binding of pVHL to HIF-1␣ demands hydroxylation of Pro564 and/or Pro402 within the oxygen-dependent degradation domain (ODD) of HIF-1␣ (Ivan et al., 2001;Jaakkola et al., 2001;Masson et al., 2001). Hydroxylation is mediated by prolyl hydroxylases, also known as PH domain-containing enzymes (PHD, i.e., PHD1 to PHD4; Bruick and McKnight, 2001;Epstein et al., 2001;Oehme et al., 2002). In addition to regulating HIF-1␣ protein stability, oxygen affects the transcriptional activity of HIF-1, by regulating hydroxylation of a critical Asn803 residue within the C-terminal transactivation domain (CTAD) of HIF-1␣ (Lando et al., 2002). The asparagine hydroxylase known as FIH (factor inhibiting HIF; Mahon et al., 2001;Hewitson et al., 2002) renders CTAD unable to bind the coactivator p300/CBP. Thus, hypoxia attenuates Pro564/402 as well as Asn803 modifications, provoking protein stabilization and coactivator recruitment, which concomitantly results...

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“…MEK-ERK1/2 links growth factor receptors with nerve growth factor and brain-derived neurotrophic factor, to exert neuroprotective effects such as NMDA receptor modulation and reduction of glutamate excitotoxicity [29] . MEK-ERK1/2 also phosphorylates hypoxia-inducible factor 1, a transcription factor required for the cell adaptation to acute and chronic hypoxia [30] . In addition, here p38 MAPK is found to have no effect on the preconditioning of sevoflurane, thus the role of p38 MAPK in preconditioning is disputed.…”

Section: Discussionmentioning

confidence: 99%

Duplicate preconditioning with sevoflurane in vitro improves neuroprotection in rat brain via activating the extracellular signal-regulated protein kinase

et al. 2010

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Abstract:Objective Sevoflurane preconditioning has been demonstrated to reduce cerebral ischemia-reperfusion (IR) injury, but the underlying mechanisms have not been fully elucidated. Besides, different protocols would usually lead to different results. The objective of this study was to determine whether dual exposure to sevoflurane improves the effect of anesthetic preconditioning against oxygen and glucose deprivation (OGD) injury in vitro. Methods Rat hippocampal slices under normoxic conditions (95% O 2 /5% CO 2 ) were pre-exposed to sevoflurane 1, 2 and 3 minimum alveolar concentration (MAC) for 30 min, once or twice, with 15-min washout after each exposure. The slices were then subjected to 13-min OGD treatment (95% N 2 /5% CO 2 , glucose-free), followed by 30-min reoxygenation. The population spikes (PSs) were recorded in the CA1 region of rat hippocampus. The percentage of PS amplitude at the end of 30-min reoxygenation to that before OGD treatment was calculated, since it could indicate the recovery degree of neuronal function. In addition, to assess the role of mitogen-activated protein kinases (MAPKs) in preconditioning, U0126, an inhibitor of extracellular signal-regulated protein kinase (MEK-ERK1/2, ERK1/2 MAPK), and SB203580, an inhibitor of p38 MAPK, were separately added 10 min before sevoflurane exposure. Results Preconditioning once with sevoflurane 1, 2, and 3 MAC increased the percentage of PS amplitude at the end of 30-min reoxygenation to that before OGD treatment, from (15.13±3.79)% (control) to (31.88±5.36)%, (44.00±5.01)%, and (49.50±6.25)%, respectively, and twice preconditioning with sevoflurane 1, 2, and 3 MAC increased the percentage to (38.53±4.36)%, (50.74±7.05)% and (55.86±6.23)%, respectively. The effect of duplicate preconditioning with sevoflurane 3 MAC was blocked by U0126 [(16.23±4.62)%]. Conclusion Sevoflurane preconditioning can induce neuroprotection against OGD injury in vitro, and preconditioning twice enhances this effect. Besides, the activation of extracellular signal-regulated protein kinase (MEK-ERK1/2, ERK1/2 MAPK) may be involved in this process.

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

Cited by 124 publications

References 55 publications

Role for casein kinase 2 in the regulation of HIF‐1 activity

Role for casein kinase 2 in the regulation of HIF‐1 activity

Calpain Mediates a von Hippel-Lindau Protein–independent Destruction of Hypoxia-inducible Factor-1α

Duplicate preconditioning with sevoflurane in vitro improves neuroprotection in rat brain via activating the extracellular signal-regulated protein kinase

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