scholarly journals Carboxyl-Terminal Transactivation Activity of Hypoxia-Inducible Factor 1α Is Governed by a von Hippel-Lindau Protein-Independent, Hydroxylation-Regulated Association with p300/CBP

2002 ◽  
Vol 22 (9) ◽  
pp. 2984-2992 ◽  
Author(s):  
Nianli Sang ◽  
Jie Fang ◽  
Vickram Srinivas ◽  
Irene Leshchinsky ◽  
Jaime Caro
Keyword(s):  
Hypoxia Inducible Factor ◽  
Adaptation To Hypoxia ◽  
Physical Interaction ◽  
Prolyl Hydroxylases ◽  
Von Hippel Lindau ◽  
Hypoxia Inducible Factor 1 ◽  
Transactivation Activity ◽  
Oxygen Homeostasis ◽  
Stimulation Of

ABSTRACT Hypoxia-inducible factor 1 complex (HIF-1) plays a pivotal role in oxygen homeostasis and adaptation to hypoxia. Its function is controlled by both the protein stability and the transactivation activity of its alpha subunit, HIF-1α. Hydroxylation of at least two prolyl residues in the oxygen-dependent degradation domain of HIF-1α regulates its interaction with the von Hippel-Lindau protein (VHL) that targets HIF-1α for ubiquitination and proteasomal degradation. Several prolyl hydroxylases have been found to specifically hydroxylate HIF-1α. In this report, we investigated possible roles of VHL and hydroxylases in the regulation of the transactivation activity of the C-terminal activating domain (CAD) of HIF-1α. We demonstrate that regulation of the transactivation activity of HIF-1α CAD also involves hydroxylase activity but does not require functional VHL. In addition, stimulation of the CAD activity by a hydoxylase inhibitor, hypoxia, and desferrioxamine was severely blocked by the adenoviral oncoprotein E1A but not by an E1A mutant defective in targeting p300/CBP. We further demonstrate that a hydroxylase inhibitor, hypoxia, and desferrioxamine promote the functional and physical interaction between HIF-1α CAD and p300/CBP in vivo. Taken together, our data provide evidence that hypoxia-regulated stabilization and transcriptional stimulation of HIF-1α function are regulated through partially overlapping but distinguishable pathways.

Involvement of oxygen-sensing pathways in physiologic and pathologic erythropoiesis

Blood ◽  
2009 ◽  
Vol 114 (10) ◽  
pp. 2015-2019 ◽  
Author(s):  
Gregg L. Semenza
Keyword(s):  
Blood Cells ◽  
Tissue Oxygenation ◽  
Hypoxia Inducible Factor ◽  
Α Subunit ◽  
Vhl Gene ◽  
Von Hippel Lindau ◽  
Hypoxia Inducible Factor 1 ◽  
Oxygen Homeostasis ◽  
Genes Encoding ◽  
Asparaginyl Hydroxylase

Abstract Red blood cells deliver O2 from the lungs to every cell in the human body. Reduced tissue oxygenation triggers increased production of erythropoietin by hypoxia-inducible factor 1 (HIF-1), which is a transcriptional activator composed of an O2-regulated α subunit and a constitutively expressed β subunit. Hydroxylation of HIF-1α or HIF-2α by the asparaginyl hydroxylase FIH-1 blocks coactivator binding and transactivation. Hydroxylation of HIF-1α or HIF-2α by the prolyl hydroxylase PHD2 is required for binding of the von Hippel-Lindau protein (VHL), leading to ubiquitination and proteasomal degradation. Mutations in the genes encoding VHL, PHD2, and HIF-2α have been identified in patients with familial erythrocytosis. Patients with Chuvash polycythemia, who are homozygous for a missense mutation in the VHL gene, have multisystem pathology attributable to dysregulated oxygen homeostasis. Intense efforts are under way to identify small molecule hydroxylase inhibitors that can be administered chronically to selectively induce erythropoiesis without undesirable side effects.

scholarly journals Hypoxia and Oxygen-Sensing Signaling in Gene Regulation and Cancer Progression

