Journal articles: 'Hypoxia regulators'

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Barth, Dominik A., Felix Prinz, Julia Teppan, Katharina Jonas, Christiane Klec, and Martin Pichler. "Long-Noncoding RNA (lncRNA) in the Regulation of Hypoxia-Inducible Factor (HIF) in Cancer." Non-Coding RNA 6, no. 3 (July 6, 2020): 27. http://dx.doi.org/10.3390/ncrna6030027.

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Hypoxia is dangerous for oxygen-dependent cells, therefore, physiological adaption to cellular hypoxic conditions is essential. The transcription factor hypoxia-inducible factor (HIF) is the main regulator of hypoxic metabolic adaption reducing oxygen consumption and is regulated by gradual von Hippel-Lindau (VHL)-dependent proteasomal degradation. Beyond physiology, hypoxia is frequently encountered within solid tumors and first drugs are in clinical trials to tackle this pathway in cancer. Besides hypoxia, cancer cells may promote HIF expression under normoxic conditions by altering various upstream regulators, cumulating in HIF upregulation and enhanced glycolysis and angiogenesis, altogether promoting tumor proliferation and progression. Therefore, understanding the underlying molecular mechanisms is crucial to discover potential future therapeutic targets to evolve cancer therapy. Long non-coding RNAs (lncRNA) are a class of non-protein coding RNA molecules with a length of over 200 nucleotides. They participate in cancer development and progression and might act as either oncogenic or tumor suppressive factors. Additionally, a growing body of evidence supports the role of lncRNAs in the hypoxic and normoxic regulation of HIF and its subunits HIF-1α and HIF-2α in cancer. This review provides a comprehensive update and overview of lncRNAs as regulators of HIFs expression and activation and discusses and highlights potential involved pathways.

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Cummins, Eoin P., and Cormac T. Taylor. "Hypoxia and inflammation." Biochemist 39, no. 4 (August 1, 2017): 34–36. http://dx.doi.org/10.1042/bio03904034.

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Uncontrolled or non-resolving inflammation is central to the pathophysiology of clinically important conditions including inflammatory bowel disease (IBD), psoriasis, atherosclerosis and arthritis. A combination of increased oxygen demand and decreased supply renders the local microenvironment of chronically inflamed tissues oxygen deprived (hypoxic), leading to the expression of a programme of genes that promote adaptation to the hypoxic challenge. This ancient and ubiquitous adaptive transcriptional pathway is governed by a transcription factor termed the hypoxia-inducible factor (HIF). Originally identified in the search for regulators of hypoxia-induced erythropoietin expression and adaptation to high altitude, HIF has been more recently recognized as a major regulator of immune cell function, which is central to the control of immunity and inflammation. Indeed, recent studies have demonstrated that the use of drugs targeting the HIF pathway may be of benefit in the treatment of chronic inflammatory disease.

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Stichternoth, Catrin, and Joachim F. Ernst. "Hypoxic Adaptation by Efg1 Regulates Biofilm Formation by Candida albicans." Applied and Environmental Microbiology 75, no. 11 (April 3, 2009): 3663–72. http://dx.doi.org/10.1128/aem.00098-09.

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ABSTRACT Hypoxia is encountered frequently by Candida albicans during systemic infection of the human host. We tested if hypoxia allows biofilm formation by C. albicans, which is a major cause of perseverance and antifungal resistance in C. albicans infections. Using an in vitro biofilm system, we unexpectedly discovered that several positive regulators of biofilm formation during normoxia, including Tec1, Ace2, Czf1, Och1, and Als3, had little or no influence on biofilm development during hypoxia, irrespective of the carbon dioxide level, indicating that C. albicans biofilm pathways differ depending on the oxygen level. In contrast, the Efg1 and Flo8 regulators were required for both normoxic and hypoxic biofilm formation. To explore the role of Efg1 during hypoxic and/or biofilm growth, we determined transcriptome kinetics following release of EFG1 expression by a system under transcriptional control of a doxycycline-inducible promoter. During hypoxia, Efg1 rapidly induced expression of all major classes of genes known to be associated with normoxic biofilm formation, including genes involved in glycolysis, sulfur metabolism, and antioxidative and peroxisome activities, as well as genes for iron uptake. The results suggest that hypoxic adaptation mediated by the Efg1 and Flo8 regulators is required even during normoxic biofilm development, while hypoxic biofilm formation in deep tissues or in organs may generate foci of C. albicans infections.

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Womeldorff, Matthew, David Gillespie, and Randy L. Jensen. "Hypoxia-inducible factor–1 and associated upstream and downstream proteins in the pathophysiology and management of glioblastoma." Neurosurgical Focus 37, no. 6 (December 2014): E8. http://dx.doi.org/10.3171/2014.9.focus14496.

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Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with an exceptionally poor patient outcome despite aggressive therapy including surgery, radiation, and chemotherapy. This aggressive phenotype may be associated with intratumoral hypoxia, which probably plays a key role in GBM tumor growth, development, and angiogenesis. A key regulator of cellular response to hypoxia is the protein hypoxia-inducible factor–1 (HIF-1). An examination of upstream hypoxic and nonhypoxic regulation of HIF-1 as well as a review of the downstream HIF-1–regulated proteins may provide further insight into the role of this transcription factor in GBM pathophysiology. Recent insights into upstream regulators that intimately interact with HIF-1 could provide potential therapeutic targets for treatment of this tumor. The same is potentially true for HIF-1–mediated pathways of glycolysis-, angiogenesis-, and invasion-promoting proteins. Thus, an understanding of the relationship between HIF-1, its upstream protein regulators, and its downstream transcribed genes in GBM pathogenesis could provide future treatment options for the care of patients with these tumors.

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Bracken, C. P., M. L. Whitelaw, and D. J. Peet. "The hypoxia-inducible factors: key transcriptional regulators of hypoxic responses." Cellular and Molecular Life Sciences (CMLS) 60, no. 7 (July 1, 2003): 1376–93. http://dx.doi.org/10.1007/s00018-003-2370-y.

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Lu, Xin, and Yibin Kang. "Hypoxia and Hypoxia-Inducible Factors: Master Regulators of Metastasis." Clinical Cancer Research 16, no. 24 (October 20, 2010): 5928–35. http://dx.doi.org/10.1158/1078-0432.ccr-10-1360.

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Li, Xiaochen, Yuanzhou He, Yongjian Xu, Xiaomin Huang, Jin Liu, Min Xie, and Xiansheng Liu. "KLF5 mediates vascular remodeling via HIF-1α in hypoxic pulmonary hypertension." American Journal of Physiology-Lung Cellular and Molecular Physiology 310, no. 4 (February 15, 2016): L299—L310. http://dx.doi.org/10.1152/ajplung.00189.2015.

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Hypoxic pulmonary hypertension (HPH) is characterized by active vasoconstriction and profound vascular remodeling. KLF5, a zinc-finger transcription factor, is involved in the excessive proliferation and apoptotic resistance phenotype associated with monocrotaline-induced pulmonary hypertension. However, the molecular mechanisms of KLF5-mediated pathogenesis of HPH are largely undefined. Adult male Sprague-Dawley rats were exposed to normoxia or hypoxia (10% O2) for 4 wk. Hypoxic rats developed pulmonary arterial remodeling and right ventricular hypertrophy with significantly increased right ventricular systolic pressure. The levels of KLF5 and hypoxia-inducible factor-1α (HIF-1α) were upregulated in distal pulmonary arterial smooth muscle from hypoxic rats. The knockdown of KLF5 via short-hairpin RNA attenuated chronic hypoxia-induced hemodynamic and histological changes in rats. The silencing of either KLF5 or HIF-1α prevented hypoxia-induced (5%) proliferation and migration and promoted apoptosis in human pulmonary artery smooth muscle cells. KLF5 was immunoprecipitated with HIF-1α under hypoxia and acted as an upstream regulator of HIF-1α. The cell cycle regulators cyclin B1 and cyclin D1 and apoptosis-related proteins including bax, bcl-2, survivin, caspase-3, and caspase-9, were involved in the regulation of KLF5/HIF-1α-mediated cell survival. This study demonstrated that KLF5 plays a crucial role in hypoxia-induced vascular remodeling in an HIF-1α-dependent manner and provided a better understanding of the pathogenesis of HPH.

