Multiple Factors Affecting Cellular Redox Status and Energy Metabolism Modulate Hypoxia-Inducible Factor Prolyl Hydroxylase Activity In Vivo and In Vitro

Pan, Yi; Mansfield, Kyle D.; Bertozzi, Cara C.; Руденко, Вікторія; Chan, Denise A.; Giaccia, Amato J.; Simon, M. Celeste

doi:10.1128/mcb.01223-06

Cited by 287 publications

(253 citation statements)

References 58 publications

Supporting

Mentioning

245

Contrasting

Unclassified

Order By: Relevance

“…To understand the mechanism of this induction, we explored a role for ROS, which have been shown to stabilize HIF1a. 10,18 Treatment of cells with NAC confirmed a critical role for ROS, as this antioxidant completely blocked 0.1 Gy-induced increase of HIF1a (Figure 4d). A requirement of HIF1a in 0.1 Gy-induced expression of glycolytic genes (Figure 4e), and GLUT-1 and 3 (Figure 4f) was demonstrated by HIF1a knockdown.…”

Section: Resultsmentioning

confidence: 70%

“…14,15 Under certain normoxic conditions, however, HIF-1a expression can also be increased. For instance, the NFkB pathway stimulates transcription of HIF-1a, 16,17 the PI3K/AKT/mTOR pathway promotes HIF-1a mRNA translation 18 and ROS inhibits HIF-1a degradation. 10 Upon induction, HIF-1a stimulates transcription of genes encoding glucose transporters and enzymes of glycolysis and the pentose phosphate pathway (PPP).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Low-dose radiation exposure induces a HIF-1-mediated adaptive and protective metabolic response

et al. 2014

View full text Add to dashboard Cite

Because of insufficient understanding of the molecular effects of low levels of radiation exposure, there is a great uncertainty regarding its health risks. We report here that treatment of normal human cells with low-dose radiation induces a metabolic shift from oxidative phosphorylation to aerobic glycolysis resulting in increased radiation resistance. This metabolic change is highlighted by upregulation of genes encoding glucose transporters and enzymes of glycolysis and the oxidative pentose phosphate pathway, concomitant with downregulation of mitochondrial genes, with corresponding changes in metabolic flux through these pathways. Mechanistically, the metabolic reprogramming depends on HIF1a, which is induced specifically by lowdose irradiation linking the metabolic pathway with cellular radiation dose response. Increased glucose flux and radiation resistance from low-dose irradiation are also observed systemically in mice. This highly sensitive metabolic response to lowdose radiation has important implications in understanding and assessing the health risks of radiation exposure.

show abstract

Section: Resultsmentioning

confidence: 70%

mentioning

confidence: 99%

Low-dose radiation exposure induces a HIF-1-mediated adaptive and protective metabolic response

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Experimental oxidative stress mimics hypoxia with regard to the stabilization of HIFa subunits [20,25]. In addition, it has been proposed that the physiological hypoxic stabilization of HIFa requires inhibition of prolyl-hydroxylases by mitochondria-derived reactive oxygen species (ROS), which are thought to oxidize ferrous to ferric iron, thereby depleting the enzymes from an essential cofactor [26,27].…”

Section: Discussionmentioning

confidence: 99%

Redox control of iron regulatory protein 2 stability

2011

View full text Add to dashboard Cite

Edited by Stuart Ferguson Keywords:Iron metabolism Iron regulatory protein 2 Proteasome Oxidative stress Hypoxia a b s t r a c t Iron regulatory protein 2 (IRP2) is a critical switch for cellular and systemic iron homeostasis. In iron-deficient or hypoxic cells, IRP2 binds to mRNAs containing iron responsive elements (IREs) and regulates their expression. Iron promotes proteasomal degradation of IRP2 via the F-box protein FBXL5. Here, we explored the effects of oxygen and cellular redox status on IRP2 stability. We show that iron-dependent decay of tetracycline-inducible IRP2 proceeds efficiently under mild hypoxic conditions (3% oxygen) but is compromised in severe hypoxia (0.1% oxygen). A treatment of cells with exogenous H 2 O 2 protects IRP2 against iron and increases its IRE-binding activity. IRP2 is also stabilized during menadione-induced oxidative stress. These data demonstrate that the degradation of IRP2 in iron-replete cells is not only oxygen-dependent but also sensitive to redox perturbations.

show abstract

“…This leads to fundamental changes in mitochondrial functions including the accumulation of TCA cycle intermediates [26]. Since HIF-regulating prolyl-4-hydroxylases utilise -ketoglutarate as a co-substrate and produce succinate during their catalytic activity, it is not surprising that the accumulation of succinate blocks these hydroxylases [27]. Indeed, loss-of-function mutations in succinate dehydrogenase were found to be inhibitory towards PHDs leading to the stabilisation of HIF- subunits and succinate was identified as the mediator of this effect [28,29].…”

Section: Metabolic Feedbackmentioning

confidence: 99%

Understanding complexity in the HIF signaling pathway using systems biology and mathematical modeling

2016

View full text Add to dashboard Cite

show abstract

Multiple Factors Affecting Cellular Redox Status and Energy Metabolism Modulate Hypoxia-Inducible Factor Prolyl Hydroxylase Activity In Vivo and In Vitro

Abstract: Prolyl hydroxylation of hypoxible-inducible factor alpha (HIF-␣

Cited by 287 publications

References 58 publications

Low-dose radiation exposure induces a HIF-1-mediated adaptive and protective metabolic response

Low-dose radiation exposure induces a HIF-1-mediated adaptive and protective metabolic response

Redox control of iron regulatory protein 2 stability

Understanding complexity in the HIF signaling pathway using systems biology and mathematical modeling

Contact Info

Product

Resources

About