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Gregg L Semenza - One of the best experts on this subject based on the ideXlab platform.
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Hypoxia Inducible Factor 1 mediates pancreatic β cell dysfunction by intermittent Hypoxia
American Journal of Physiology-cell Physiology, 2020Co-Authors: Ning Wang, Gregg L Semenza, Xuefeng Shi, Shakil A Khan, Benjamin Wang, Nanduri R Prabhakar, Jayasri NanduriAbstract:The role of Hypoxia-Inducible Factor (HIF)-1 in pancreatic β-cell response to intermittent Hypoxia (IH) was examined. Studies were performed on adult wild-type (WT), HIF-1α heterozygous (HET), β-ce...
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Hypoxia-Inducible Factor 1 and Cardiovascular Disease
Annual review of physiology, 2013Co-Authors: Gregg L SemenzaAbstract:Cardiac function is required for blood circulation and systemic oxygen delivery. However, the heart has intrinsic oxygen demands that must be met to maintain effective contractility. Hypoxia-Inducible Factor 1 (HIF-1) is a transcription Factor that functions as a master regulator of oxygen homeostasis in all metazoan species. HIF-1 controls oxygen delivery, by regulating angiogenesis and vascular remodeling, and oxygen utilization, by regulating glucose metabolism and redox homeostasis. Analysis of animal models suggests that by activation of these homeostatic mechanisms, HIF-1 plays a critical protective role in the pathophysiology of ischemic heart disease and pressure-overload heart failure.
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regulation of oxygen homeostasis by Hypoxia Inducible Factor 1
Physiology, 2009Co-Authors: Gregg L SemenzaAbstract:Metazoan organisms are dependent on a continuous supply of O2 for survival. Hypoxia-Inducible Factor 1 (HIF-1) is a transcription Factor that regulates oxygen homeostasis and plays key roles in dev...
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Hypoxia-Inducible Factor 1 and cancer pathogenesis.
IUBMB life, 2008Co-Authors: Gregg L SemenzaAbstract:Hypoxia-Inducible Factor 1 (HIF-1) is a transcriptional activator that mediates adaptive responses to Hypoxia. HIF-1 activity is increased in the majority of human cancers as a result of genetic alterations and intratumoral Hypoxia. HIF-1 activates the transcription of genes that increase O2 availability by stimulating angiogenesis or that reprogram cellular metabolism to adapt to reduced O2 availability. Proof of principle studies in mouse models suggests that inhibition of HIF-1 activity may have therapeutic effects, especially in combination with other anticancer drugs. © 2008 IUBMB IUBMB Life, 60(9): 591–597, 2008
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regulation of physiological responses to continuous and intermittent Hypoxia by Hypoxia Inducible Factor 1
Experimental Physiology, 2006Co-Authors: Gregg L SemenzaAbstract:Hypoxia-Inducible Factor 1 (HIF-1) is a heterodimeric transcription Factor composed of HIF-1α and HIF-1β subunits that functions as a master regulator of oxygen homeostasis. Oxygen-dependent hydroxylation of HIF-1α provides a mechanism that allows changes in oxygenation to be transduced to the nucleus, leading to changes in gene expression. Hypoxia-Inducible Factor 1 plays critical roles in development, physiology and disease pathogenesis. Analyses of mice that are heterozygous for a null allele at the locus encoding the HIF-1α subunit have demonstrated that partial deficiency of HIF-1 is sufficient to impair multiple physiological responses to continuous and intermittent Hypoxia.
Peng Gao - One of the best experts on this subject based on the ideXlab platform.
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High-throughput screening identifies CHMP4A associated with Hypoxia-Inducible Factor 1.