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Catrina, Sergiu-Bogdan, and Xiaowei Zheng. "Hypoxia and hypoxia-inducible factors in diabetes and its complications." Diabetologia 64, no. 4 (January 26, 2021): 709–16. http://dx.doi.org/10.1007/s00125-021-05380-z.

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AbstractHypoxia-inducible factors (HIFs) are the key regulators of oxygen homeostasis in response to hypoxia. In diabetes, multiple tissues are hypoxic but adaptive responses to hypoxia are impaired due to insufficient activation of HIF signalling, which results from inhibition of HIF-1α stability and function due to hyperglycaemia and elevated fatty acid levels. In this review, we will summarise and discuss current findings about the regulation of HIF signalling in diabetes and the pathogenic roles of hypoxia and dysregulated HIF signalling in the development of diabetes and its complications. The therapeutic potential of targeting HIF signalling for the prevention and treatment of diabetes and related complications is also discussed. Graphical abstract

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Kabakov, Alexander E., and Anna O. Yakimova. "Hypoxia-Induced Cancer Cell Responses Driving Radioresistance of Hypoxic Tumors: Approaches to Targeting and Radiosensitizing." Cancers 13, no. 5 (March 4, 2021): 1102. http://dx.doi.org/10.3390/cancers13051102.

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Within aggressive malignancies, there usually are the “hypoxic zones”—poorly vascularized regions where tumor cells undergo oxygen deficiency through inadequate blood supply. Besides, hypoxia may arise in tumors as a result of antiangiogenic therapy or transarterial embolization. Adapting to hypoxia, tumor cells acquire a hypoxia-resistant phenotype with the characteristic alterations in signaling, gene expression and metabolism. Both the lack of oxygen by itself and the hypoxia-responsive phenotypic modulations render tumor cells more radioresistant, so that hypoxic tumors are a serious challenge for radiotherapy. An understanding of causes of the radioresistance of hypoxic tumors would help to develop novel ways for overcoming this challenge. Molecular targets for and various approaches to radiosensitizing hypoxic tumors are considered in the present review. It is here analyzed how the hypoxia-induced cellular responses involving hypoxia-inducible factor-1, heat shock transcription factor 1, heat shock proteins, glucose-regulated proteins, epigenetic regulators, autophagy, energy metabolism reprogramming, epithelial–mesenchymal transition and exosome generation contribute to the radioresistance of hypoxic tumors or may be inhibited for attenuating this radioresistance. The pretreatments with a multitarget inhibition of the cancer cell adaptation to hypoxia seem to be a promising approach to sensitizing hypoxic carcinomas, gliomas, lymphomas, sarcomas to radiotherapy and, also, liver tumors to radioembolization.

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Titova, O. N., N. A. Kuzubova, and E. S. Lebedeva. "The role of the hypoxia signaling pathway in cellular adaptation to hypoxia." Russian Medical Inquiry 4, no. 4 (2020): 207–13. http://dx.doi.org/10.32364/2587-6821-2020-4-4-207-213.

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The review presents an analysis of scientific publications in recent years devoted to the study on the cellular-molecular mechanism of cellular adaptation to hypoxia. In many respiratory diseases (chronic obstructive pulmonary disease, chronic respiratory failure, etc.), the balance between the cells’ need for oxygen and its delivery is disrupted. It complicates the course of the diseases and is a potential factor in their progression. The microenvironment in the inflammatory areas becomes hypoxic (so-called inflammatory hypoxia). The formation of long-term adaptation to pathological hypoxia is associated with the expression of a specific hypoxia-induced factor (HIF). It serves as a transcription activator for more than 300 genes and is a key regulator of various cellular and systemic responses to hypoxia, including angiogenesis, cell proliferation, cellular migration, regeneration, antigen presentation, cytokine and antimicrobial peptide production, phagocytosis, apoptosis, and cellular metabolic reprogramming. The article also considers the complex cross-interaction between HIF signaling and the nuclear transcription factor κB — NF-κB) signaling pathway (one of the main regulators of inflammation and immune responses). Possible therapeutic methods for controlling inflammation and immune-related diseases based on the principle of regulating the HIF signaling pathway are discussed. KEYWORDS: respiratory diseases, hypoxia, hypoxia-induced factor, adaptation, inflammation, immunity, targeted therapy. FOR CITATION: Titova O.N., Kuzubova N.A., Lebedeva E.S. The role of the hypoxia signaling pathway in cellular adaptation to hypoxia. Russian Medical Inquiry. 2020;4(4):207–213. DOI: 10.32364/2587-6821-2020-4-4-207-213.

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Bono, Hidemasa, and Kiichi Hirota. "Meta-Analysis of Hypoxic Transcriptomes from Public Databases." Biomedicines 8, no. 1 (January 9, 2020): 10. http://dx.doi.org/10.3390/biomedicines8010010.

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Hypoxia is the insufficiency of oxygen in the cell, and hypoxia-inducible factors (HIFs) are central regulators of oxygen homeostasis. In order to obtain functional insights into the hypoxic response in a data-driven way, we attempted a meta-analysis of the RNA-seq data from the hypoxic transcriptomes archived in public databases. In view of methodological variability of archived data in the databases, we first manually curated RNA-seq data from appropriate pairs of transcriptomes before and after hypoxic stress. These included 128 human and 52 murine transcriptome pairs. We classified the results of experiments for each gene into three categories: upregulated, downregulated, and unchanged. Hypoxic transcriptomes were then compared between humans and mice to identify common hypoxia-responsive genes. In addition, meta-analyzed hypoxic transcriptome data were integrated with public ChIP-seq data on the known human HIFs, HIF-1 and HIF-2, to provide insights into hypoxia-responsive pathways involving direct transcription factor binding. This study provides a useful resource for hypoxia research. It also demonstrates the potential of a meta-analysis approach to public gene expression databases for selecting candidate genes from gene expression profiles generated under various experimental conditions.

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Emerling, Brooke M., Leonidas C. Platanias, Emma Black, Angel R. Nebreda, Roger J. Davis, and Navdeep S. Chandel. "Mitochondrial Reactive Oxygen Species Activation of p38 Mitogen-Activated Protein Kinase Is Required for Hypoxia Signaling." Molecular and Cellular Biology 25, no. 12 (June 15, 2005): 4853–62. http://dx.doi.org/10.1128/mcb.25.12.4853-4862.2005.

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ABSTRACT Mammalian cells have the ability to sense low oxygen levels (hypoxia). An adaptive response to hypoxia involves the induction of the transcription factor hypoxia-inducible factor 1 (HIF-1). The intracellular signaling pathways that regulate HIF-1 activation during hypoxia remain unknown. Here, we demonstrate that p38α − / − cells fail to activate HIF-1 under hypoxic conditions. Cells deficient in Mkk3 and Mkk6, the upstream regulators of p38α, also fail to activate HIF-1 under hypoxic conditions. The p38α − / − cells are able to activate HIF-1 in response to anoxia or iron chelators during normoxia. Furthermore, the hypoxic activation of p38α and HIF-1 was abolished by myxothiazol, a mitochondrial complex III inhibitor, and glutathione peroxidase 1 (GPX1), a scavenger of hydrogen peroxide. Thus, the activation of p38α and HIF-1 is dependent on the generation of mitochondrial reactive oxygen species. These results provide genetic evidence that p38 mitogen-activated protein kinase signaling is essential for HIF-1 activation.

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Wu, Bo, Huajian Teng, Li Zhang, Hong Li, Jing Li, Lina Wang, and Hongzhu Li. "Interaction of Hydrogen Sulfide with Oxygen Sensing under Hypoxia." Oxidative Medicine and Cellular Longevity 2015 (2015): 1–9. http://dx.doi.org/10.1155/2015/758678.

