JunD Reduces Tumor Angiogenesis by Protecting Cells from Oxidative Stress

Gerald, Damien; Berra, Edurne; Frapart, Yves; Chan, Denise A.; Giaccia, Amato J.; Mansuy, Daniel; Pouysségur, Jacques; Yaniv, Moshe; Mechta‐Grigoriou, Fatima

doi:10.1016/j.cell.2004.08.025

Cited by 526 publications

(442 citation statements)

References 55 publications

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“…Reactive oxygen species were reported to inhibit PHD activity under normoxic conditions by oxidizing the PHD cofactors ferrous iron and ascorbate (Figure 3) (Gerald et al, 2004). It is therefore tempting to speculate that ROS also play a role in the pseudohypoxic response of SDH (and maybe FH)-deficient tumours.…”

Section: Signalling By Reactive Oxygen Speciesmentioning

confidence: 99%

Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer

2006

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The phenomenon of enhanced glycolysis in tumours has been acknowledged for decades, but biochemical evidence to explain it is only just beginning to emerge. A significant hint as to the triggers and advantages of enhanced glycolysis in tumours was supplied by the recent discovery that succinate dehydrogenase (SDH) and fumarate hydratase (FH) are tumour suppressors and which associated, for the first time, mitochondrial enzymes and their dysfunction with tumorigenesis. Further steps forward showed that the substrates of SDH and FH, succinate and fumarate, respectively, can mediate a 'metabolic signalling' pathway. Succinate or fumarate, which accumulate in mitochondria owing to the inactivation of SDH or FH, leak out to the cytosol, where they inhibit a family of prolyl hydroxylase enzymes (PHDs). Depending on the PHD inhibited, two newly recognized pathways that support tumour maintenance may ensue: affected cells become resistant to certain apoptotic signals and/or activate a pseudohypoxic response that enhances glycolysis and is conveyed by hypoxia-inducible factor.

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Section: Signalling By Reactive Oxygen Speciesmentioning

confidence: 99%

Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer

2006

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“…H 2 O 2 may cause a local Fenton reaction to shift iron ions from Fe þ 2 to Fe þ 3 causing inactivation of the enzyme. 62 A combination of oxygen, iron, TCA cycle intermediate availability and ROS signaling might optimize the hydroxylation of HIFa proteins. 63 Furthermore, recent studies have indicated that HIF-1 activation might prevent excessive ROS production in hypoxic cells by regulating mitochondrial respiration through increased gene expression of PDK1 (PDH (pyruvate dehydrogenase) kinase 1) and switching of cytochrome c oxidase subunit IV isoforms.…”