Life sciences, 2010Co-Authors: Taiping Shi, Yunqiao Dong, Peng GaoAbstract:Tumor Hypoxia is a common phenomenon and Hypoxia-Inducible Factor-1 is the transcription Factor that is most closely associated with Hypoxia. Hypoxia-Inducible Factor-1 is overexpressed in most solid tumors and plays a vital role in hypoxic acclimatization, energy metabolism, tumor angiogenesis, tumor invasion, and drug tolerance in cancer cells. We aimed to identify novel human genes associated with the stability and transcriptional activity of Hypoxia-Inducible Factor-1. A cell-based dual luciferase reporter system based on a Hypoxia responsive element luciferase reporter gene was constructed to screen 409 novel human genes cloned in our lab. Western blot analysis was used to examine the changes in the expression level of Hypoxia-Inducible Factor-1 α, and RT-PCR analysis was used to detect the transcription level of adenylate kinase 3. Our results demonstrated that chromatin-modifying protein 4A could significantly up-regulate the Hypoxia responsive element luciferase activity under both normoxic and cobalt chloride-induced hypoxic environment in HeLa cells. Moreover, Chromatin-modifying protein 4A could increase the expression of Hypoxia-Inducible Factor-1 α protein under normoxic condition, and enhance the transcription level of adenylate kinase 3, which is one of the target genes of Hypoxia-Inducible Factor-1. The functional screening platform therefore can be applied for the high-throughput screening of Hypoxia-Inducible Factor-1-related genes, which would provide new insights into underlying molecular mechanisms that may regulate Hypoxia in mammalian cells. Copyright © 2010 Elsevier Inc. All rights reserved.
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High-throughput screening identifies CHMP4A associated with Hypoxia-Inducible Factor 1.
Life Sciences, 2010Co-Authors: Taiping Shi, Yunqiao Dong, Peng GaoAbstract:Abstract Aims Tumor Hypoxia is a common phenomenon and Hypoxia-Inducible Factor-1 is the transcription Factor that is most closely associated with Hypoxia. Hypoxia–Inducible Factor–1 is overexpressed in most solid tumors and plays a vital role in hypoxic acclimatization, energy metabolism, tumor angiogenesis, tumor invasion, and drug tolerance in cancer cells. We aimed to identify novel human genes associated with the stability and transcriptional activity of Hypoxia–Inducible Factor–1. Main methods A cell-based dual luciferase reporter system based on a Hypoxia responsive element luciferase reporter gene was constructed to screen 409 novel human genes cloned in our lab. Western blot analysis was used to examine the changes in the expression level of Hypoxia–Inducible Factor–1 α, and RT-PCR analysis was used to detect the transcription level of adenylate kinase 3. Key findings Our results demonstrated that chromatin-modifying protein 4A could significantly up-regulate the Hypoxia responsive element luciferase activity under both normoxic and cobalt chloride-induced hypoxic environment in HeLa cells. Moreover, Chromatin–modifying protein 4A could increase the expression of Hypoxia–Inducible Factor–1 α protein under normoxic condition, and enhance the transcription level of adenylate kinase 3, which is one of the target genes of Hypoxia–Inducible Factor–1. Significance The functional screening platform therefore can be applied for the high-throughput screening of Hypoxia–Inducible Factor–1-related genes, which would provide new insights into underlying molecular mechanisms that may regulate Hypoxia in mammalian cells.
William G Kaelin - One of the best experts on this subject based on the ideXlab platform.
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loss of Hypoxia Inducible Factor prolyl hydroxylase activity in cardiomyocytes phenocopies ischemic cardiomyopathy
Circulation, 2010Co-Authors: Javid Moslehi, Yoji Andrew Minamishima, Donna Neuberg, David M Charytan, Robert F Padera, Sabina Signoretti, Ronglih Liao, William G KaelinAbstract:Background— Ischemic cardiomyopathy is the major cause of heart failure and a significant cause of morbidity and mortality. The degree of left ventricular dysfunction in this setting is often out of proportion to the amount of overtly infarcted tissue, and how decreased delivery of oxygen and nutrients leads to impaired contractility remains incompletely understood. The Prolyl Hydroxylase Domain-Containing Protein (PHD) prolyl hydroxylases are oxygen-sensitive enzymes that transduce changes in oxygen availability into changes in the stability of the Hypoxia-Inducible Factor transcription Factor, a master regulator of genes that promote survival in a low-oxygen environment. Methods and Results— We found that cardiac-specific PHD inactivation causes ultrastructural, histological, and functional changes reminiscent of ischemic cardiomyopathy over time. Moreover, long-term expression of a stabilized Hypoxia-Inducible Factor α variant in cardiomyocytes also led to dilated cardiomyopathy. Conclusion— Sustained ...