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Based on the discovery of endogenous H2S production, many in depth studies show this gasotransmitter with a variety of physiological and pathological functions. Three enzymes, cystathionineβ-synthase (CBS), cystathionineγ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (MST), are involved in enzymatic production of H2S. Emerging evidence has elucidated an important protective role of H2S in hypoxic conditions in many mammalian systems. However, the mechanisms by which H2S senses and responses to hypoxia are largely elusive. Hypoxia-inducible factors (HIFs) function as key regulators of oxygen sensing, activating target genes expression under hypoxia. Recent studies have shown that exogenous H2S regulates HIF action in different patterns. The activation of carotid bodies is a sensitive and prompt response to hypoxia, rapidly enhancing general O2supply. H2S has been identified as an excitatory mediator of hypoxic sensing in the carotid bodies. This paper presents a brief review of the roles of these two pathways which contribute to hypoxic sensing of H2S.

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Hasvold, Grete, Christin Lund-Andersen, Malin Lando, Sebastian Patzke, Sissel Hauge, ZhenHe Suo, Heidi Lyng, and Randi G. Syljuåsen. "Hypoxia-induced alterations of G2 checkpoint regulators." Molecular Oncology 10, no. 5 (January 8, 2016): 764–73. http://dx.doi.org/10.1016/j.molonc.2015.12.015.

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Zhang, Jinwei, Wanling Qiu, Jideng Ma, Yujie Wang, Zihui Hu, Keren Long, Xun Wang, et al. "miR-27a-5p Attenuates Hypoxia-induced Rat Cardiomyocyte Injury by Inhibiting Atg7." International Journal of Molecular Sciences 20, no. 10 (May 16, 2019): 2418. http://dx.doi.org/10.3390/ijms20102418.

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Acute myocardial infarction (AMI) is an ischemic heart disease with high mortality worldwide. AMI triggers a hypoxic microenvironment and induces extensive myocardial injury, including autophagy and apoptosis. MiRNAs, which are a class of posttranscriptional regulators, have been shown to be involved in the development of ischemic heart diseases. We have previously reported that hypoxia significantly alters the miRNA transcriptome in rat cardiomyoblast cells (H9c2), including miR-27a-5p. In the present study, we further investigated the potential function of miR-27a-5p in the cardiomyocyte response to hypoxia, and showed that miR-27a-5p expression was downregulated in the H9c2 cells at different hypoxia-exposed timepoints and the myocardium of a rat AMI model. Follow-up experiments revealed that miR-27a-5p attenuated hypoxia-induced cardiomyocyte injury by regulating autophagy and apoptosis via Atg7, which partly elucidated the anti-hypoxic injury effects of miR-27a-5p. Taken together, this study shows that miR-27a-5p has a cardioprotective effect on hypoxia-induced H9c2 cell injury, suggesting it may be a novel target for the treatment of hypoxia-related heart diseases.

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Watts, Deepika, Diana Gaete, Diego Rodriguez, David Hoogewijs, Martina Rauner, Sundary Sormendi, and Ben Wielockx. "Hypoxia Pathway Proteins are Master Regulators of Erythropoiesis." International Journal of Molecular Sciences 21, no. 21 (October 30, 2020): 8131. http://dx.doi.org/10.3390/ijms21218131.

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Erythropoiesis is a complex process driving the production of red blood cells. During homeostasis, adult erythropoiesis takes place in the bone marrow and is tightly controlled by erythropoietin (EPO), a central hormone mainly produced in renal EPO-producing cells. The expression of EPO is strictly regulated by local changes in oxygen partial pressure (pO2) as under-deprived oxygen (hypoxia); the transcription factor hypoxia-inducible factor-2 induces EPO. However, erythropoiesis regulation extends beyond the well-established hypoxia-inducible factor (HIF)–EPO axis and involves processes modulated by other hypoxia pathway proteins (HPPs), including proteins involved in iron metabolism. The importance of a number of these factors is evident as their altered expression has been associated with various anemia-related disorders, including chronic kidney disease. Eventually, our emerging understanding of HPPs and their regulatory feedback will be instrumental in developing specific therapies for anemic patients and beyond.

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Frakolaki, Efseveia, Panagiota Kaimou, Maria Moraiti, Katerina Kalliampakou, Kalliopi Karampetsou, Eleni Dotsika, Panagiotis Liakos, et al. "The Role of Tissue Oxygen Tension in Dengue Virus Replication." Cells 7, no. 12 (December 1, 2018): 241. http://dx.doi.org/10.3390/cells7120241.

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Low oxygen tension exerts a profound effect on the replication of several DNA and RNA viruses. In vitro propagation of Dengue virus (DENV) has been conventionally studied under atmospheric oxygen levels despite that in vivo, the tissue microenvironment is hypoxic. Here, we compared the efficiency of DENV replication in liver cells, monocytes, and epithelial cells under hypoxic and normoxic conditions, investigated the ability of DENV to induce a hypoxia response and metabolic reprogramming and determined the underlying molecular mechanism. In DENV-infected cells, hypoxia had no effect on virus entry and RNA translation, but enhanced RNA replication. Overexpression and silencing approaches as well as chemical inhibition and energy substrate exchanging experiments showed that hypoxia-mediated enhancement of DENV replication depends on the activation of the key metabolic regulators hypoxia-inducible factors 1α/2α (HIF-1α/2α) and the serine/threonine kinase AKT. Enhanced RNA replication correlates directly with an increase in anaerobic glycolysis producing elevated ATP levels. Additionally, DENV activates HIF and anaerobic glycolysis markers. Finally, reactive oxygen species were shown to contribute, at least in part through HIF, both to the hypoxia-mediated increase of DENV replication and to virus-induced hypoxic reprogramming. These suggest that DENV manipulates hypoxia response and oxygen-dependent metabolic reprogramming for efficient viral replication.

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Chakraborty, Abhishek A., Tuomas Laukka, Matti Myllykoski, Alison E. Ringel, Matthew A. Booker, Michael Y. Tolstorukov, Yuzhong Jeff Meng, et al. "Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate." Science 363, no. 6432 (March 14, 2019): 1217–22. http://dx.doi.org/10.1126/science.aaw1026.

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Oxygen sensing is central to metazoan biology and has implications for human disease. Mammalian cells express multiple oxygen-dependent enzymes called 2-oxoglutarate (OG)-dependent dioxygenases (2-OGDDs), but they vary in their oxygen affinities and hence their ability to sense oxygen. The 2-OGDD histone demethylases control histone methylation. Hypoxia increases histone methylation, but whether this reflects direct effects on histone demethylases or indirect effects caused by the hypoxic induction of the HIF (hypoxia-inducible factor) transcription factor or the 2-OG antagonist 2-hydroxyglutarate (2-HG) is unclear. Here, we report that hypoxia promotes histone methylation in a HIF- and 2-HG–independent manner. We found that the H3K27 histone demethylase KDM6A/UTX, but not its paralog KDM6B, is oxygen sensitive. KDM6A loss, like hypoxia, prevented H3K27 demethylation and blocked cellular differentiation. Restoring H3K27 methylation homeostasis in hypoxic cells reversed these effects. Thus, oxygen directly affects chromatin regulators to control cell fate.

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Barreca, Maria Magdalena, Chiara Zichittella, Riccardo Alessandro, and Alice Conigliaro. "Hypoxia-Induced Non-Coding RNAs Controlling Cell Viability in Cancer." International Journal of Molecular Sciences 22, no. 4 (February 12, 2021): 1857. http://dx.doi.org/10.3390/ijms22041857.

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Hypoxia, a characteristic of the tumour microenvironment, plays a crucial role in cancer progression and therapeutic response. The hypoxia-inducible factors (HIF-1α, HIF-2α, and HIF-3α), are the master regulators in response to low oxygen partial pressure, modulating hypoxic gene expression and signalling transduction pathways. HIFs’ activation is sufficient to change the cell phenotype at multiple levels, by modulating several biological activities from metabolism to the cell cycle and providing the cell with new characteristics that make it more aggressive. In the past few decades, growing numbers of studies have revealed the importance of non-coding RNAs (ncRNAs) as molecular mediators in the establishment of hypoxic response, playing important roles in regulating hypoxic gene expression at the transcriptional, post-transcriptional, translational, and posttranslational levels. Here, we review recent findings on the different roles of hypoxia-induced ncRNAs in cancer focusing on the data that revealed their involvement in tumour growth.

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Sellam, Adnane, Marco van het Hoog, Faiza Tebbji, Cécile Beaurepaire, Malcolm Whiteway, and André Nantel. "Modeling the Transcriptional Regulatory Network That Controls the Early Hypoxic Response in Candida albicans." Eukaryotic Cell 13, no. 5 (March 28, 2014): 675–90. http://dx.doi.org/10.1128/ec.00292-13.