2020 ◽  
Vol 21 (21) ◽  
pp. 8162
Author(s):  
Guang Yang ◽  
Rachel Shi ◽  
Qing Zhang
Keyword(s):  
Gene Regulation ◽  
Cancer Progression ◽  
Current Knowledge ◽  
Oxygen Sensing ◽  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylases ◽  
Von Hippel Lindau ◽  
Oxygen Homeostasis ◽  
Jmjc Domain ◽  
Encoding Protein

Oxygen homeostasis regulation is the most fundamental cellular process for adjusting physiological oxygen variations, and its irregularity leads to various human diseases, including cancer. Hypoxia is closely associated with cancer development, and hypoxia/oxygen-sensing signaling plays critical roles in the modulation of cancer progression. The key molecules of the hypoxia/oxygen-sensing signaling include the transcriptional regulator hypoxia-inducible factor (HIF) which widely controls oxygen responsive genes, the central members of the 2-oxoglutarate (2-OG)-dependent dioxygenases, such as prolyl hydroxylase (PHD or EglN), and an E3 ubiquitin ligase component for HIF degeneration called von Hippel–Lindau (encoding protein pVHL). In this review, we summarize the current knowledge about the canonical hypoxia signaling, HIF transcription factors, and pVHL. In addition, the role of 2-OG-dependent enzymes, such as DNA/RNA-modifying enzymes, JmjC domain-containing enzymes, and prolyl hydroxylases, in gene regulation of cancer progression, is specifically reviewed. We also discuss the therapeutic advancement of targeting hypoxia and oxygen sensing pathways in cancer.

scholarly journals Protective Effect of the HIF-1A Pro582Ser Polymorphism on Severe Diabetic Retinopathy

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Neda Rajamand Ekberg ◽  
Sofie Eliasson ◽  
Young Wen Li ◽  
Xiaowei Zheng ◽  
Katerina Chatzidionysiou ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Protective Effect ◽  
Hypoxia Inducible Factor ◽  
Adaptation To Hypoxia ◽  
Relative Resistance ◽  
Transactivation Activity ◽  
Oxygen Homeostasis ◽  
Repressive Effect ◽  
Effect Of Glucose

Objective. Hypoxia is central in the pathogenesis of diabetic retinopathy (DR). Hypoxia-inducible factor-1 (HIF-1) is the key mediator in cellular oxygen homeostasis that facilitates the adaptation to hypoxia. HIF-1 is repressed by hyperglycemia contributing by this to the development of complications in diabetes. Recent work has shown that the HIF-1A Pro582Ser polymorphism is more resistant to hyperglycemia-mediated repression, thus protecting against the development of diabetic nephropathy. In this study, we have investigated the effect of the HIF-1A Pro582Ser polymorphism on the development of DR and further dissected the mechanisms by which the polymorphism confers a relative resistance to the repressive effect of hyperglycemia. Research Design and Method. 703 patients with type 1 diabetes mellitus from one endocrine department were included in the study. The degree of retinopathy was correlated to the HIF-1A Pro582Ser polymorphism. The effect of glucose on a stable HIF-1A construct with a Pro582Ser mutation was evaluated in vitro. Results. We identified a protective effect of HIF-1A Pro582Ser against developing severe DR with a risk reduction of 95%, even when adjusting for known risk factors for DR such as diabetes duration, hyperglycemia, and hypertension. The Pro582Ser mutation does not cancel the destabilizing effect of glucose but is followed by an increased transactivation activity even in high glucose concentrations. Conclusion. The HIF-1A genetic polymorphism has a protective effect on the development of severe DR. Moreover, the relative resistance of the HIF-1A Pro582Ser polymorphism to the repressive effect of hyperglycemia is due to the transactivation activity rather than the protein stability of HIF-1α.

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 Characterization of the pVHL Interactome in Human Testis Using High-Throughput Library Screening

2021 ◽  
Author(s):  
Antonella Falconieri ◽  
Giovanni Minervini ◽  
Federica Quaglia ◽  
Geppo Sartori ◽  
Silvio C.E. Tosatto
Keyword(s):  
Hypoxia Inducible Factor ◽  
Conditional Knockout ◽  
Human Testis ◽  
Adaptation To Hypoxia ◽  
Library Screening ◽  
Mice Model ◽  
Von Hippel Lindau ◽  
Hypoxia Inducible Factor 1 ◽  
Increased Risk ◽  
Human Proteins