Christopher J. Schofield - One of the best experts on this subject based on the ideXlab platform.
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Evidence for the slow reaction of Hypoxia-Inducible Factor prolyl hydroxylase 2 with oxygen.
The FEBS journal, 2010Co-Authors: Emily Flashman, Lee M. Hoffart, Refaat B. Hamed, J. Martin Bollinger, Carsten Krebs, Christopher J. SchofieldAbstract:The response of animals to Hypoxia is mediated by the Hypoxia-Inducible transcription Factor. Human Hypoxia-Inducible Factor is regulated by four Fe(II)- and 2-oxoglutarate-dependent oxygenases: prolyl hydroxylase domain enzymes 1-3 catalyse hydroxylation of two prolyl-residues in Hypoxia-Inducible Factor, triggering its degradation by the proteasome. Factor inhibiting Hypoxia-Inducible Factor catalyses the hydroxylation of an asparagine-residue in Hypoxia-Inducible Factor, inhibiting its transcriptional activity. Collectively, the Hypoxia-Inducible Factor hydroxylases negatively regulate Hypoxia-Inducible Factor in response to increasing oxygen concentration. Prolyl hydroxylase domain 2 is the most important oxygen sensor in human cells; however, the underlying kinetic basis of the oxygen-sensing function of prolyl hydroxylase domain 2 is unclear. We report analyses of the reaction of prolyl hydroxylase domain 2 with oxygen. Chemical quench/MS experiments demonstrate that reaction of a complex of prolyl hydroxylase domain 2, Fe(II), 2-oxoglutarate and the C-terminal oxygen-dependent degradation domain of Hypoxia-Inducible Factor-α with oxygen to form hydroxylated C-terminal oxygen-dependent degradation domain and succinate is much slower (approximately 100-fold) than for other similarly studied 2-oxoglutarate oxygenases. Stopped flow/UV-visible spectroscopy experiments demonstrate that the reaction produces a relatively stable species absorbing at 320 nm; Mossbauer spectroscopic experiments indicate that this species is likely not a Fe(IV)=O intermediate, as observed for other 2-oxoglutarate oxygenases. Overall, the results obtained suggest that, at least compared to other studied 2-oxoglutarate oxygenases, prolyl hydroxylase domain 2 reacts relatively slowly with oxygen, a property that may be associated with its function as an oxygen sensor.
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The inhibition of Factor inhibiting Hypoxia-Inducible Factor (FIH) by β-oxocarboxylic acids
Chemical communications (Cambridge England), 2005Co-Authors: Biswadip Banerji, Michael A. Mcdonough, Ana Conejo-garcia, Luke A. Mcneill, Matthew R. G. Buck, Kirsty S. Hewitson, Neil J. Oldham, Christopher J. SchofieldAbstract:Cyclic β-oxocarboxylic acids inhibit Factor inhibiting Hypoxia-Inducible Factor via ligation to the active site iron.
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Factor inhibiting Hypoxia-Inducible Factor (FIH) and other asparaginyl hydroxylases
Biochemical Society Transactions, 2004Co-Authors: David E. Lancaster, Michael A. Mcdonough, Christopher J. SchofieldAbstract:FIH (Factor inhibiting Hypoxia-Inducible Factor), an asparaginyl β-hydroxylase belonging to the super-family of 2-oxoglutarate and Fe(II)-dependent dioxygenases, catalyses hydroxylation of Asn-803 of Hypoxia-Inducible Factor, a transcription Factor that regulates the mammalian hypoxic response. Only one other asparaginyl β-hydroxylase, which catalyses hydroxylation of both aspartyl and asparaginyl residues in EGF (epidermal growth Factor)-like domains, has been characterized. In the light of recent crystal structures of FIH, we compare FIH with the EGFH (EGF β-hydroxylase) and putative asparagine/asparaginyl hydroxylases. Sequence analyses imply that EGFH does not contain the HXD/E iron-binding motif characteristic of most of the 2-oxoglutarate oxygenases.