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ABSTRACTWe determined the changes in transcriptional profiles that occur in the first hour following the transfer ofCandida albicansto hypoxic growth conditions. The impressive speed of this response is not compatible with current models of fungal adaptation to hypoxia that depend on the depletion of sterol and heme. Functional analysis using Gene Set Enrichment Analysis (GSEA) identified the Sit4 phosphatase, Ccr4 mRNA deacetylase, and Sko1 transcription factor (TF) as potential regulators of the early hypoxic response. Cells mutated in these and other regulators exhibit a delay in their transcriptional responses to hypoxia. Promoter occupancy data for 29 TFs were combined with the transcriptional profiles of 3,111in vivotarget genes in a Network Component Analysis (NCA) to produce a model of the dynamic and highly interconnected TF network that controls this process. With data from the TF network obtained from a variety of sources, we generated an edge and node model that was capable of separating many of the hypoxia-upregulated and -downregulated genes. Upregulated genes are centered on Tye7, Upc2, and Mrr1, which are associated with many of the gene promoters that exhibit the strongest activations. The connectivity of the model illustrates the high redundancy of this response system and the challenges that lie in determining the individual contributions of specific TFs. Finally, treating cells with an inhibitor of the oxidative phosphorylation chain mimics most of the early hypoxic profile, which suggests that this response may be initiated by a drop in ATP production.

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Collard, Charles D., Cuneyt Bukusoglu, Azin Agah, Sean P. Colgan, Wende R. Reenstra, B. Paul Morgan, and Gregory L. Stahl. "Hypoxia-induced expression of complement receptor type 1 (CR1, CD35) in human vascular endothelial cells." American Journal of Physiology-Cell Physiology 276, no. 2 (February 1, 1999): C450—C458. http://dx.doi.org/10.1152/ajpcell.1999.276.2.c450.

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Reoxygenation of hypoxic human umbilical vein endothelial cells (HUVECs) increases protein expression of the complement regulators CD46 and CD55. As the receptor for C3b is known to be present on injured bovine endothelial cells, we investigated whether hypoxia or inflammatory mediators induce complement receptor type 1 (CR1; CD35) expression on HUVECs. CR1 protein expression increased 3.7 ± 0.6-fold as measured by ELISA on HUVECs following hypoxia (48 h, 1% O2). Colocalization of CD35 and von Willebrand factor by confocal microscopy confirmed that CD35 was predominantly intracellular. Lipopolysaccharide or tumor necrosis factor-α also significantly increased HUVEC CR1 protein expression. Western blot analysis of neutrophil or hypoxic HUVEC lysates revealed a 221-kDa CR1 band under nonreducing conditions. RT-PCR of hypoxic HUVEC mRNA revealed a single band that, after sequencing, was identified as CD35. In situ hybridization of hypoxic HUVECs, but not normoxic HUVECs or fibroblasts, demonstrated increased CD35 mRNA. Hypoxic HUVECs bound immune complexes and acted as a cofactor for factor I-mediated cleavage of C3b. Thus hypoxia induces functional HUVEC CR1 expression.

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Mohammad Shaik, Anjum, Valli Harisomayajula, Saranya M.L, Phani Greeshma Veeramachaneni, Samhitha Reddy Gaddam, and Suryanarayana Veeravilli. "THERAPEUTIC TARGETING OF HYPOXIA-INDUCIBLE FACTOR SIGNALING PATHWAYS- A PROMISING APPROACH IN CANCER TREATMENT." International Journal of Advanced Research 8, no. 9 (September 30, 2020): 1332–37. http://dx.doi.org/10.21474/ijar01/11793.

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Oxygen and nutrients are delivered to the cells with the help of the vascular networking system, which makes availability of oxygen as primary regulator for many processes. Low oxygen availability condition activates the Hypoxia Inducible Factors (HIF), which are transcription regulators helping in the expression of genes related to cell cycle regulation and angiogenesis. HIF is hence regarded as the master regulator of angiogenesis. The oxygen deprival is due to the increased consumption of oxygen in the tumor microenvironment and in turn leads to hypoxia. A thorough understanding of how hypoxia influences angiogenesis mediated by several pathways has become essential for identifying novel strategies targeting HIF thereby blocking angiogenesis. In this review we would discuss about the HIF signaling pathways and altered functions of immune cells due to hypoxia by considering that reducing or targeting hypoxia may in turn prevent the suppression of anti-tumor immune response.

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Vaknin, Yakir, Falk Hillmann, Rossana Iannitti, Netali Ben Baruch, Hana Sandovsky-Losica, Yona Shadkchan, Luigina Romani, Axel Brakhage, Olaf Kniemeyer, and Nir Osherov. "Identification and Characterization of a Novel Aspergillus fumigatus Rhomboid Family Putative Protease, RbdA, Involved in Hypoxia Sensing and Virulence." Infection and Immunity 84, no. 6 (April 11, 2016): 1866–78. http://dx.doi.org/10.1128/iai.00011-16.

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Aspergillus fumigatusis the most common pathogenic mold infecting humans and a significant cause of morbidity and mortality in immunocompromised patients. In invasive pulmonary aspergillosis,A. fumigatusspores are inhaled into the lungs, undergoing germination and invasive hyphal growth. The fungus occludes and disrupts the blood vessels, leading to hypoxia and eventual tissue necrosis. The ability of this mold to adapt to hypoxia is regulated in part by the sterol regulatory element binding protein (SREBP) SrbA and the DscA to DscD Golgi E3 ligase complex critical for SREBP activation by proteolytic cleavage. Loss of the genes encoding these proteins results in avirulence. To identify novel regulators of hypoxia sensing, we screened theNeurospora crassagene deletion library under hypoxia and identified a novel rhomboid family protease essential for hypoxic growth. Deletion of theA. fumigatusrhomboid homologrbdAresulted in an inability to grow under hypoxia, hypersensitivity to CoCl2, nikkomycin Z, fluconazole, and ferrozine, abnormal swollen tip morphology, and transcriptional dysregulation—accurately phenocopying deletion ofsrbA. In vivo,rbdAdeletion resulted in increased sensitivity to phagocytic killing, a reduced inflammatory Th1 and Th17 response, and strongly attenuated virulence. Phenotypic rescue of the ΔrbdAmutant was achieved by expression and nuclear localization of the N terminus of SrbA, including its HLH domain, further indicating that RbdA and SrbA act in the same signaling pathway. In summary, we have identified RbdA, a novel putative rhomboid family protease inA. fumigatusthat mediates hypoxia adaptation and fungal virulence and that is likely linked to SrbA cleavage and activation.

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Egners, Antje, Merve Erdem, and Thorsten Cramer. "The Response of Macrophages and Neutrophils to Hypoxia in the Context of Cancer and Other Inflammatory Diseases." Mediators of Inflammation 2016 (2016): 1–10. http://dx.doi.org/10.1155/2016/2053646.

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Lack of oxygen (hypoxia) is a hallmark of a multitude of acute and chronic diseases and can be either beneficial or detrimental for organ restitution and recovery. In the context of inflammation, hypoxia is particularly important and can significantly influence the course of inflammatory diseases. Macrophages and neutrophils, the chief cellular components of innate immunity, display distinct properties when exposed to hypoxic conditions. Virtually every aspect of macrophage and neutrophil function is affected by hypoxia, amongst others, morphology, migration, chemotaxis, adherence to endothelial cells, bacterial killing, differentiation/polarization, and protumorigenic activity. Prominent arenas of macrophage and neutrophil function, for example, acute/chronic inflammation and the microenvironment of solid tumors, are characterized by low oxygen levels, demonstrating the paramount importance of the hypoxic response for proper function of these cells. Members of the hypoxia-inducible transcription factor (HIF) family emerged as pivotal molecular regulators of macrophages and neutrophils. In this review, we will summarize the molecular responses of macrophages and neutrophils to hypoxia in the context of cancer and other chronic inflammatory diseases and discuss the potential avenues for therapeutic intervention that arise from this knowledge.

