Nitric oxide inhibits HIF-1α protein accumulation under hypoxic conditions: implication of 2-oxoglutarate and iron

Kozhukhar, Anna; Yasinska, Inna M.; Sumbayev, Vadim V.

doi:10.1016/j.biochi.2005.09.007

Cited by 34 publications

(34 citation statements)

References 37 publications

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“…2-Oxoglutarate, like succinate, is a product of the citric acid cycle. In hypoxia, it has been hypothesized that nitric oxide causes mitochondrial dysfunction and thereby 2OG and Fe 2ϩ upregulation mediated by the reactive oxygen species peroxynitrite (56). Increased intracellular 2OG and Fe 2ϩ then contribute to increased hydroxylation of HIF1␣ by the PHDs.…”

Section: Resultsmentioning

confidence: 99%

“…Of all reactive oxygen species, H 2 O 2 seems to be the one with the noticeable effect on the HIF1 system (20,34,61). However, the reactive oxygen species peroxynitrite may serve as an oxygen donor during HIF1␣ hydroxylation, as well as mediate Fe 2ϩ and 2OG release from the mitochondria (56,89), and effects of superoxide on HIF1␣ have been shown in renal carcinoma (46) and renal medullary interstitial cells (103).…”

Section: Discussionmentioning

confidence: 99%

“…Another change could be in the recruitment of ascorbate as a free radical scavenger, preventing ascorbate from reducing ferric iron and/or preventing ascorbate from binding directly to the PHDs. If ROS increased rather than decreased free Fe 2ϩ , as suggested by some experiments, HIF1␣ hydroxylation would instead increase (56). Additionally, 2-oxoglutarate (2OG) and succinate (SC) are also compounds involved in HIF1␣ hydroxylation whose concentrations could be altered by free radicals and mitochondrial dysfunction (38,56,71).…”

mentioning

confidence: 99%

“…If ROS increased rather than decreased free Fe 2ϩ , as suggested by some experiments, HIF1␣ hydroxylation would instead increase (56). Additionally, 2-oxoglutarate (2OG) and succinate (SC) are also compounds involved in HIF1␣ hydroxylation whose concentrations could be altered by free radicals and mitochondrial dysfunction (38,56,71). A fourth mechanism by which ROS could influ-ence the HIF1 pathway is through changing the availability of oxygen to bind directly to the PHDs or changing PHD phosphorylation.…”

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confidence: 99%

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Reactive Oxygen Species Regulate Hypoxia-Inducible Factor 1α Differentially in Cancer and Ischemia

Qutub

Popel

2008

Molecular and Cellular Biology

169

130

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In exercise, as well as cancer and ischemia, hypoxia-inducible factor 1 (HIF1) transcriptionally activates hundreds of genes vital for cell homeostasis and angiogenesis. While potentially beneficial in ischemia, upregulation of the HIF1 transcription factor has been linked to inflammation, poor prognosis in many cancers, and decreased susceptibility of tumors to radiotherapy and chemotherapy. Considering HIF1's function, HIF1␣ protein and its hydroxylation cofactors look increasingly attractive as therapeutic targets. Independently, antioxidants have shown promise in lowering the risk of some cancers and improving neurological and cardiac function following ischemia. The mechanism of how different antioxidants and reactive oxygen species influence HIF1␣ expression has drawn interest and intense debate. Here we present an experimentally based computational model of HIF1␣ protein degradation that represents how reactive oxygen species and antioxidants likely affect the HIF1 pathway differentially in cancer and ischemia. We use the model to demonstrate effects on HIF1␣ expression from combined doses of five potential therapeutically targeted compounds (iron, ascorbate, hydrogen peroxide, 2-oxoglutarate, and succinate) influenced by cellular oxidation-reduction and involved in HIF1␣ hydroxylation. Results justify the hypothesis that reactive oxygen species work by two opposite ways on the HIF1 system. We also show how tumor cells and cells under ischemic conditions would differentially respond to reactive oxygen species via changes to HIF1␣ expression over the course of hours to days, dependent on extracellular hydrogen peroxide levels and largely independent of initial intracellular levels, during hypoxia.The transcription factor hypoxia-inducible factor (HIF) plays a critical role in the mammalian response to oxygen (O 2 ) levels. HIF1, the first characterized member of the HIF family, transcriptionally activates hundreds of genes associated with angiogenesis in cancer, exercise, and ischemia, as well as energy metabolism, nutrient transport, cell cycle, and cell migration (85, 98).HIF1␣ and HIF1␤ make up the HIF1 heterodimer. The ␤-subunit is constitutively expressed in cells. Expression of the ␣-subunit may be induced by a number of pathways, and its degradation is highly sensitive to O 2 levels. Called a master switch for hypoxic gene expression (76, 85), intracellular HIF1␣ in normoxia is experimentally undetectable; during hypoxia, it rapidly accumulates in the cell nucleus and triggers gene expression. Molecular players involved in this process have come to light over the past 6 years; research has begun to define roles for prolyl hydroxylases, iron, ascorbate, hydrogen peroxide, 2-oxoglutarate, succinate, and von Hippel-Lindau protein in the HIF1 pathway.Concomitantly, the study of reactive oxygen species (ROS) and the interest in antioxidants as potential dietary supplements for prevention of cancer, cardiac dysfunction, and neurodegeneration has grown rapidly. Ongoing debate surrounds the role of these co...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Reactive Oxygen Species Regulate Hypoxia-Inducible Factor 1α Differentially in Cancer and Ischemia

Qutub

Popel

2008

Molecular and Cellular Biology

169

130

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“…It has been shown that NO-mediated inhibition of respiration alters activation of hypoxia responsive targets in cells such that increased NO interferes with the upregulation of molecules required by cells to adapt to hypoxic stress [51,52] . This may also have the effect of changing oxygen gradients in tissues.…”

Section: Production In Complexⅰ(c) O2 •-Dismutation To Hydrogen Peromentioning

confidence: 99%

Novel interactions of mitochondria and reactive oxygen/nitrogen species in alcohol mediated liver disease

Mantena

King²,

Andringa³

et al. 2007

WJG

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In SilicoModeling of Angiogenesis at Multiple Scales: From Nanoscale to Organ System

Qutub

Gabhann

Karagiannis

et al. 2010

Multiscale Modeling of Particle Interactions

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Nitric oxide inhibits HIF-1α protein accumulation under hypoxic conditions: implication of 2-oxoglutarate and iron

Cited by 34 publications

References 37 publications

Reactive Oxygen Species Regulate Hypoxia-Inducible Factor 1α Differentially in Cancer and Ischemia

Reactive Oxygen Species Regulate Hypoxia-Inducible Factor 1α Differentially in Cancer and Ischemia

Novel interactions of mitochondria and reactive oxygen/nitrogen species in alcohol mediated liver disease

In SilicoModeling of Angiogenesis at Multiple Scales: From Nanoscale to Organ System

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