Functional impairment of the von Hippel-Lindau (pVHL) tumor suppressor is causative of a familiar increased risk to develop cancer. As E3 substrate recognition particle, pVHL marks for degradation the hypoxia inducible factor 1α (HIF-1α) in normoxic conditions, thus acting as a key regulator of both acute and chronic cell adaptation to hypoxia. Further evidence showed pVHL to also play relevant roles in microtubules stabilization, participate in the formation of the extracellular matrix, as well as to regulate cell senescence and apoptosis. Male mice model carrying VHL gene conditional knockout present significative abnormalities in testis development paired with defects in spermatogenesis and infertility, indicating that pVHL exerts testis-specific roles, at least in mice. Here, we describe 55 novel interactors of the human pVHL obtained by testis-tissue library screening. We show that pVHL interacts with multiple human proteins directly involved in spermatogenesis and reproductive metabolism, suggesting that, in addition to its role in cancer formation, pVHL may be pivotal in the correct gonads development also in human.

scholarly journals Tumor Necrosis Factor-α Causes Accumulation of a Ubiquitinated Form of Hypoxia Inducible Factor-1α through a Nuclear Factor-κB-Dependent Pathway

2003 ◽  
Vol 14 (6) ◽  
pp. 2216-2225 ◽  
Author(s):  
Jie Zhou ◽  
Tobias Schmid ◽  
Bernhard Brüne
Keyword(s):  
Hypoxia Inducible Factor ◽  
Nuclear Factor Κb ◽  
Metabolic Adaptation ◽  
Adaptation To Hypoxia ◽  
Nuclear Factor ◽  
Human Embryonic Kidney Cells ◽  
Von Hippel Lindau ◽  
Hypoxia Inducible Factor 1 ◽  
Tnf Α ◽  
Factor Α

Hypoxia-inducible factor-1 (HIF-1) is a regulator of metabolic adaptation to hypoxia. It is now appreciated that HIF-1α accumulation is achieved under normoxic conditions by various factors, such as TNF-α. Here, it was our intention to gain insight into the signaling mechanisms used by TNF-α to stimulate HIF-1α. In tubular LLC-PK1or human embryonic kidney cells, TNF-α induced accumulation of HIF-1α protein but not HIF-1α mRNA. Blocking nuclear factor (NF)-κB with sulfasalazine or expression of an IκB superrepressor attenuated HIF-1α accumulation, whereas transfection of active p50/p65-NF-κB subunits mimicked a TNF-α response. Experiments with actinomycin D and cycloheximide also pointed to a transcriptional and translational process in facilitating the TNF-α response. Interestingly, and in contrast to established hypoxic signaling concepts, TNF-α elicited HIF-1α accumulation in a ubiquitinated form that still bound the von Hippel-Lindau (pVHL) protein. These data indicate that HIF-1α accumulation by TNF-α demands the NF-κB pathway, preserves ubiquitination of HIF-1α, and allows the HIF-1α-pVHL interaction.

scholarly journals A small molecule HIF-1α stabilizer that accelerates diabetic wound healing

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Guodong Li ◽  
Chung-Nga Ko ◽  
Dan Li ◽  
Chao Yang ◽  
Wanhe Wang ◽  
...  
Keyword(s):  
Wound Healing ◽  
Small Molecule ◽  
Hypoxia Inducible Factor ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Impaired Wound Healing ◽  
Von Hippel Lindau ◽  
Design And Synthesis

AbstractImpaired wound healing and ulcer complications are a leading cause of death in diabetic patients. In this study, we report the design and synthesis of a cyclometalated iridium(III) metal complex 1a as a stabilizer of hypoxia-inducible factor-1α (HIF-1α). In vitro biophysical and cellular analyses demonstrate that this compound binds to Von Hippel-Lindau (VHL) and inhibits the VHL–HIF-1α interaction. Furthermore, the compound accumulates HIF-1α levels in cellulo and activates HIF-1α mediated gene expression, including VEGF, GLUT1, and EPO. In in vivo mouse models, the compound significantly accelerates wound closure in both normal and diabetic mice, with a greater effect being observed in the diabetic group. We also demonstrate that HIF-1α driven genes related to wound healing (i.e. HSP-90, VEGFR-1, SDF-1, SCF, and Tie-2) are increased in the wound tissue of 1a-treated diabetic mice (including, db/db, HFD/STZ and STZ models). Our study demonstrates a small molecule stabilizer of HIF-1α as a promising therapeutic agent for wound healing, and, more importantly, validates the feasibility of treating diabetic wounds by blocking the VHL and HIF-1α interaction.

