How oxygen makes its presence felt: Figure 1.

Kaelin, William G.

doi:10.1101/gad.1003602

Cited by 141 publications

(86 citation statements)

References 41 publications

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“…HIF-1 is composed of 2 subunits, HIF-1α and HIF-1β. Whereas the β-subunit protein is constitutively expressed, the stability of the α -subunit and its transcriptional activity are controlled by the intracellular oxygen concentration (Ivan et al, 2001;Kaelin, 2002). In addition to the oxygen-dependent regulation of HIF-1α activity, several reports have demonstrated that HIF-1α expression is modulated by a variety of cytokines and growth factors in oxygen-independent pathway (Feldser et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

A novel thiol compound, N-acetylcysteine amide, attenuates allergic airway disease by regulating activation of NF-κB and hypoxia-inducible factor-1α

Lee

Kim²,

Park³

et al. 2007

Exp Mol Med

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Reactive oxygen species (ROS) play an important role in the pathogenesis of airway inflammation and hyperresponsiveness. Recent studies have demonstrated that antioxidants are able to reduce airway inflammation and hyperreactivity in animal models of allergic airway disease. A newly developed antioxidant, small molecular weight thiol compound, N-acetylcysteine amide (AD4) has been shown to increase cellular levels of glutathione and to attenuate oxidative stress related disorders such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. However, the effects of AD4 on allergic airway disease such as asthma are unknown. We used ovalbumin (OVA)-inhaled mice to evaluate the role of AD4 in allergic airway disease. In this study with OVA-inhaled mice, the increased ROS generation, the increased levels of Th2 cytokines and VEGF, the increased vascular permeability, the increased mucus production, and the increased airway resistance in the lungs were significantly reduced by the administration of AD4. We also found that the administration of AD4 decreased the increases of the NF-κB and hypoxia-inducible factor-1α (HIF-1α ) levels in nuclear protein extracts of lung tissues after OVA inhalation. These results suggest that AD4 attenuates airway inflammation and hyperresponsiveness by regulating activation of NF-κB and HIF-1α as well as reducing ROS generation in allergic airway disease.

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Section: Discussionmentioning

confidence: 99%

A novel thiol compound, N-acetylcysteine amide, attenuates allergic airway disease by regulating activation of NF-κB and hypoxia-inducible factor-1α

Lee

Kim²,

Park³

et al. 2007

Exp Mol Med

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“…Sequences of recombinant plasmids were confirmed using a Big Dye Terminator kit and an ABI automated sequencer. The sources of pSX/g7F, pcDNA3-HA-HIF-1␣, pGEX-HIF-1␣-(531-575), pcDNA3-FLAG-VHL, and (eHRE) 3 -Luc have been described previously (12,34).…”

Section: Cell Cultures and Reagentsmentioning

confidence: 99%

“…The cellular response to hypoxia provides a cardinal example of this (1)(2)(3). Low oxygen tension (1% O 2 ) induces a battery of genes that allow cells to increase their uptake of glucose (through up-regulation of specific isoforms of the glucose transporter) and shift utilization of this energy source from aerobic to glycolytic metabolism (through up-regulation of genes such as phosphofructokinase, aldolase, and glyceraldehyde-3-phosphate dehydrogenase, among others) (4).…”

mentioning

confidence: 99%

Sequence Determinants in Hypoxia-inducible Factor-1α for Hydroxylation by the Prolyl Hydroxylases PHD1, PHD2, and PHD3

