scholarly journals Hypoxia-Inducible Factor 1 Is an Inductor of Transcription Factor Activating Protein 2 Epsilon Expression during Chondrogenic Differentiation

2015 ◽  
Vol 2015 ◽  
pp. 1-15 ◽  
Author(s):  
Stephan Niebler ◽  
Peter Angele ◽  
Richard Kujat ◽  
Anja K. Bosserhoff
Keyword(s):  
Transcription Factor ◽  
Chondrogenic Differentiation ◽  
Mrna Level ◽  
Marker Gene ◽  
Hypoxia Inducible Factor ◽  
Oxygen Deprivation ◽  
Hypoxia Inducible Factor 1 ◽  
Hypoxia Marker

The transcription factor AP-2ε(activating enhancer-binding protein epsilon) is expressed in cartilage of humans and mice. However, knowledge about regulatory mechanisms influencing AP-2εexpression is limited. Using quantitative real time PCR, we detected a significant increase in AP-2εmRNA expression comparing initial and late stages of chondrogenic differentiation processesin vitroandin vivo. Interestingly, in these samples the expression pattern of the prominent hypoxia marker geneangiopoietin-like 4 (Angptl4)strongly correlated with that ofAP-2εsuggesting that hypoxia might represent an external regulator of AP-2εexpression in mammals. In order to show this, experiments directly targeting the activity of hypoxia-inducible factor-1 (HIF1), the complex mediating responses to oxygen deprivation, were performed. While the HIF1-activating compounds 2,2′-dipyridyl and desferrioxamine resulted in significantly enhanced mRNA concentration of AP-2ε, siRNA against HIF1αled to a significantly reduced expression rate ofAP-2ε. Additionally, we detected a significant upregulation of the AP-2εmRNA level after oxygen deprivation. In sum, these different experimental approaches revealed a novel role for the HIF1 complex in the regulation of theAP-2εgene in cartilaginous cells and underlined the important role of hypoxia as an important external regulatory stimulus during chondrogenic differentiation modulating the expression of downstream transcription factors.

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.

Activating transcription factor 2 increases transactivation and protein stability of hypoxia-inducible factor 1α in hepatocytes

2009 ◽  
Vol 424 (2) ◽  
pp. 285-296 ◽  
Author(s):  
Jeong Hae Choi ◽  
Hyun Kook Cho ◽  
Yung Hyun Choi ◽  
JaeHun Cheong
Keyword(s):  
Transcription Factor ◽  
Protein Stability ◽  
Gene Transcription ◽  
Hypoxia Inducible Factor ◽  
Protein Stabilization ◽  
Hypoxic Conditions ◽  
Tumour Suppressor Protein ◽  
Activating Transcription Factor

HIF-1 (hypoxia inducible factor 1) performs a crucial role in mediating the response to hypoxia. However, other transcription factors are also capable of regulating hypoxia-induced target-gene transcription. In a previous report, we demonstrated that the transcription factor ATF-2 (activating transcription factor 2) regulates hypoxia-induced gene transcription, along with HIF-1α. In the present study, we show that the protein stability of ATF-2 is induced by hypoxia and the hypoxia-mimic CoCl2 (cobalt chloride), and that ATF-2 induction enhances HIF-1α protein stability via direct protein interaction. The knockdown of ATF-2 using small interfering RNA and translation-inhibition experiments demonstrated that ATF-2 plays a key role in the maintenance of the expression level and transcriptional activity of HIF-1α. Furthermore, we determined that ATF-2 interacts directly with HIF-1α both in vivo and in vitro and competes with the tumour suppressor protein p53 for HIF-1α binding. Collectively, these results show that protein stabilization of ATF-2 under hypoxic conditions is required for the induction of the protein stability and transactivation activity of HIF-1α for efficient hypoxia-associated gene expression.

scholarly journals HIF-1–dependent repression of equilibrative nucleoside transporter (ENT) in hypoxia

2005 ◽  
Vol 202 (11) ◽  
pp. 1493-1505 ◽  
Author(s):  
Holger K. Eltzschig ◽  
Parween Abdulla ◽  
Edgar Hoffman ◽  
Kathryn E. Hamilton ◽  
Dionne Daniels ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Nucleoside Transporter ◽  
In Vivo Models ◽  
Equilibrative Nucleoside Transporter ◽  
Hypoxia Inducible Factor 1 ◽  
And Function