scholarly journals Inhibitor of DNA Binding 1 Is Induced during Kidney Ischemia-Reperfusion and Is Critical for the Induction of Hypoxia-Inducible Factor-1α

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Dan Wen ◽  
Yan-Fang Zou ◽  
Yao-Hui Gao ◽  
Qian Zhao ◽  
Yin-Yin Xie ◽  
...  
Keyword(s):  
Dna Binding ◽  
Ischemia Reperfusion ◽  
Hypoxia Inducible Factor ◽  
Kidney Injury ◽  
Mrna Levels ◽  
Hypoxia Inducible Factor 1 ◽  
Renal Tubular ◽  
Inhibitor Of Dna Binding

In this study, rat models of acute kidney injury (AKI) induced by renal ischemia-reperfusion (I/R) and HK-2 cell models of hypoxia-reoxygenation (H/R) were established to investigate the expression of inhibitor of DNA binding 1 (ID1) in AKI, and the regulation relationship between ID1 and hypoxia-inducible factor 1 alpha (HIF-1α). Through western blot, quantitative real-time PCR, immunohistochemistry, and other experiment methods, the induction of ID1 after renal I/R in vivo was observed, which was expressed mainly in renal tubular epithelial cells (TECs). ID1 expression was upregulated in in vitro H/R models at both the protein and mRNA levels. Via RNAi, it was found that ID1 induction was inhibited with silencing of HIF-1α. Moreover, the suppression of ID1 mRNA expression could lead to decreased expression and transcription of HIF-1αduring hypoxia and reoxygenation. In addition, it was demonstrated that both ID1 and HIF-1αcan regulate the transcription of twist. This study demonstrated that ID1 is induced in renal TECs during I/R and can regulate the transcription and expression of HIF-1α.

scholarly journals The Hypoxia-Inducible Factor 2α N-Terminal and C-Terminal Transactivation Domains Cooperate To Promote Renal Tumorigenesis In Vivo

2007 ◽  
Vol 27 (6) ◽  
pp. 2092-2102 ◽  
Author(s):  
Qin Yan ◽  
Steven Bartz ◽  
Mao Mao ◽  
Lianjie Li ◽  
William G. Kaelin
Keyword(s):  
Transcriptional Activation ◽  
Hypoxia Inducible Factor ◽  
Gene Activation ◽  
Tumor Formation ◽  
Transactivation Domain ◽  
Renal Carcinogenesis ◽  
Von Hippel Lindau ◽  
Transactivation Domains ◽  
Relative Contribution

ABSTRACT Hypoxia-inducible factor (HIF) is a heterodimeric transcription factor, consisting of an alpha subunit and a beta subunit, that controls cellular responses to hypoxia. HIFα contains two transcriptional activation domains called the N-terminal transactivation domain (NTAD) and the C-terminal transactivation domain (CTAD). HIFα is destabilized by prolyl hydroxylation catalyzed by EglN family members. In addition, CTAD function is inhibited by asparagine hydroxylation catalyzed by FIH1. Both hydroxylation reactions are linked to oxygen availability. The von Hippel-Lindau tumor suppressor protein (pVHL) is frequently mutated in kidney cancer and is part of the ubiquitin ligase complex that targets prolyl hydroxylated HIFα for destruction. Recent studies suggest that HIF2α plays an especially important role in promoting tumor formation by pVHL-defective renal carcinoma cells among the three HIFα paralogs. Here we dissected the relative contribution of the two HIF2α transactivation domains to hypoxic gene activation and renal carcinogenesis and investigated the regulation of the HIF2α CTAD by FIH1. We found that the HIF2α NTAD is capable of activating both artificial and naturally occurring HIF-responsive promoters in the absence of the CTAD. Moreover, we found that the HIF2α CTAD, in contrast to the HIF1α CTAD, is relatively resistant to the inhibitory effects of FIH1 under normoxic conditions and that, perhaps as a result, both the NTAD and CTAD cooperate to promote renal carcinogenesis in vivo.

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