Huang

Zhao

Mooney

et al. 2002

Journal of Biological Chemistry

286

246

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Hypoxia-inducible factor (HIF) is a heterodimeric transcription factor induced by hypoxia. Under normoxic conditions, site-specific proline hydroxylation of the ␣ subunits of HIF allows recognition by the von Hippel-Lindau tumor suppressor protein (VHL), a component of an E3 ubiquitin ligase complex that targets these subunits for degradation by the ubiquitin-proteasome pathway. Under hypoxic conditions, this hydroxylation is inhibited, allowing the ␣ subunits of HIF to escape VHL-mediated degradation. Three enzymes, prolyl hydroxylase domain-containing proteins 1, 2, and 3 (PHD1, -2, and -3; also known as HIF prolyl hydroxylase 3, 2, and 1, respectively), have recently been identified that catalyze proline hydroxylation of HIF ␣ subunits. These enzymes hydroxylate specific prolines in HIF ␣ subunits in the context of a strongly conserved LXXLAP sequence motif (where X indicates any amino acid and P indicates the hydroxylacceptor proline). We report here that PHD2 has the highest specific activity toward the primary hydroxylation site of HIF-1␣. Furthermore, and unexpectedly, mutations can be tolerated at the ؊5, ؊2, and ؊1 positions (relative to proline) of the LXXLAP motif. Thus, these results provide evidence that the only obligatory residue for proline hydroxylation in HIF-1␣ is the hydroxylacceptor proline itself.A critical means by which cells respond to stress is by the modulation of gene expression. The cellular response to hypoxia provides a cardinal example of this (1-3). Low oxygen tension (1% O 2 ) induces a battery of genes that allow cells to increase their uptake of glucose (through up-regulation of specific isoforms of the glucose transporter) and shift utilization of this energy source from aerobic to glycolytic metabolism (through up-regulation of genes such as phosphofructokinase, aldolase, and glyceraldehyde-3-phosphate dehydrogenase, among others) (4). Low oxygen tension also induces the upregulation of genes involved in local and systemic responses to hypoxia. An example of the former is vascular endothelial growth factor, a potent angiogenic agent, whereas an example of the latter is erythropoietin, the central regulator of red blood cell maturation. Hypoxia-inducible factor (HIF)1 is a transcription factor that is the master regulator of all of the above genes (1, 2). HIF is heterodimeric and comprises an ␣ and a ␤ subunit, both of which in turn are members of the PAS family of transcription factors. The ␤ subunit is a member of the aryl hydrocarbon nuclear translocator family of proteins. Three ␣ subunit isoforms have been identified, HIF-1␣, HIF-2␣, and HIF-3␣ (5-9). The central mechanism by which HIF is activated by hypoxia is by regulated stabilization of the ␣ subunit. In the case of HIF-1␣, the most intensively studied isoform, two proline residues, Pro-402 and Pro-564, are constitutively hydroxylated under normoxic conditions (10 -13). This hydroxylation allows binding by the von Hippel-Lindau tumor suppressor protein (VHL) (14), the substrate recognition component of an E3 ubiquit...

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“…Many cellular responses to hypoxia are mediated through hypoxia inducible factors (HIFs), members of the PAS family of basic helix-loop-helix transcription factors (3). HIFs function as heterodimeric DNA-binding proteins composed of HIF-␣ and HIF-␤ [or aryl hydrocarbon receptor nuclear translocator (ARNT)] subunits.…”

mentioning

confidence: 99%

Hypoxia inducible factor 1α regulates T cell receptor signal transduction

Neumann

Yang

Biju

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

107

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Low oxygen pressures exist in many solid tissues, including primary and secondary lymphoid organs. One key element in cellular adaptation to hypoxia is induced expression of hypoxia inducible factor (Hif) 1␣. Here, we have examined the effect of Hif-1␣, isolated from the myriad other effects of hypoxia, on T cell receptor (TCR) signaling in thymocytes. Because pVHL (von Hippel-Lindau protein) directs the proteolysis of Hif-1␣ under ''normoxic'' conditions, we achieved constitutive stabilization of Hif-1␣ through thymic deletion of Vhlh and reversed Hif-1␣ stabilization with double deletion of Vhlh and Hif-1␣. We found that constitutive activity of Hif-1␣ resulted in diminished Ca 2؉ response upon TCR crosslinking despite equivalent activation of phospholipase C␥1, normal intracellular Ca 2؉ stores, and normal entry of Ca 2؉ across the plasma membrane. Altered Ca 2؉ response was instead due to accelerated removal of Ca 2؉ from the cytoplasm into intracellular compartments, which occurred in association with Hif-1␣-dependent overexpression of the calcium pump SERCA2 (sarcoplasmic͞ endoplasmic reticulum calcium ATPase 2). These data suggest a unique mechanism for control of TCR signaling through Hif-1␣, which may be operative at the physiologic oxygen tensions seen in solid lymphoid organs.calcium ͉ lymphocytes

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How oxygen makes its presence felt: Figure 1.

Cited by 141 publications

References 41 publications

A novel thiol compound, N-acetylcysteine amide, attenuates allergic airway disease by regulating activation of NF-κB and hypoxia-inducible factor-1α

A novel thiol compound, N-acetylcysteine amide, attenuates allergic airway disease by regulating activation of NF-κB and hypoxia-inducible factor-1α

Sequence Determinants in Hypoxia-inducible Factor-1α for Hydroxylation by the Prolyl Hydroxylases PHD1, PHD2, and PHD3

Hypoxia inducible factor 1α regulates T cell receptor signal transduction

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