Extracellular adenosine (Ado) has been implicated as central signaling molecule during conditions of limited oxygen availability (hypoxia), regulating physiologic outcomes as diverse as vascular leak, leukocyte activation, and accumulation. Presently, the molecular mechanisms that elevate extracellular Ado during hypoxia are unclear. In the present study, we pursued the hypothesis that diminished uptake of Ado effectively enhances extracellular Ado signaling. Initial studies indicated that the half-life of Ado was increased by as much as fivefold after exposure of endothelia to hypoxia. Examination of expressional levels of the equilibrative nucleoside transporter (ENT)1 and ENT2 revealed a transcriptionally dependent decrease in mRNA, protein, and function in endothelia and epithelia. Examination of the ENT1 promoter identified a hypoxia inducible factor 1 (HIF-1)–dependent repression of ENT1 during hypoxia. Using in vitro and in vivo models of Ado signaling, we revealed that decreased Ado uptake promotes vascular barrier and dampens neutrophil tissue accumulation during hypoxia. Moreover, epithelial Hif1α mutant animals displayed increased epithelial ENT1 expression. Together, these results identify transcriptional repression of ENT as an innate mechanism to elevate extracellular Ado during hypoxia.

scholarly journals Hypoxia-Mediated Down-Regulation of Bid and Bax in Tumors Occurs via Hypoxia-Inducible Factor 1-Dependent and -Independent Mechanisms and Contributes to Drug Resistance

2004 ◽  
Vol 24 (7) ◽  
pp. 2875-2889 ◽  
Author(s):  
Janine T. Erler ◽  
Christopher J. Cawthorne ◽  
Kaye J. Williams ◽  
Marianne Koritzinsky ◽  
Bradley G. Wouters ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Solid Tumors ◽  
Hypoxia Inducible Factor ◽  
Oxygen Deprivation ◽  
Translation Efficiency ◽  
Down Regulation ◽  
Drug Induced ◽  
Human Colon Cancer ◽  
Hypoxia Inducible Factor 1

ABSTRACT Solid tumors with disorganized, insufficient blood supply contain hypoxic cells that are resistant to radiotherapy and chemotherapy. Drug resistance, an obstacle to curative treatment of solid tumors, can occur via suppression of apoptosis, a process controlled by pro- and antiapoptotic members of the Bcl-2 protein family. Oxygen deprivation of human colon cancer cells in vitro provoked decreased mRNA and protein levels of proapoptotic Bid and Bad. Hypoxia-inducible factor 1 (HIF-1) was dispensable for the down-regulation of Bad but required for that of Bid, consistent with the binding of HIF-1α to a hypoxia-responsive element (positions −8484 to −8475) in the bid promoter. Oxygen deprivation resulted in proteosome-independent decreased expression of Bax in vitro, consistent with a reduction in global translation efficiency. The physiological relevance of Bid and Bax down-regulation was confirmed in tumors in vivo. Oxygen deprivation resulted in decreased drug-induced apoptosis and clonogenic resistance to agents with different mechanisms of action. The contribution of Bid and/or Bax down-regulation to drug responsiveness was demonstrated by the relative resistance of normoxic cells that had no or reduced expression of Bid and/or Bax and by the finding that forced expression of Bid in hypoxic cells resulted in increased sensitivity to the topoisomerase II inhibitor etoposide.

scholarly journals The quinoxaline di-N-oxide DCQ blocks breast cancer metastasis in vitro and in vivo by targeting the hypoxia inducible factor-1 pathway

2014 ◽  
Vol 13 (1) ◽  
pp. 12 ◽  
Author(s):  
Khaled Ghattass ◽  
Sally El-Sitt ◽  
Kazem Zibara ◽  
Saide Rayes ◽  
Makhluf J Haddadin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Metastasis ◽  
Hypoxia Inducible Factor ◽  
Breast Cancer Metastasis ◽  
Hypoxia Inducible Factor 1

scholarly journals Molecular Docking and Drug-Likeness for the Identification of Inhibitory Action of Acetogenins from Annona muricata as Potential Anticancer against Hypoxia Inducible Factor 1 Alpha

2018 ◽  
Vol 11 (3) ◽  
pp. 1301-1307
Author(s):  
Supri I. Handayani ◽  
Rahmiati Rahmiati ◽  
Lisnawati Rahmadi ◽  
Rosmalena Rosmalena ◽  
Vivitri D. Prasasty
Keyword(s):  
Molecular Docking ◽  
Hypoxia Inducible Factor ◽  
Binding Energies ◽  
Binding Modes ◽  
Annona Muricata ◽  
Chemical Structures ◽  
Hypoxia Inducible Factor 1 ◽  
Human Cancers