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Azzouzi, Hamid el, Stefanos Leptidis, Pieter A. Doevendans, and Leon J. De Windt. "HypoxamiRs: regulators of cardiac hypoxia and energy metabolism." Trends in Endocrinology & Metabolism 26, no. 9 (September 2015): 502–8. http://dx.doi.org/10.1016/j.tem.2015.06.008.

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Schito, Luana, and Gregg L. Semenza. "Hypoxia-Inducible Factors: Master Regulators of Cancer Progression." Trends in Cancer 2, no. 12 (December 2016): 758–70. http://dx.doi.org/10.1016/j.trecan.2016.10.016.

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Osorio-Fuentealba, César, Juan Antonio Valdés, Denise Riquelme, Jorge Hidalgo, Cecilia Hidalgo, and María Angélica Carrasco. "Hypoxia stimulates via separate pathways ERK phosphorylation and NF-κB activation in skeletal muscle cells in primary culture." Journal of Applied Physiology 106, no. 4 (April 2009): 1301–10. http://dx.doi.org/10.1152/japplphysiol.91224.2008.

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Mammalian cells sense oxygen levels and respond to hypoxic conditions through the regulation of multiple signaling pathways and transcription factors. Here, we investigated the effects of hypoxia on the activity of two transcriptional regulators, ERK1/2 and NF-κB, in skeletal muscle cells in primary culture. We found that hypoxia significantly enhanced ERK1/2 phosphorylation and that it stimulated NF-κB-dependent gene transcription as well as nuclear translocation of a green fluorescent protein-labeled p65 NF-κB isoform. Phosphorylation of ERK1/2- and NF-κB-dependent transcription by hypoxia required calcium entry through L-type calcium channels. Calcium release from ryanodine-sensitive stores was also necessary for ERK1/2 activation but not for NF-κB-dependent-transcription. N-acetylcysteine, a general scavenger of reactive oxygen species, blocked hypoxia-induced ROS generation but did not affect the stimulation of ERK1/2 phosphorylation induced by hypoxia. In contrast, NF-κB activation was significantly inhibited by N-acetylcysteine and did not depend on ERK1/2 stimulation, as shown by the lack of effect of the upstream ERK inhibitor U-0126. These separate pathways of activation of ERK1/2 and NF-κB by hypoxia may contribute to muscle adaptation in response to hypoxic conditions.

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Phenn, Julia, Jan Pané-Farré, Nikolai Meukow, Annelie Klein, Anne Troitzsch, Patrick Tan, Stephan Fuchs, et al. "RegAB Homolog of Burkholderia pseudomallei is the Master Regulator of Redox Control and involved in Virulence." PLOS Pathogens 17, no. 5 (May 28, 2021): e1009604. http://dx.doi.org/10.1371/journal.ppat.1009604.

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Burkholderia pseudomallei, the etiological agent of melioidosis in humans and animals, often occupies environmental niches and infection sites characterized by limited concentrations of oxygen. Versatile genomic features enable this pathogen to maintain its physiology and virulence under hypoxia, but the crucial regulatory networks employed to switch from oxygen dependent respiration to alternative terminal electron acceptors (TEA) like nitrate, remains poorly understood. Here, we combined a Tn5 transposon mutagenesis screen and an anaerobic growth screen to identify a two-component signal transduction system with homology to RegAB. We show that RegAB is not only essential for anaerobic growth, but also for full virulence in cell lines and a mouse infection model. Further investigations of the RegAB regulon, using a global transcriptomic approach, identified 20 additional regulators under transcriptional control of RegAB, indicating a superordinate role of RegAB in the B. pseudomallei anaerobiosis regulatory network. Of the 20 identified regulators, NarX/L and a FNR homolog were selected for further analyses and a role in adaptation to anaerobic conditions was demonstrated. Growth experiments identified nitrate and intermediates of the denitrification process as the likely signal activateing RegAB, NarX/L, and probably of the downstream regulators Dnr or NsrR homologs. While deletions of individual genes involved in the denitrification process demonstrated their important role in anaerobic fitness, they showed no effect on virulence. This further highlights the central role of RegAB as the master regulator of anaerobic metabolism in B. pseudomallei and that the complete RegAB-mediated response is required to achieve full virulence. In summary, our analysis of the RegAB-dependent modulon and its interconnected regulons revealed a key role for RegAB of B. pseudomallei in the coordination of the response to hypoxic conditions and virulence, in the environment and the host.

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McNamee, Eóin N., Darlynn Korns Johnson, Dirk Homann, and Eric T. Clambey. "Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function." Immunologic Research 55, no. 1-3 (September 9, 2012): 58–70. http://dx.doi.org/10.1007/s12026-012-8349-8.

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Gerasimovskaya, Evgenia V., Doug A. Tucker, and Kurt R. Stenmark. "Activation of phosphatidylinositol 3-kinase, Akt, and mammalian target of rapamycin is necessary for hypoxia-induced pulmonary artery adventitial fibroblast proliferation." Journal of Applied Physiology 98, no. 2 (February 2005): 722–31. http://dx.doi.org/10.1152/japplphysiol.00715.2004.

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In contrast to cell types in which exposure to hypoxia causes a general reduction of metabolic activity, a remarkable feature of pulmonary artery adventitial fibroblasts is their ability to proliferate in response to hypoxia. Previous studies have suggested that ERK1/2, phosphatidylinositol 3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR) are activated by hypoxia and play a role in a variety of cell responses. However, the pathways involved in mediating hypoxia-induced proliferation are largely unknown. Using pharmacological inhibitors, we established that PI3K-Akt, mTOR-p70 ribosomal protein S6 kinase (p70S6K), and EKR1/2 signaling pathways play a critical role in hypoxia-induced adventitial fibroblast proliferation. We found that exposure of serum-starved fibroblasts to 3% O2resulted in a time-dependent activation of PI3K and transient phosphorylation of Akt. However, activation of PI3K was not required for activation of ERK1/2, implying a parallel involvement of these pathways in the proliferative response of fibroblasts to hypoxia. We found that hypoxia induced significant increases in mTOR, p70S6K, 4E-BP1, and S6 ribosomal protein phosphorylation, as well as dramatic increases in p70S6K activity. The activation of p70S6K/S6 pathway was sensitive to inhibition by rapamycin and LY294002, indicating that mTOR and PI3K/Akt are upstream signaling regulators. However, the magnitude of hypoxia-induced p70S6K activity and phosphorylation suggests involvement of additional signaling pathways. Thus our data demonstrate that hypoxia-induced adventitial fibroblast proliferation requires activation and interaction of PI3K, Akt, mTOR, p70S6K, and ERK1/2 and provide evidence for hypoxic regulation of protein translational pathways in cells exhibiting the capability to proliferate under hypoxic conditions.

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Steffens, Bianka, and Margret Sauter. "G proteins as regulators in ethylene-mediated hypoxia signaling." Plant Signaling & Behavior 5, no. 4 (April 2010): 375–78. http://dx.doi.org/10.4161/psb.5.4.10910.

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Mamlouk, Soulafa, and Ben Wielockx. "Hypoxia-inducible factors as key regulators of tumor inflammation." International Journal of Cancer 132, no. 12 (November 2, 2012): 2721–29. http://dx.doi.org/10.1002/ijc.27901.

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Myllyharju, J. "Prolyl 4-hydroxylases, master regulators of the hypoxia response." Acta Physiologica 208, no. 2 (April 12, 2013): 148–65. http://dx.doi.org/10.1111/apha.12096.

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Gordan, John D., and M. Celeste Simon. "Hypoxia-inducible factors: central regulators of the tumor phenotype." Current Opinion in Genetics & Development 17, no. 1 (February 2007): 71–77. http://dx.doi.org/10.1016/j.gde.2006.12.006.

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Ning, W., T. J. Chu, C. J. Li, A. M. K. Choi, and D. G. Peters. "Genome-wide analysis of the endothelial transcriptome under short-term chronic hypoxia." Physiological Genomics 18, no. 1 (June 17, 2004): 70–78. http://dx.doi.org/10.1152/physiolgenomics.00221.2003.

