Oxygen sensing and hypoxia-induced responses

2007 ◽  
Vol 43 ◽  
pp. 1-16 ◽  
Author(s):  
Mathew L. Coleman ◽  
Peter J. Ratcliffe
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Oxygen Sensing ◽  
Hypoxia Inducible Factor ◽  
Signalling Pathway ◽  
Adaptation To Hypoxia ◽  
Induced Responses ◽  
Intracellular Proteins ◽  
Multicellular Organisms ◽  
Direct Incorporation

Low cellular oxygenation (hypoxia) represents a significant threat to the viability of affected tissues. Multicellular organisms have evolved a highly conserved signalling pathway that directs many of the changes in gene expression that underpin physiological oxygen homoeostasis. Oxygen-sensing enzymes in this pathway control the activity of the HIF (hypoxia-inducible factor) transcription factor by the direct incorporation of molecular oxygen into the post-translational hydroxylation of specific residues. This represents the canonical hypoxia signalling pathway which regulates a plethora of genes involved in adaptation to hypoxia. The HIF hydroxylases have been identified in other biological contexts, consistent with the possibility that they have other substrates. Furthermore, several intracellular proteins have been demonstrated, directly or indirectly, to be hydroxylated, although the protein hydroxylases responsible have yet to be identified. This chapter will summarize what is currently known about the canonical HIF hydroxylase signalling pathway and will speculate on the existence of other oxygen-sensing enzymes and the role they may play in signalling hypoxia through other pathways.

scholarly journals The HIF target ATG9A is essential for epithelial barrier function and tight junction biogenesis

2020 ◽  
Vol 31 (20) ◽  
pp. 2249-2258
Author(s):  
Alexander S. Dowdell ◽  
Ian M. Cartwright ◽  
Matthew S. Goldberg ◽  
Rachael Kostelecky ◽  
Tyler Ross ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Tight Junction ◽  
Barrier Function ◽  
Intestinal Epithelial Cells ◽  
Hypoxia Inducible Factor ◽  
Epithelial Barrier ◽  
Adaptation To Hypoxia ◽  
Intestinal Epithelial ◽  
Hypoxia Response ◽  
Epithelial Barrier Function

The transcription factor hypoxia-inducible factor (HIF) mediates adaptation to hypoxia. We found that HIF regulates the autophagy protein ATG9A in intestinal epithelial cells. Subsequent knockdown of ATG9A resulted in tight junction mislocalization and cytoskeletal defects. These results suggest a link among the hypoxia response, autophagy, and junctional biogenesis.

scholarly journals Structure of the N-terminal domain of the protein Expansion: an `Expansion' to the Smad MH2 fold

2015 ◽  
Vol 71 (4) ◽  
pp. 844-853 ◽  
Author(s):  
Mads Beich-Frandsen ◽  
Eric Aragón ◽  
Marta Llimargas ◽  
Jordi Benach ◽  
Antoni Riera ◽  
...  
Keyword(s):  
Gene Expression ◽  
Crystal Structure ◽  
Transcription Factor ◽  
Protein Interaction ◽  
Signalling Pathway ◽  
Interaction Site ◽  
Terminal Domain ◽  
Smad Proteins ◽  
Helical Region

Gene-expression changes observed inDrosophilaembryos after inducing the transcription factor Tramtrack led to the identification of the protein Expansion. Expansion contains an N-terminal domain similar in sequence to the MH2 domain characteristic of Smad proteins, which are the central mediators of the effects of the TGF-β signalling pathway. Apart from Smads and Expansion, no other type of protein belonging to the known kingdoms of life contains MH2 domains. To compare the Expansion and Smad MH2 domains, the crystal structure of the Expansion domain was determined at 1.6 Å resolution, the first structure of a non-Smad MH2 domain to be characterized to date. The structure displays the main features of the canonical MH2 fold with two main differences: the addition of an α-helical region and the remodelling of a protein-interaction site that is conserved in the MH2 domain of Smads. Owing to these differences, to the new domain was referred to as Nα-MH2. Despite the presence of the Nα-MH2 domain, Expansion does not participate in TGF-β signalling; instead, it is required for other activities specific to the protostome phyla. Based on the structural similarities to the MH2 fold, it is proposed that the Nα-MH2 domain should be classified as a new member of the Smad/FHA superfamily.

