Hypoxia-inducible factor 1α protein expression is controlled by oxygen-regulated ubiquitination that is disrupted by deletions and missense mutations

Sutter, Carrie Hayes; Laughner, Erik; Semenza, Gregg L.

doi:10.1073/pnas.080072497

Cited by 264 publications

(178 citation statements)

References 32 publications

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“…19 But the fact that CNS could express HIF-1a was first revealed when it was detected in the ischemic brain resulting from permanent middle cerebral artery occlusion. 11 Since ischemia and the subsequent hypoxia are the focus of secondary SCI, here we hypothesized that HIF-1a and its target genes should be involved in the biological process of the injured spinal cord and that their involvement could have an important impact on the courses of the disease.…”

Section: Discussionmentioning

confidence: 99%

The experimental study of hypoxia-inducible factor-1α and its target genes in spinal cord injury

Xiaowei

Ninghui

et al. 2005

Spinal Cord

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Study design: Animal model of compressive spinal cord injury (SCI), reverse transcriptionpolymerase chain reaction (RT-PCR), in situ hybridization (ISH), immunohistochemistry (IHC) and enzymehistochemistry (EHC) were used to test the hypothesis that hypoxia-inducible factor-1a (HIF-1a) and the target genes activated by HIF-1a are involved in cell hypoxia tolerance and tissue vascularity to help injured tissue to go through the stress disease. Objective:To determine whether HIF-1a and its target genes associated with hypoxia tolerance and neovascularization take part in the pathophysiological procedure of SCI in rats. Setting: Yunnan University, China. Methods:Random-bred adult male Sprague-Dawley (SD) rats weighing 250750 g were prepared for compressive SCI models. After receiving compressive injury at T 10 , rats were sacrificed at different times from 6 h to 1 week after injury. The injured cords were removed, and HIF-1a and its target genes were assayed by RT-PCR, ISH, IHC and EHC. The data were statistically analyzed.

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Section: Discussionmentioning

confidence: 99%

The experimental study of hypoxia-inducible factor-1α and its target genes in spinal cord injury

Xiaowei

Ninghui

et al. 2005

Spinal Cord

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“…Under nonhypoxic conditions the HIF-1␣ subunit is subjected to ubiquitination and proteasomal degradation (3). In response to hypoxia, ubiquitination and degradation of HIF-1␣ are inhibited, resulting in rapid accumulation of the protein (4). In addition, the activity of the HIF-1␣ transactivation domains is induced by hypoxia (5,6).…”

Section: Molecular Biologymentioning

confidence: 99%

Hypoxia-Inducible Factor 1: Control of Oxygen Homeostasis in Health and Disease

2001

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“…It has been located to the amino acid residues 401-603 of human HIF-1␣. This region overlaps with a vHL binding domain (526 -641) (16,17) and comprises two essential proline residues (Pro-402 and Pro-564) that are hydroxylated by PHDs under normoxic conditions (4,5). To gain further insight into the mechanism of ODD-dependent protein stabilization, we generated chimeric proteins in which the C-terminal part of the ODD region of human HIF-1␣ (residues 530 -603) was fused to the GFP or luciferase open reading frames (Fig.…”

Section: Csa Inhibits Hre-mediated Transcription and Prevents The Hypmentioning

confidence: 99%

Cyclosporin A Prevents the Hypoxic Adaptation by Activating Hypoxia-inducible Factor-1α Pro-564 Hydroxylation

D’Angelo¹,

Duplan²,

Vigne

et al. 2003

Journal of Biological Chemistry

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Cells respond to low oxygen tensions by up-regulating the expression of genes involved in angiogenesis (e.g. vascular endothelial growth factor), erythropoiesis (e.g. erythropoietin), and glycolysis. The transcriptional activation of target genes is induced by a common transcription factor, hypoxia-inducible factor-1 (HIF-1). 1 HIF-1 was first identified as a heterodimeric transactivator that recognizes a specific DNA sequence, termed hypoxia-responsive element (HRE) in the 3Ј-untranslated region of the erythropoietin gene (1). HIF-1 consists of two subunits, HIF-1␣ and the aryl hydrocarbon receptor nuclear translocator, both of which belong to the large family of basic helixloop-helix-per-arnt-sim transcription factors (2, 3). Under normoxic conditions, HIF-1␣ subunits are unstable, being rapidly targeted to the ubiquitin-proteasome pathway. Degradation is mediated by a ubiquitin-protein isopeptide ligase (E3) complex, in which the von Hippel-Lindau protein (vHL) binds to a specific hydroxylated proline residue (Pro-564) within the oxygen-dependent degradation (ODD) domain of HIF-1␣ (4, 5). A major action of hypoxia is to suppress prolyl hydroxylation and degradation of HIF-1␣ by the proteasome. As a consequence, the protein accumulates, migrates to the nucleus, and associates with the aryl hydrocarbon receptor nuclear translocator, and the complex interacts with the HRE of target genes (6, 7). The importance of this mechanism is ascertained by the facts that vessel formation is hampered in HIF-1␣ Ϫ/Ϫ knock out mice (8) and that mutations in the vHL gene cause hereditary cancer syndrome associated with dysregulated angiogenesis and up-regulation of hypoxia-sensitive genes.Cyclosporin A (CsA) is a potent immunosuppressive agent used after organ transplantation and in the treatment of several autoimmune diseases. CsA is well known to be nephrotoxic probably as a consequence of the constriction of renal vessels and of the resulting hypoxia. Circumstantial evidence further suggests that CsA interferes with the hypoxic signaling cascade. (i) Maruyama et al. (9) reported that CsA inhibited vascular endothelial growth factor production by human lymphocytes. (ii) CsA inhibits erythropoietin production in anemic mice (10). (iii) Kang et al. (11) reported that vascular endothelial growth factor reverses some of the post-CsA-mediated hypertension and nephropathy in the rat. (iv) Erythropoietin deficiency has been proposed as a cause of the anemia observed in children following cardiac transplantation (12). These would suggest that CsA inhibits the cellular responses that are mediated by HIF-1␣ and HRE.In the present study, we examine the possible influence of CsA on the hypoxic signaling. Results show that CsA inhibits hypoxia-induced gene transcription by preventing hypoxia-induced and ODD-dependent stabilization of HIF-1␣. We also show that CsA stimulates a kidney prolyl hydroxylase activity that specifically modifies Pro-564 in the ODD domain of HIF-1␣. MATERIALS AND METHODSMaterials-Culture medium, restriction, and ...

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Hypoxia-inducible factor 1α protein expression is controlled by oxygen-regulated ubiquitination that is disrupted by deletions and missense mutations

Cited by 264 publications

References 32 publications

The experimental study of hypoxia-inducible factor-1α and its target genes in spinal cord injury

The experimental study of hypoxia-inducible factor-1α and its target genes in spinal cord injury

Hypoxia-Inducible Factor 1: Control of Oxygen Homeostasis in Health and Disease

Cyclosporin A Prevents the Hypoxic Adaptation by Activating Hypoxia-inducible Factor-1α Pro-564 Hydroxylation

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