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We have utilized serial analysis of gene expression (SAGE) to analyze the temporal response of human aortic endothelial cells (HAECs) to short-term chronic hypoxia at the level of transcription. Primary cultures of HAECs were exposed to 1% O2 hypoxia for 8 and 24 h and compared with identical same passage cells cultured under standard (5% CO2-95% air) conditions. A total of 121,446 tags representing 37,096 unique tags were sequenced and genes whose expression levels were modulated by hypoxia identified by novel statistical analyses. Hierarchical clustering of genes displaying statistically significant hypoxia-responsive alterations in expression revealed temporal modulation of a number of major functional gene families including those encoding heat shock factors, glycolytic enzymes, extracellular matrix factors, cytoskeletal factors, apoptotic factors, cell cycle regulators and angiogenic factors. Within these families we documented the coordinated modulation of both previously known hypoxia-responsive genes, numerous genes whose expressions have not been previously shown to be altered by hypoxia, tags matching uncharacterized UniGene entries and entirely novel tags with no UniGene match. These preliminary data, which indicate a reduction in cell cycle progression, elevated metabolic stress and increased cytoskeletal remodeling under acute hypoxic stress, provide a foundation for further analyses of the molecular mechanisms underlying the endothelial response to short-term chronic hypoxia.

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You, Baiyang, Yanbo Liu, Jia Chen, Xiao Huang, Huihui Peng, Zhaoya Liu, Yixin Tang, et al. "Vascular peroxidase 1 mediates hypoxia-induced pulmonary artery smooth muscle cell proliferation, apoptosis resistance and migration." Cardiovascular Research 114, no. 1 (November 27, 2017): 188–99. http://dx.doi.org/10.1093/cvr/cvx234.

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Abstract Aims Reactive oxygen species (ROS) play essential roles in the pulmonary vascular remodelling associated with hypoxia-induced pulmonary hypertension (PH). Vascular peroxidase 1 (VPO1) is a newly identified haeme-containing peroxidase that accelerates oxidative stress development in the vasculature. This study aimed to determine the potential role of VPO1 in hypoxia-induced PH-related vascular remodelling. Methods and results The vascular morphology and VPO1 expression were assessed in the pulmonary arteries of Sprague–Dawley (SD) rats. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) and VPO1 expression and HOCl production were significantly increased in hypoxic rats, which also exhibited obvious vascular remodelling. Furthermore, a hypoxia-induced PH model was generated by exposing primary rat pulmonary artery smooth muscle cells (PASMCs) to hypoxic conditions (3% O2, 48 h), which significantly increased the expression of NOX4 and VPO1 and the production of HOCl. These hypoxic changes were accompanied by enhanced proliferation, apoptosis resistance, and migration. In PASMCs, hypoxia-induced changes, including effects on the expression of cell cycle regulators (cyclin B1 and cyclin D1), apoptosis-related proteins (bax, bcl-2, and cleaved caspase-3), migration promoters (matrix metalloproteinases 2 and 9), and NF-κB expression, as well as the production of HOCl, were all inhibited by silencing VPO1 with small interfering RNAs. Moreover, treatment with HOCl under hypoxic conditions upregulated NF-κB expression and enhanced proliferation, apoptosis resistance, and migration in PASMCs, whereas BAY 11-7082 (an inhibitor of NF-κB) significantly inhibited these effects. Conclusion Collectively, these results demonstrate that VPO1 promotes hypoxia-induced proliferation, apoptosis resistance, and migration in PASMCs via the NOX4/VPO1/HOCl/NF-κB signalling pathway.

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Cristofaro, Ilaria, Chiara Limongi, Paola Piscopo, Alessio Crestini, Claudia Guerriero, Mario Fiore, Luciano Conti, Annamaria Confaloni, and Ada Maria Tata. "M2 Receptor Activation Counteracts the Glioblastoma Cancer Stem Cell Response to Hypoxia Condition." International Journal of Molecular Sciences 21, no. 5 (March 2, 2020): 1700. http://dx.doi.org/10.3390/ijms21051700.

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Glioblastoma multiforme (GBM) is the most malignant brain tumor. Hypoxic condition is a predominant feature of the GBM contributing to tumor growth and resistance to conventional therapies. Hence, the identification of drugs able to impair GBM malignancy and aggressiveness is considered of great clinical relevance. Previously, we demonstrated that the activation of M2 muscarinic receptors, through the agonist arecaidine propargyl ester (Ape), arrests cell proliferation in GBM cancer stem cells (GSCs). In the present work, we have characterized the response of GSCs to hypoxic condition showing an upregulation of hypoxia-inducible factors and factors involved in the regulation of GSCs survival and proliferation. Ape treatment in hypoxic conditions is however able to inhibit cell cycle progression, causing a significant increase of aberrant mitosis with consequent decreased cell survival. Additionally, qRT-PCR analysis suggest that Ape downregulates the expression of stemness markers and miR-210 levels, one of the main regulators of the responses to hypoxic condition in different tumor types. Our data demonstrate that Ape impairs the GSCs proliferation and survival also in hypoxic condition, negatively modulating the adaptive response of GSCs to hypoxia.

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Shevchenko, N. S., N. V. Krutenko, T. V. Zimnytska, and K. V. Voloshyn. "The role of hypoxia-inducible factors in the development of chronic pathology." Ukrainian Biochemical Journal 93, no. 4 (September 13, 2021): 18–25. http://dx.doi.org/10.15407/ubj93.04.018.

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This review highlights the current understanding of hypoxia-inducible factors (HIFs) role as regulators of oxygen-dependent reactions and inducers of genes expression in human organism. The focus is on the most significant relationships between the activation or inhibition of the HIFs intracellular system and development of the inflammatory process in various organs, chronic diseases of gastrointestinal tract, osteoarticular system, kidneys as well as hematological, endocrine and metabolic disorders.

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Liu, Weiwei, Yan Wang, Zhimei Qiu, Ranzun Zhao, Zhijiang Liu, Wenming Chen, Junbo Ge, and Bei Shi. "CircHIPK3 regulates cardiac fibroblast proliferation, migration and phenotypic switching through the miR-152-3p/TGF-β2 axis under hypoxia." PeerJ 8 (August 25, 2020): e9796. http://dx.doi.org/10.7717/peerj.9796.

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Background The occurrence of pathological cardiac fibrosis is attributed to tissue hypoxia. Circular RNAs play significant regulatory roles in multiple cardiovascular diseases and are involved in the regulation of physiological and pathophysiological processes. CircHIPK3 has been identified as the one of the most crucial regulators in cardiac fibrosis. However, the mechanisms by which circHIPK3 regulates cardiac fibrosis under hypoxia remain unclear. Our study aimed to determine circHIPK3 expression in cardiac fibroblasts (CFs) and investigate the functions of circHIPK3 in hypoxia environment. Methods The expression level of circHIPK3 in CFs under hypoxia (1% O2) was analyzed by qRT-PCR. The role of circHIPK3 on the proliferation and migration of CFs were determined by EdU, cell wound scratch assay and cell cycle. The expression of proteins associated with phenotypic transformation in CFs in vitro was examined by immunofluorescence assay and western blot. Bioinformatics analysis, dual luciferase activity assay and RNA fluorescent in situ hybridization assay revealed that miR-152-3p was identified as a target of circHIPK3 and that TGF-β2 was targeted by miR-152-3p. Results CircHIPK3 expression was significantly upregulated in CFs in a hypoxic environment. In vitro, overexpressing circHIPK3 obviously promoted CF proliferation, migration and phenotypic changes under hypoxia, but those processes were suppressed by circHIPK3 silencing. CircHIPK3 acted as an endogenous miR-152-3p sponge and miR-152-3p aggravated circHIPK3 silencing induced inhibition of CF proliferation, migration, phenotypic transformation and TGF-β2 expression in vitro. In summary, circHIPK3 plays a pivotal role in the development of cardiac fibrosis by targeting the miR-152-3p/TGF-β2 axis. Conclusions These findings demonstrated that circHIPK3 acted as a miR-152-3p sponge to regulate CF proliferation, migration and phenotypic transformation through TGF-β2, revealing that modulation of circHIPK3 expression may represent a potential target to promote the transition of hypoxia-induced CFs to myofibroblasts.

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Shah, Ajit N., Daniela Cadinu, R. Michael Henke, Xiantong Xin, Ranita Ghosh Dastidar, and Li Zhang. "Deletion of a subgroup of ribosome-related genes minimizes hypoxia-induced changes and confers hypoxia tolerance." Physiological Genomics 43, no. 14 (July 2011): 855–72. http://dx.doi.org/10.1152/physiolgenomics.00232.2010.