Section: Unanswered Questionsmentioning

confidence: 99%

Mitochondrial complex III regulates hypoxic activation of HIF

2008

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Decreases in oxygen levels are observed in physiological processes, such as development, and pathological situations, such as tumorigenesis and ischemia. In the complete absence of oxygen (anoxia), mammalian cells are unable to generate sufficient energy for survival, so a mechanism for sensing a decrease in the oxygen level (hypoxia) before it reaches a critical point is crucial for the survival of the organism. In response to decreased oxygen levels, cells activate the transcription factors hypoxiainducible factors (HIFs), which lead to metabolic adaptation to hypoxia, as well as to generate new vasculature to increase oxygen supply. How cells sense decreases in oxygen levels to regulate HIF activation has been hotly debated. Emerging evidence indicates that reactive oxygen species (ROS) generated by mitochondrial complex III are required for hypoxic activation of HIF. This review examines the current knowledge about the role of mitochondrial ROS in HIF activation, as well as implications of ROS-level regulation in pathological processes such as cancer. Oxygen Homeostasis and HIF Maintaining oxygen homeostasis is critical for survival and proper function of cells and organisms. 1 Reduced oxygen levels (hypoxia) initiates proper placental and vascular development. Hypoxia also has a causal role in pathological conditions such as ischemia-related diseases and cancer. A complete absence of oxygen (anoxia) results in cell death. 2 ATP synthesis is ablated, and most cells undergo apoptosis soon after anoxia exposure. 3-5 Cells exposed to hypoxia, or reduced oxygen levels, on the other hand, are able to maintain normal ATP synthesis and survive. 5,6 However, as cells replicate in a hypoxic environment, they reduce the oxygen supply even further and generate levels of local anoxia. Therefore, cells must respond quickly to decreasing oxygen levels before reaching an anoxic state (Figure 1).Mammalian cells respond to hypoxia by activating broadaction transcription factors named hypoxia-inducible factors, or HIFs, which are expressed by virtually all cells of the body. 7-9 Three members of the HIF family exist, named HIF1, HIF2 and HIF-3. 10-13 HIFs bind to hypoxia-responsive elements, consensus sequences in the promoter region of more than one hundred genes, activating the transcription of genes that allow the cell to adapt to and survive in the hypoxic environment. 14,15 Genes regulated by HIFs include glucose transporter that allow the cells to efficiently import glucose to continue generating ATP despite reduced nutrient availability; and genes that reorganize the microenvironment to bring in oxygen, such as vascular endothelial growth factor, which stimulates formation of new blood vessels. [16][17][18] Importantly for tumorigenesis, HIF also turns on genes such as insulin-like growth factor 2,19 which induces cellular survival and proliferation, as well as those that promote tumor invasion and migration, such as matrix metalloproteinase-2. 20 These factors contribute to tumor growth and invasion and metastasis, im...

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“…These most likely involve the PHDs, since recent work employing a cellular prolyl hydroxylase reporter, which utilizes hydroxylation-specific mobility shifts on SDS-PAGE gels to monitor the hydroxylation of HIFα in vivo, showed that mitochondrial inhibitors and the anti-oxidant Mito-Q affect cellular hydroxylase activity [26]. One report has shown that elevated ROS levels due to genetic ablation of the transcription factor JunD and consequent downregulation of its anti-oxidant target genes, leads to PHD2 inactivation via oxidation of ferrous iron in the catalytic domain as determined by electron paramagnetic resonance spectroscopy [80]. However, it remains to be determined whether physiological levels of ROS produced during hypoxia can have the same effect on PHD2.…”

Section: Potential Mechanisms For Ros In Cellular O 2 Sensingmentioning

confidence: 99%

Reactive oxygen species and cellular oxygen sensing

Cash

Pan

Simon

2007

Free Radical Biology and Medicine

164

100

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Many organisms activate adaptive transcriptional programs to help them cope with decreased oxygen levels, or hypoxia, in their environment. These responses are triggered by various oxygen sensing systems in bacteria, yeast and metazoans. In metazoans, the hypoxia inducible factors (HIFs) mediate the adaptive transcriptional response to hypoxia by upregulating genes involved in maintaining bioenergetic homeostasis. The HIFs in turn are regulated by HIF-specific prolyl hydroxlase activity, which is sensitive to cellular oxygen levels and other factors such as tricarboxylic acid cycle metabolites and reactive oxygen species (ROS). Establishing a role for ROS in cellular oxygen sensing has been challenging since ROS are intrinsically unstable and difficult to measure. However, recent advances in fluorescence energy transfer resonance (FRET)-based methods for measuring ROS are alleviating some of the previous difficulties associated with dyes and luminescent chemicals. In addition, new genetic models have demonstrated that functional mitochondrial electron transport and associated ROS production during hypoxia are required for HIF stabilization in mammalian cells. Current efforts are directed at how ROS mediate prolyl hydroxylase activity and hypoxic HIF stabilization. Progress in understanding this process has been enhanced by the development of the FRET-based ROS probe, an vivo prolyl hydroxylase reporter and various genetic models harboring mutations in components of the mitochondrial electron transport chain.

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JunD Reduces Tumor Angiogenesis by Protecting Cells from Oxidative Stress

Cited by 526 publications

References 55 publications

Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer

Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer

Mitochondrial complex III regulates hypoxic activation of HIF

Reactive oxygen species and cellular oxygen sensing

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