PHD2 in tumour angiogenesis

Chan, Denise A.; Giaccia, Amato J.

doi:10.1038/sj.bjc.6605682

Cited by 66 publications

(42 citation statements)

References 38 publications

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“…The PHDs family include PHD1, PHD2 and PHD3. PHD2 is believed to be a key oxygen sensor that hydroxylates HIF‐1α and promotes its degradation 36, 37. OH‐HIF‐1α levels were markedly decreased in PQ group.…”

Section: Discussionmentioning

confidence: 98%

A positive feedback loop promotes HIF‐1α stability through miR‐210‐mediated suppression of RUNX3 in paraquat‐induced EMT

Zhu

Meng

Xie

et al. 2017

J Cellular Molecular Medi

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Irreversible pulmonary fibrosis induced by paraquat (PQ) poisoning is the major cause of death in patients with PQ poisoning. The epithelial–mesenchymal transition (EMT) is postulated to be one of the main mechanisms of pulmonary fibrosis. Here, we investigated the role of miR‐210 in PQ‐induced EMT and its relationship with hypoxia‐inducible factor‐1α (HIF‐1α). Western blotting, immunofluorescence, immunoprecipitation and other methods were used in this study. We found that miR‐210 expression was significantly increased after PQ poisoning, and it may be regulated by HIF‐1α. Overexpression of miR‐210 further increased the HIF‐1α protein level and promoted EMT. Moreover, miR‐210 knock‐down reduced the HIF‐1α protein level and decreased the degree of EMT. Runt‐related transcription factor‐3 (RUNX3), a direct target of miR‐210, was inhibited by miR‐210 in response to PQ poisoning. RUNX3 increased the hydroxylation ability of prolyl hydroxylase domain‐containing protein 2 (PHD2), a key enzyme that promotes HIF‐1α degradation. PHD2 immunoprecipitated with RUNX3 and its level changed similarly to that of RUNX3. The expression of the HIF‐1α protein was significantly reduced when RUNX3 was overexpressed. HIF‐1α protein levels were markedly increased when RUNX3 was silenced. Based on these results, a positive feedback loop may exist between miR‐210 and HIF‐1α. The mechanism may function through miR‐210‐mediated repression of RUNX3, which further decreases the hydroxylation activity of PHD2, enhances the stability of HIF‐1α, and promotes PQ‐induced EMT, aggravating the progression of pulmonary fibrosis. This study further elucidates the mechanism of PQ‐induced pulmonary fibrosis and may provide a new perspective for the future development of therapies.

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Section: Discussionmentioning

confidence: 98%

A positive feedback loop promotes HIF‐1α stability through miR‐210‐mediated suppression of RUNX3 in paraquat‐induced EMT

Zhu

Meng

Xie

et al. 2017

J Cellular Molecular Medi

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“…How PHD2 can be downregulated in some tumours whilst acting as an oncogene in others [40] remains unclear [41]. Mutations in PHD2 associated with increased risk of tumours have been reported [42] and epigenetic silencing has been proposed for PHD3 [43].…”

Section: Phd2 Integration Of Lactate-driven Angiogenesismentioning

confidence: 99%

Endothelial cell metabolism and tumour angiogenesis: glucose and glutamine as essential fuels and lactate as the driving force

2013

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Abstract. Polet F, Feron O (Universit e catholique de Louvain (UCL), Brussels, Belgium) Endothelial cell metabolism and tumour angiogenesis: glucose and glutamine as essential fuels and lactate as the driving force (Review). J Intern Med 2013; 273: 156-165.Angiogenic endothelial cells and tumour cells can survive under hypoxic conditions and even proliferate and migrate in a low-oxygen environment. In both cell types, high rates of glycolysis (i.e. conversion of glucose to lactate) and glutaminolysis provide most of the required biosynthetic intermediates and energy to support sprouting and cell division without coupling to oxidative phosphorylation. This metabolic preference is observed under hypoxic conditions, but also in situations in which oxygen is present. In the case of tumour cells, this is known as the Warburg effect and is largely governed by oncogenes. In endothelial cells lining tumour blood vessels, the option of respirationindependent metabolism allows the neovasculature to resist the hostile environment of fluctuating oxygen tension (ranging from severe hypoxia to quasi-normal levels of oxygen). In addition, accumulation in tumours of lactate, the end-product of glycolysis, largely contributes to the angiogenic phenotype through inhibition of prolyl hydroxylase 2 and the activation of HIF1a and NFjB. Activation of the latter in a hypoxia-independent manner leads to the increased production of interleukin-8/CXCL8 which drives the autocrine stimulation of endothelial cell proliferation and maturation of neovessels. In conclusion, the addiction of proliferating endothelial cells for glucose and glutamine as fuels and the driving force of lactate to promote angiogenesis provide novel potential treatment options without the disadvantages of conventional anti-angiogenic drugs.

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“…Under hypoxic conditions, the α -subunit does not get hydroxylated. Thus, the α -subunit accumulates and forms the functional heterodimer with the β -subunit, which then translocates into the nucleus to activate the transcription of genes with HIF-1 response element (HRE) (Chan and Giaccia , 2010 ). Garayoa et al (2000) discovered several HREs in the human AM promoter, and went further to demonstrate HIF-1-mediated up-regulation of AM under hypoxic conditions (Figure 2 ).…”

Section: Am Is Up-regulated As An Adaptive Stress Response In Brain Imentioning

confidence: 99%

“…HIF-1 is a heterodimeric transcription factor that consists of a β -subunit and an oxygen-sensitive α -subunit (Chan and Giaccia , 2010 ). Under normoxic conditions, the α -subunit becomes hydroxylated on two conserved proline residues by prolyl hydroxylases.…”

Section: Am Is Up-regulated As An Adaptive Stress Response In Brain Imentioning

confidence: 99%

The critical role of adrenomedullin and its binding protein, AMBP-1, in neuroprotection

Cheyuo

Yang

Wang

2012

Biological Chemistry

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Chronic neurodegenerative disorders and acute injuries of the central nervous system exert a prohibitive economic burden, which is aggravated by an unmet medical need for the development of effective neurotherapeutics. The evolutionarily conserved neuropeptide, adrenomedullin (AM), and its binding protein, AMBP-1, also known as complement factor H, play important roles in brain physiology, and their expression is altered in brain pathology. In this review, we discuss the molecular regulation of AM and AMBP-1 and the pivotal roles they play in neuroprotection following brain injury. We assess the reciprocal synergistic effects of AM and AMBP-1 and make suggestions for the design of a novel combination neurotherapy devoid of the potential hypotensive effects of AM while optimizing its neuroprotective property.

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PHD2 in tumour angiogenesis

Cited by 66 publications

References 38 publications

A positive feedback loop promotes HIF‐1α stability through miR‐210‐mediated suppression of RUNX3 in paraquat‐induced EMT

A positive feedback loop promotes HIF‐1α stability through miR‐210‐mediated suppression of RUNX3 in paraquat‐induced EMT

Endothelial cell metabolism and tumour angiogenesis: glucose and glutamine as essential fuels and lactate as the driving force

The critical role of adrenomedullin and its binding protein, AMBP-1, in neuroprotection

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