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Hypoxia is a widely occurring condition experienced by diverse organisms under numerous physiological and disease conditions. To probe the molecular mechanisms underlying hypoxia responses and tolerance, we performed a genome-wide screen to identify mutants with enhanced hypoxia tolerance in the model eukaryote, the yeast Saccharomyces cerevisiae . Yeast provides an excellent model for genomic and proteomic studies of hypoxia. We identified five genes whose deletion significantly enhanced hypoxia tolerance. They are RAI1, NSR1, BUD21, RPL20A, and RSM22, all of which encode functions involved in ribosome biogenesis. Further analysis of the deletion mutants showed that they minimized hypoxia-induced changes in polyribosome profiles and protein synthesis. Strikingly, proteomic analysis by using the iTRAQ profiling technology showed that a substantially fewer number of proteins were changed in response to hypoxia in the deletion mutants, compared with the parent strain. Computational analysis of the iTRAQ data indicated that the activities of a group of regulators were regulated by hypoxia in the wild-type parent cells, but such regulation appeared to be diminished in the deletion strains. These results show that the deletion of one of the genes involved in ribosome biogenesis leads to the reversal of hypoxia-induced changes in gene expression and related regulators. They suggest that modifying ribosomal function is an effective mechanism to minimize hypoxia-induced specific protein changes and to confer hypoxia tolerance. These results may have broad implications in understanding hypoxia responses and tolerance in diverse eukaryotes ranging from yeast to humans.

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Rytkönen, Kalle T., Taija Heinosalo, Mehrad Mahmoudian, Xinghong Ma, Antti Perheentupa, Laura L. Elo, Matti Poutanen, and Günter P. Wagner. "Transcriptomic responses to hypoxia in endometrial and decidual stromal cells." Reproduction 160, no. 1 (July 2020): 39–51. http://dx.doi.org/10.1530/rep-19-0615.

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Human reproductive success depends on a properly decidualized uterine endometrium that allows implantation and the formation of the placenta. At the core of the decidualization process are endometrial stromal fibroblasts (ESF) that differentiate to decidual stromal cells (DSC). As variations in oxygen levels are functionally relevant in endometrium both upon menstruation and during placentation, we assessed the transcriptomic responses to hypoxia in ESF and DSC. In both cell types, hypoxia-upregulated genes in classical hypoxia pathways such as glycolysis and the epithelial mesenchymal transition. In DSC, hypoxia restored an ESF-like transcriptional state for a subset of transcription factors that are known targets of the progesterone receptor, suggesting that hypoxia partially interferes with progesterone signaling. In both cell types, hypoxia modified transcription of several inflammatory transcription factors that are known regulators of decidualization, including decreased transcription of STATs and increased transcription of CEBPs. We observed that hypoxia-upregulated genes in ESF and DSC had a significant overlap with genes previously detected to be upregulated in endometriotic stromal cells. Promoter analysis of the genes in this overlap suggested the hypoxia-upregulated Jun/Fos and CEBP transcription factors as potential drivers of endometriosis-associated transcription. Using immunohistochemistry, we observed increased expression of JUND and CEBPD in endometriosis lesions compared to healthy endometria. Overall, the findings suggest that hypoxic stress establishes distinct transcriptional states in ESF and DSC and that hypoxia influences the expression of genes that contribute to the core gene regulation of endometriotic stromal cells.

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Favier, François B., Frédéric Costes, Aurélia Defour, Régis Bonnefoy, Etienne Lefai, Stéphane Baugé, André Peinnequin, Henri Benoit, and Damien Freyssenet. "Downregulation of Akt/mammalian target of rapamycin pathway in skeletal muscle is associated with increased REDD1 expression in response to chronic hypoxia." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 298, no. 6 (June 2010): R1659—R1666. http://dx.doi.org/10.1152/ajpregu.00550.2009.

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Although it is well established that chronic hypoxia leads to an inexorable loss of skeletal muscle mass in healthy subjects, the underlying molecular mechanisms involved in this process are currently unknown. Skeletal muscle atrophy is also an important systemic consequence of chronic obstructive pulmonary disease (COPD), but the role of hypoxemia in this regulation is still debated. Our general aim was to determine the molecular mechanisms involved in the regulation of skeletal muscle mass after exposure to chronic hypoxia and to test the biological relevance of our findings into the clinical context of COPD. Expression of positive and negative regulators of skeletal muscle mass were explored 1) in the soleus muscle of rats exposed to severe hypoxia (6,300 m) for 3 wk and 2) in vastus lateralis muscle of nonhypoxemic and hypoxemic COPD patients. In rodents, we observed a marked inhibition of the mammalian target of rapamycin (mTOR) pathway together with a strong increase in regulated in development and DNA damage response 1 (REDD1) expression and in its association with 14-3-3, a mechanism known to downregulate the mTOR pathway. Importantly, REDD1 overexpression in vivo was sufficient to cause skeletal muscle fiber atrophy in normoxia. Finally, the comparative analysis of skeletal muscle in hypoxemic vs. nonhypoxemic COPD patients confirms that hypoxia causes an inhibition of the mTOR signaling pathway. We thus identify REDD1 as a negative regulator of skeletal muscle mass during chronic hypoxia. Translation of this fundamental knowledge into the clinical investigation of COPD shows the interest to develop therapeutic strategies aimed at inhibiting REDD1.

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Luo, Weibo, Ivan Chen, Yan Chen, Duah Alkam, Yingfei Wang, and Gregg L. Semenza. "PRDX2 and PRDX4 are negative regulators of hypoxia-inducible factors under conditions of prolonged hypoxia." Oncotarget 7, no. 6 (February 2, 2016): 6379–97. http://dx.doi.org/10.18632/oncotarget.7142.

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Raff, Hershel, Lauren Jacobson, and William E. Cullinan. "Elevated corticosterone and inhibition of ACTH responses to CRH and ether in the neonatal rat: effect of hypoxia from birth." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 285, no. 5 (November 2003): R1224—R1230. http://dx.doi.org/10.1152/ajpregu.00259.2003.

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Hypoxia is a common cause of neonatal morbidity and mortality. We have previously demonstrated a dramatic ACTH-independent activation of adrenal steroidogenesis in hypoxic neonatal rats, leading to increases in circulating corticosterone levels. The purpose of the present study was to determine if this ACTH-independent increase in corticosterone inhibits the ACTH response to acute stimuli. Neonatal rats were exposed to normoxia (control) or hypoxia from birth to 5 or 7 days of age. At the end of the exposure, plasma ACTH and corticosterone were measured before and after either ether vapors were administered for 3 min or CRH (10 μg/kg) was given intraperitoneally. Thyroid function, pituitary pro-opiomelanocortin (POMC) mRNA and ACTH content, and hypothalamic corticotropin-releasing hormone (CRH), neuropeptide Y (NPY), and AVP mRNA were also assessed. Hypoxia led to a significant increase in corticosterone without a large increase in ACTH, confirming previous studies. The ACTH responses to ether or CRH administration were almost completely inhibited in hypoxic pups. Hypoxia did not affect the established regulators of the neonatal hypothalamic-pituitary-adrenal axis, including pituitary POMC or ACTH content, hypothalamic CRH, NPY, or AVP mRNA (parvo- or magnocellular), or thyroid function. We conclude that hypoxia from birth to 5 or 7 days of age leads to an attenuated ACTH response to acute stimuli, most likely due to glucocorticoid negative feedback. The neural and biochemical mechanism of this effect has yet to be elucidated.

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Lee, Hsiu-Chi, and Shaw-Jenq Tsai. "Endocrine targets of hypoxia-inducible factors." Journal of Endocrinology 234, no. 1 (July 2017): R53—R65. http://dx.doi.org/10.1530/joe-16-0653.

