Regulation of angiogenesis by hypoxia: role of the HIF system

Pugh, Christopher W.; Ratcliffe, Peter J.

doi:10.1038/nm0603-677

Cited by 2,214 publications

(1,726 citation statements)

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“…This insulin effect is blunted in obese, insulin-resistant Zucker fa/fa rats [4], which represent an animal model of insulin resistance [5]. It is not known whether insulin acts on the VEGF gene directly or via the transcription factor hypoxia-inducible factor-1 (HIF-1), named for its ability to mediate cellular adaptation to oxygen deficiency [6,7].…”

Section: Introductionmentioning

confidence: 99%

“…VEGF is one of its target genes [6,7]. HIF-1 is composed of an α-subunit and a β-subunit [6,7]. HIF-1β is a constitutively expressed nuclear translocator protein which binds HIF-1α and allows it to exert its transcriptional effects, whereas HIF-1α is a cytosolic protein able to translocate to the nucleus where it associates with HIF-1β and binds to a consensus sequence present in the hypoxia response element (HRE) in the promoters of the oxygen-controlled target genes, thus inducing their expression [6,7].…”

Section: Introductionmentioning

confidence: 99%

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Insulin activates hypoxia-inducible factor-1α in human and rat vascular smooth muscle cells via phosphatidylinositol-3 kinase and mitogen-activated protein kinase pathways: impairment in insulin resistance owing to defects in insulin signalling

et al. 2006

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Insulin activates hypoxia-inducible factor-1α in human and rat vascular smooth muscle cells via phosphatidylinositol-3 kinase and mitogen-activated protein kinase pathways: impairment in insulin resistance owing to defects in insulin signalling

et al. 2006

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“…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.…”

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confidence: 99%

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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“…Son niveau d'expression est contrôlé par la disponibilité de l'oxygène dans les tissus : l'hypoxie est un régulateur positif via la voie de l'hypoxia inducing factor (HIF) [3]. Le VEGF-A, surexprimé dans de nombreux modèles tumoraux [4,5], peut lier trois types de récepteurs membranaires à activité tyrosine kinase.…”

Section: Ciblage De La Voie Du Vascular Endothelial Growth Factor (Veunclassified