Adrian L. Harris - One of the best experts on this subject based on the ideXlab platform.
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Nuclear Localization of Factor Inhibitor Hypoxia-Inducible Factor in Prostate Cancer Is Associated With Poor Prognosis
The Journal of urology, 2011Co-Authors: Nadeem Shaida, Peter Chan, Helen Turley, Catherine M. Jones, Suresh Kanga, Robert W. Ritchie, Peter Malone, Adrian L. Harris, Stephen B. FoxAbstract:Purpose: We determined the role of Factor inhibiting Hypoxia-Inducible Factor-1 in prostate cancer specimens.Materials and Methods: A tissue microarray of 152 prostate cancers was constructed and stained for Factor inhibiting Hypoxia-Inducible Factor-1, Hypoxia-Inducible Factor-1α and 2α, and glucose transporter 1 as a prototypical downstream target of Hypoxia-Inducible Factor-1α. Correlation analysis was done between these variables, and between Factor inhibiting Hypoxia-Inducible Factor-1, and clinical and pathological variables, including prostate specific antigen as a surrogate of recurrence.Results: Factor inhibiting Hypoxia-Inducible Factor-1 was expressed in the cytoplasm and/or the nucleus in 86.5% of tumors, including exclusive cytoplasmic expression in 51.3% and exclusive nuclear expression in 5.3%. Any nuclear and exclusive expression of Factor inhibiting Hypoxia-Inducible Factor was associated with poor prognosis on univariate analysis (p = 0.007 and 0.042, respectively). On multivariate analy...
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Hypoxia-Inducible Factor-2 is a novel regulator of aberrant CXCL12 expression in multiple myeloma plasma cells.
Haematologica, 2009Co-Authors: Sally Martin, Adrian L. Harris, Peter Diamond, Sharon A. Williams, Daniel J. Peet, Nobutaka Fujii, Stan Gronthos, Andrew C.w. ZannettinoAbstract:Background Multiple myeloma is an incurable malignancy of bone marrow plasma cells. Progression of multiple myeloma is accompanied by an increase in bone marrow angiogenesis. Studies from our laboratory suggest a role for the CXCL12 chemokine in this process, with circulating levels of CXCL12 correlating with bone marrow angiogenesis in patients with multiple myeloma. While the mechanisms responsible for aberrant plasma cell expression of CXCL12 remain to be determined, studies in other systems suggest a role for Hypoxia and Hypoxia-Inducible transcription Factors.Design and Methods The expression of Hypoxia-Inducible Factor protein was examined in patients’ bone marrow biopsy specimens using immunohistochemistry. The hypoxic regulation of CXCL12 was examined in multiple myeloma plasma cell lines using polymerase chain reaction and western blotting. The role of Hypoxia-Inducible Factors-1 and -2 in the regulation of CXCL12 expression was examined using over-expression and short hairpin RNA knockdown constructs, electrophoretic mobility shift assays and chromatin immunoprecipitation. The contribution of CXCL12 to Hypoxia-induced angiogenesis was examined in vivo using a subcutaneous murine model of neovascularization.Results Strong Hypoxia-Inducible Factor-2 protein expression was detected in CD138+ multiple myeloma plasma cells in patients’ biopsy specimens. Prolonged exposure to Hypoxia strongly up-regulated CXCL12 expression in multiple myeloma plasma cells and Hypoxia-Inducible Factor-2 was found to play a key role in this response. Promoter analyses revealed increased Hypoxia-Inducible Factor-2 binding to the CXCL12 promoter under hypoxic conditions. Over-expression of Hypoxia-Inducible Factor in multiple myeloma plasma cells strongly induced in vivo angiogenesis, and administration of a CXCL12 antagonist decreased Hypoxia-Inducible Factor-induced angiogenesis.Conclusions Hypoxia-Inducible Factor-2 is a newly identified regulator of CXCL12 expression in multiple myeloma plasma cells and a major contributor to multiple myeloma plasma cell-induced angiogenesis. Targeting the hypoxic niche, and more specifically Hypoxia-Inducible Factor-2, may represent a viable strategy to inhibit angiogenesis in multiple myeloma and progression of this disease.