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Endocrine is an important and tightly regulated system for maintaining body homeostasis. Endocrine glands produce hormones, which are released into blood stream to guide the target cells responding to all sorts of stimulations. For maintaining body homeostasis, the secretion and activity of a particular hormone needs to be adjusted in responding to environmental challenges such as changes in nutritional status or chronic stress. Hypoxia, a status caused by reduced oxygen availability or imbalance of oxygen consumption/supply in an organ or within a cell, is a stress that affects many physiological and pathological processes. Hypoxic stress in endocrine organs is especially critical because endocrine glands control body homeostasis. Local hypoxia affects not only the particular gland but also the downstream cells/organs regulated by hormones secreted from this gland. Hypoxia-inducible factors (HIFs) are transcription factors that function as master regulators of oxygen homeostasis. Recent studies report that aberrant expression of HIFs in endocrine organs may result in the development and/or progression of diseases including diabetes, endometriosis, infertility and cancers. In this article, we will review recent findings in HIF-mediated endocrine organ dysfunction and the systemic syndromes caused by these disorders.

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Hettiarachchi, Gaya K., Upendra K. Katneni, Ryan C. Hunt, Jacob M. Kames, John C. Athey, Haim Bar, Zuben E. Sauna, Joseph R. McGill, Juan C. Ibla, and Chava Kimchi-Sarfaty. "Translational and transcriptional responses in human primary hepatocytes under hypoxia." American Journal of Physiology-Gastrointestinal and Liver Physiology 316, no. 6 (June 1, 2019): G720—G734. http://dx.doi.org/10.1152/ajpgi.00331.2018.

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The liver is the primary source of a large number of plasma proteins and plays a critical role in multiple biological processes. Inadequate oxygen supply characterizing various clinical settings such as liver transplantation exposes the liver to hypoxic conditions. Studies assessing hypoxia-induced global translational changes in liver are lacking. Here, we employed a recently developed ribosome-profiling technique to assess global translational responses of human primary hepatocytes exposed to acute hypoxic stress (1% O2) for the short term. In parallel, transcriptome profiling was performed to assess mRNA expression changes. We found that translational responses appeared earlier and were predominant over transcriptional responses. A significant decrease in translational efficiency of several ribosome genes indicated translational inhibition of new ribosome protein synthesis in hypoxia. Pathway enrichment analysis highlighted altered translational regulation of MAPK signaling, drug metabolism, oxidative phosphorylation, and nonalcoholic fatty liver disease pathways. Gene Ontology enrichment analysis revealed terms related to translation, metabolism, angiogenesis, apoptosis, and response to stress. Transcriptional induction of genes encoding heat shock proteins was observed within 30 min of hypoxia. Induction of genes encoding stress response mediators, metabolism regulators, and proangiogenic proteins was observed at 240 min. Despite the liver being the primary source of coagulation proteins and the implicated role of hypoxia in thrombosis, limited differences were observed in genes encoding coagulation-associated proteins. Overall, our study demonstrates the predominance of translational regulation over transcription and highlights differentially regulated pathways or biological processes in short-term hypoxic stress responses of human primary hepatocytes.NEW & NOTEWORTHY The novelty of this study lies in applying parallel ribosome- and transcriptome-profiling analyses to human primary hepatocytes in hypoxia. To our knowledge, this is the first study to assess global translational responses using ribosome profiling in hypoxic hepatocytes. Our results demonstrate the predominance of translational responses over transcriptional responses in early hepatic hypoxic stress responses. Furthermore, our study reveals multiple pathways and specific genes showing altered regulation in hypoxic hepatocytes.

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Tracy, Kristin, Benjamin C. Dibling, Benjamin T. Spike, James R. Knabb, Paul Schumacker, and Kay F. Macleod. "BNIP3 Is an RB/E2F Target Gene Required for Hypoxia-Induced Autophagy." Molecular and Cellular Biology 27, no. 17 (June 18, 2007): 6229–42. http://dx.doi.org/10.1128/mcb.02246-06.

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ABSTRACT Hypoxia and nutrient deprivation are environmental stresses governing the survival and adaptation of tumor cells in vivo. We have identified a novel role for the Rb tumor suppressor in protecting against nonapoptotic cell death in the developing mouse fetal liver, in primary mouse embryonic fibroblasts, and in tumor cell lines. Loss of pRb resulted in derepression of BNip3, a hypoxia-inducible member of the Bcl-2 superfamily of cell death regulators. We identified BNIP3 as a direct target of pRB/E2F-mediated transcriptional repression and showed that pRB attenuates the induction of BNIP3 by hypoxia-inducible factor to prevent autophagic cell death. BNIP3 was essential for hypoxia-induced autophagy, and its ability to promote autophagosome formation was enhanced under conditions of nutrient deprivation. Knockdown of BNIP3 reduced cell death, and remaining deaths were necrotic in nature. These studies identify BNIP3 as a key regulator of hypoxia-induced autophagy and suggest a novel role for the RB tumor suppressor in preventing nonapoptotic cell death by limiting the extent of BNIP3 induction in cells.

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Lin, Jennie, Xuan Zhang, Chenyi Xue, Hanrui Zhang, Michael G. S. Shashaty, Sager J. Gosai, Nuala Meyer, et al. "The long noncoding RNA landscape in hypoxic and inflammatory renal epithelial injury." American Journal of Physiology-Renal Physiology 309, no. 11 (December 1, 2015): F901—F913. http://dx.doi.org/10.1152/ajprenal.00290.2015.

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Long noncoding RNAs (lncRNAs) are emerging as key species-specific regulators of cellular and disease processes. To identify potential lncRNAs relevant to acute and chronic renal epithelial injury, we performed unbiased whole transcriptome profiling of human proximal tubular epithelial cells (PTECs) in hypoxic and inflammatory conditions. RNA sequencing revealed that the protein-coding and noncoding transcriptomic landscape differed between hypoxia-stimulated and cytokine-stimulated human PTECs. Hypoxia- and inflammation-modulated lncRNAs were prioritized for focused followup according to their degree of induction by these stress stimuli, their expression in human kidney tissue, and whether exposure of human PTECs to plasma of critically ill sepsis patients with acute kidney injury modulated their expression. For three lncRNAs (MIR210HG, linc-ATP13A4-8, and linc-KIAA1737-2) that fulfilled our criteria, we validated their expression patterns, examined their loci for conservation and synteny, and defined their associated epigenetic marks. The lncRNA landscape characterized here provides insights into novel transcriptomic variations in the renal epithelial cell response to hypoxic and inflammatory stress.

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Boulahbel, Houda, Raúl V. Durán, and Eyal Gottlieb. "Prolyl hydroxylases as regulators of cell metabolism." Biochemical Society Transactions 37, no. 1 (January 20, 2009): 291–94. http://dx.doi.org/10.1042/bst0370291.

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Abstract:

Cellular response to oxygen depletion is mediated by HIF (hypoxia-inducible factor). HIF is a heterodimer consisting of a constitutively expressed subunit (HIFβ) and an oxygen-regulated subunit (HIFα). HIFα stability is regulated by prolyl hydroxylation by PHD (prolyl hydroxylase domain-containing protein) family members. PHD activity depends on the availability of molecular oxygen, making PHDs the oxygen-sensing system in animal cells. However, PHDs have recently been shown to respond to stimuli other than oxygen, such as 2-oxoglutarate (α-ketoglutarate), succinate or fumarate, as illustrated by the pseudo-hypoxic response in succinate dehydrogenase- or fumarate dehydrogenase-deficient tumours. Moreover, HIFα is not the sole PHD effector, suggesting that PHDs have functions that extend beyond oxygen sensing. Currently, we are investigating the role of PHDs in the cellular response to amino acid deprivation, a process regulated by mTOR (mammalian target of rapamycin). The precise mechanism whereby amino acids are signalling to mTOR is not fully understood. Given that 2-oxoglutarate is a limiting co-substrate for PHD activity during normoxia and that 2-oxoglutarate levels depend on amino acid availability, it is possible that PHD activity depends not only on oxygen, but also on amino acid availability, suggesting a global metabolic sensor function for PHDs which could be signalling not only to HIF, but also to mTOR.

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Hubbi, Maimon E., Weibo Luo, Jin H. Baek, and Gregg L. Semenza. "MCM Proteins Are Negative Regulators of Hypoxia-Inducible Factor 1." Molecular Cell 42, no. 5 (June 2011): 700–712. http://dx.doi.org/10.1016/j.molcel.2011.03.029.

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Journal articles on the topic 'Hypoxia regulators'

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