scholarly journals Clinical significance of expression of the marker of adaptation to hypoxia HIF-1α in pregnant women with initial forms of venous disease

2020 ◽  
Author(s):  
E. Iu. Iupatov ◽  
L. I. Maltseva ◽  
T. P. Zefirova ◽  
R. S. Zamaleeva ◽  
I. M. Ignatiev ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Pregnant Women ◽  
Hypoxia Inducible Factor ◽  
Perinatal Outcomes ◽  
Main Group ◽  
Control Group ◽  
Adaptation To Hypoxia ◽  
Venous Disease ◽  
Healthy Children ◽  
Venous Valves

Aim: to study the activity of the hypoxia marker HIF-1α (hypoxia-inducible factor-1α) in pregnant women with phlebopathy.Materials and Methods. We examined 70 women with phlebopathy in the dynamics of pregnancy. The main group consisted of 30 patients whose newborns had signs of hypoxia; the control group consisted of 40 women with healthy children. All women underwent ultrasound examinations of the veins of the lower extremities and pelvis with an assessment of vascular patency, the condition of the venous valves, and the phenomenon of platelet sludge. The expression of the HIF-1α transcription factor at 18–20 and 36 weeks was performed by real-time PCR.Results. Disorder of veins functional state was found in all pregnant women of the main group, which was accompanied by the formation of platelet sludge of varying degrees in the area of the venous valves in the majority, signs of endothelial dysfunction and venous hypoxia – an increase in the expression of the hypoxia gene HIF1-α by 2.18 times. In the women of the control group the indicators were not violated.Conclusion. The transcription factor HIF1-α can be considered a marker of unfavorable perinatal outcomes in pregnant women with signs of phlebopathy.

Persisting mild hypothermia suppresses hypoxia-inducible factor-1α protein synthesis and hypoxia-inducible factor-1-mediated gene expression

2010 ◽  
Vol 298 (3) ◽  
pp. R661-R671 ◽  
Author(s):  
Tomoharu Tanaka ◽  
Takuhiko Wakamatsu ◽  
Hiroki Daijo ◽  
Seiko Oda ◽  
Shinichi Kai ◽  
...  
Keyword(s):  
Gene Expression ◽  
Low Temperature ◽  
Hypoxia Inducible Factor ◽  
The Body ◽  
The Other ◽  
Adaptation To Hypoxia ◽  
Hypoxia Inducible Factor 1 ◽  
Other Hand

The transcription factor hypoxia-inducible factor-1 (HIF-1) plays an essential role in regulating gene expression in response to hypoxia-ischemia. Ischemia causes the tissue not only to be hypoxic but also to be hypothermic because of the hypoperfusion under certain circumstances. On the other hand, the induced hypothermia is one of the most common therapeutic modalities to extend tolerance to hypoxia. Although hypoxia elicits a variety of cellular and systemic responses at different organizational levels in the body, little is known about how hypoxia-induced responses are affected by low temperature. We examined the influence of mild hypothermic conditions (28–32°C) on HIF-1 in both in vitro and in vivo settings. In vitro experiments adopting cultured cells elucidated that hypoxia-induced HIF-1 activation was resistant to 4-h exposure to the low temperature. In contrast, exposure to the low temperature as long as 24 h suppressed HIF-1 activation and the subsequent upregulation of HIF-1 target genes such as VEGF or GLUT-1. HIF-1α protein stability in the cell was not affected by hypothermic treatment. Furthermore, intracellular ATP content was reduced under 1% O2 conditions but was not largely affected by hypothermic treatment. The evidence indicates that reduction of oxygen consumption is not largely involved in suppression of HIF-1. In addition, we demonstrated that HIF-1 DNA-binding activity and HIF-1-dependent gene expressions induced under 10% O2 atmosphere in mouse brain were not influenced by treatment under 3-h hypothermic temperature but were inhibited under 5-h treatment. On the other hand, we indicated that warming ischemic legs of mice for 24 h preserved HIF-1 activity. In this report we describe for the first time that persisting low temperature significantly reduced HIF-1α neosynthesis under hypoxic conditions, leading to a decrease in gene expression for adaptation to hypoxia in both in vitro and in vivo settings.