Hypoxia inducible factor 1 alpha (HIF-1α) regulates cell growth and differentiation which is implicated in human cancers. HIF-1α activates its cascade carcinogenesis mechanism in cancer cells. It is well-understood that signaling is initiated by HIF-1α receptor. Overexpression of HIF-1α is associated with several different human cancers, including breast cancer, lung cancer and colon cancer. Thus, HIF-1α becomes potential target of therapeutic approach in developing HIF-1α inhibitors. The aim of this research is to investigate potential inhibitors which are known as Acetogenins (AGEs) isolated from Annona muricata against HIF-1α. In order to achieve this goal, chemical structures of all compounds were retrieved from PubChem database. Molecular docking was performed by AutoDock Vina program and the resulting binding modes were analyzed with AutoDock Tools program. Among all the compounds, murihexocin A showed the best binding modes compared to other two inhibitors based on the lowest binding energies (LBE = -7.9 kcal/mol) as high as gefitinib. This was indicating that murihexocin A has favorable interaction with the essential amino acid residues at catalytic site of HIF-1α. Drug-likeness calculation of AGEs were also performed. These in silico results could be beneficial as a compound model for further studies in-vitro and in-vivo.

Myricetin-Based Self-Assembled Nanoparticles for Tumor Synergistic Therapy by Antioxidation Pathway

2021 ◽  
Vol 17 (12) ◽  
pp. 2399-2412
Author(s):  
Yumei Qian ◽  
Fang Zhao ◽  
Jing Wang ◽  
Hongxia Li ◽  
Lisheng Xu ◽  
...  
Keyword(s):  
Hypoxia Inducible Factor ◽  
Vascular Endothelial ◽  
Ferric Ions ◽  
Normal Cells ◽  
Hypoxia Inducible Factor 1 ◽  
Self Assembled ◽  
Vessel Networks ◽  
Endothelial Growth Factor

Nanoplatforms are nano-scale systems that can transport different small molecular anticancer drugs or chemosensitization motif to accumulate in tumor cells without obvious side-effect in normal cells and achieve a synergistic therapy. In this paper the new self-assembled nanoparticles (NPs) merging doxorubicin (DOX) and myricetin (MYR) with ferric ions (Fe3+) and polyphenol was employed for forming the DOX@MYR-Fe3+ NP (FDMP NP). The FDMP NPs could reduce the DOX-induced toxicity in blood; and they could not cause damage to the heart and kidney tissues by the reasons that the MYR could enhance the anti-oxidation capability in normal cells, which resulted in preventing ROS-induced damage. Additionally, the FDMP NPs were characteristic of small size (37.70 ± 6.30 nm), high DOX loading efficiency (46.67 ± 1.58%), pH-controlled release and excellent stable pharmacokinetics, that inducing drug release and enhancing drug accumulation in the tumor. Moreover, the FDMP NPs could inhibit the expression of the hypoxia-inducible factor-1 α(HIF-1α) and the key angiogenesis mediator vascular endothelial growth factor (VEGF) both in vitro and in vivo, which succeed in preventing the generation of new blood vessel networks; that is the mechanism of the synergistic effect against tumors induced by FDMP NPs.

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 HIF1 and ID1 Interplay Confers Adaptive Survival to HIF1α-Inhibition

2021 ◽  
Vol 9 ◽  
Author(s):  
Hao Geng ◽  
Hyun-Kyung Ko ◽  
Janet Pittsenbarger ◽  
Christopher T. Harvey ◽  
Changhui Xue ◽  
...  
Keyword(s):  
Hypoxia Inducible Factor ◽  
Underlying Mechanism ◽  
Glutamine Metabolism ◽  
Pathological Feature ◽  
Hypoxia Inducible Factor 1 ◽  
Promising Therapeutic Target ◽  
Hypoxic Tumor ◽  
Oncogenic Protein

Hypoxia is a universal pathological feature of solid tumors. Hypoxic tumor cells acquire metastatic and lethal phenotypes primarily through the activities of hypoxia-inducible factor 1 alpha (HIF1α). Therefore, HIF1α is considered as a promising therapeutic target. However, HIF inhibitors have not proven to be effective in clinical testing. The underlying mechanism is unclear. We report that oncogenic protein ID1 is upregulated in hypoxia by HIF1α shRNA or pharmacological inhibitors. In turn, ID1 supports tumor growth in hypoxia in vitro and in xenografts in vivo, conferring adaptive survival response and resistance. Mechanistically, ID1 proteins interfere HIF1-mediated gene transcription activation, thus ID1 protein degradation is accelerated by HIF1α-dependent mechanisms in hypoxia. Inhibitions of HIF1α rescues ID1, which compensates the loss of HIF1α by the upregulation of GLS2 and glutamine metabolism, thereby switching the metabolic dependency of HIF1α -inhibited cells from glucose to glutamine.

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