scholarly journals Regulation of Jumonji-domain-containing histone demethylases by hypoxia-inducible factor (HIF)-1α

2008 ◽  
Vol 416 (3) ◽  
pp. 387-394 ◽  
Author(s):  
Patrick J. Pollard ◽  
Christoph Loenarz ◽  
David R. Mole ◽  
Michael A. McDonough ◽  
Jonathan M. Gleadle ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Cell Lines ◽  
Epigenetic Regulation ◽  
Histone Methylation ◽  
Chromatin Immunoprecipitation ◽  
Methylation Status ◽  
Hypoxia Inducible Factor ◽  
Transcriptional Response ◽  
Histone Demethylases

The transcription factor HIF (hypoxia-inducible factor) mediates a highly pleiotrophic response to hypoxia. Many recent studies have focused on defining the extent of this transcriptional response. In the present study we have analysed regulation by hypoxia among transcripts encoding human Fe(II)- and 2-oxoglutarate-dependent oxygenases. Our results show that many of these genes are regulated by hypoxia and define two groups of histone demethylases as new classes of hypoxia-regulated genes. Patterns of induction were consistent across a range of cell lines with JMJD1A (where JMJD is Jumonji-domain containing) and JMJD2B demonstrating robust, and JMJD2C more modest, up-regulation by hypoxia. Functional genetic and chromatin immunoprecipitation studies demonstrated the importance of HIF-1α in mediating these responses. Given the importance of histone methylation status in defining patterns of gene expression under different physiological and pathophysiological conditions, these findings predict a role for the HIF system in epigenetic regulation.

scholarly journals Epstein–Barr virus-encoded EBNA1 modulates the AP-1 transcription factor pathway in nasopharyngeal carcinoma cells and enhances angiogenesis in vitro

2008 ◽  
Vol 89 (11) ◽  
pp. 2833-2842 ◽  
Author(s):  
John D. O'Neil ◽  
Thomas J. Owen ◽  
Victoria H. J. Wood ◽  
Kathryn L. Date ◽  
Robert Valentine ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Nasopharyngeal Carcinoma ◽  
Epstein Barr Virus ◽  
Cell Model ◽  
Cell Signalling ◽  
Hypoxia Inducible Factor ◽  
Barr Virus ◽  
Epstein Barr

The Epstein–Barr virus (EBV)-encoded EBNA1 protein is expressed in all virus-associated tumours, including nasopharyngeal carcinoma (NPC), where it plays an essential role in EBV genome maintenance, replication and transcription. Previous studies suggest that EBNA1 may have additional effects relevant to oncogenesis, including enhancement of cell survival, raising the possibility that EBNA1 may influence cellular gene expression. We have recently demonstrated by gene expression microarray profiling in an NPC cell model that EBNA1 influences the expression of a range of cellular genes, including those involved in transcription, translation and cell signalling. Here, we report for the first time that EBNA1 enhances activity of the AP-1 transcription factor in NPC cells and demonstrate that this is achieved by EBNA1 binding to the promoters of c-Jun and ATF2, enhancing their expression. In addition, we demonstrate elevated expression of the AP-1 targets interleukin 8, vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α in response to EBNA1 expression, which enhances microtubule formation in an in vitro angiogenesis assay. Furthermore, we confirm elevation of VEGF and the phosphorylated isoforms of c-Jun and ATF2 in NPC biopsies. These findings implicate EBNA1 in the angiogenic process and suggest that this viral protein might directly contribute to the development and aggressively metastatic nature of NPC.

scholarly journals Hypoxic regulation of erythropoiesis and iron metabolism

2010 ◽  
Vol 299 (1) ◽  
pp. F1-F13 ◽  
Author(s):  
Volker H. Haase
Keyword(s):  
Transcription Factor ◽  
Blood Cell ◽  
Molecular Basis ◽  
Molecular Mechanisms ◽  
Oxygen Sensor ◽  
Hypoxia Inducible Factor ◽  
Adaptation To Hypoxia ◽  
Cellular Adaptation ◽  
Hypoxic Induction ◽  
Highly Sensitive

The kidney is a highly sensitive oxygen sensor and plays a central role in mediating the hypoxic induction of red blood cell production. Efforts to understand the molecular basis of oxygen-regulated erythropoiesis have led to the identification of erythropoietin (EPO), which is essential for normal erythropoiesis and to the purification of hypoxia-inducible factor (HIF), the transcription factor that regulates EPO synthesis and mediates cellular adaptation to hypoxia. Recent insights into the molecular mechanisms that control and integrate cellular and systemic erythropoiesis-promoting hypoxia responses and their potential as a therapeutic target for the treatment of renal anemia are discussed in this review.

HIF-1, a Mediator of the Molecular Response to Hypoxia

Physiology ◽  
1997 ◽  
Vol 12 (5) ◽  
pp. 214-218 ◽  
Author(s):  
M Gassmann ◽  
RH Wenger
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Oxygen Delivery ◽  
Oxygen Supply ◽  
Oxygen Sensing ◽  
Molecular Response ◽  
Recent Information ◽  
Anatomy And Physiology ◽  
Signaling Mechanisms ◽  
Molecular Anatomy

Normal oxygen delivery is essential for vertebrate homeostasis. Adaptation to changes in oxygen supply involves complex but specific changes in gene expression. This review summarizes recent information on the molecular anatomy and physiology of the first hypoxia-inducible transcription factor (HIF-1) discovered in mammals. Identifications of HIF-1 provides an important tool for investigating oxygen-sensing and signaling mechanisms.

scholarly journals p300 relieves p53-evoked transcriptional repression of hypoxia-inducible factor-1 (HIF-1)

2004 ◽  
Vol 380 (1) ◽  
pp. 289-295 ◽  
Author(s):  
Tobias SCHMID ◽  
Jie ZHOU ◽  
Roman KÖHL ◽  
Bernhard BRÜNE
Keyword(s):  
Transcription Factor ◽  
Transcriptional Repression ◽  
Hypoxia Inducible Factor ◽  
Severe Hypoxia ◽  
Metabolic Adaptation ◽  
Adaptation To Hypoxia ◽  
P53 Expression ◽  
Hypoxia Inducible Factor 1 ◽  
Reporter Activity

HIF-1 (hypoxia-inducible factor-1), a heterodimeric transcription factor comprising HIF-1α and HIF-1β subunits, serves as a key regulator of metabolic adaptation to hypoxia. HIF-1 activity largely increases during hypoxia by attenuating pVHL (von Hippel–Lindau protein)-dependent ubiquitination and subsequent 26 S-proteasomal degradation of HIF-1α. Besides HIF-1, the transcription factor and tumour suppressor p53 accumulates and is activated under conditions of prolonged/severe hypoxia. Recently, the interaction between p53 and HIF-1α was reported to evoke HIF-1α degradation. Destruction of HIF-1α by p53 was corroborated in the present study by using pVHL-deficient RCC4 (renal carcinoma) cells, supporting the notion of a pVHL-independent degradation process. In addition, low p53 expression repressed HIF-1 transactivation without affecting HIF-1α protein amount. Establishing that p53-evoked inhibition of HIF-1 reporter activity was relieved upon co-transfection of p300 suggested competition between p53 and HIF-1 for limiting amounts of the shared co-activator p300. This assumption was confirmed by showing competitive binding of in vitro transcription/translation-generated p53 and HIF-1α to the CH1 domain of p300 in vitro. We conclude that low p53 expression attenuates HIF-1 transactivation by competing for p300, whereas high p53 expression destroys the HIF-1α protein and thereby eliminates HIF-1 reporter activity. Thus once p53 becomes activated under conditions of severe hypoxia/anoxia, it contributes to terminating HIF-1 responses.

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