The Experts below are selected from a list of 74298 Experts worldwide ranked by ideXlab platform
Gregg L Semenza - One of the best experts on this subject based on the ideXlab platform.
-
Intratumoral Hypoxia and Mechanisms of Immune Evasion Mediated by Hypoxia-Inducible Factors.
Physiology (Bethesda Md.), 2021Co-Authors: Gregg L SemenzaAbstract:Activation of the innate and adaptive immune systems represents a promising strategy for defeating cancer. However, during tumor progression, cancer cells battle to shift the balance from immune activation to immunosuppression. Critical sites of this battle are regions of intratumoral hypoxia, and a major driving force for immunosuppression is the activity of Hypoxia-Inducible Factors, which regulate the transcription of large batteries of genes in both cancer and stromal cells that block the infiltration and activity of cytotoxic T lymphocytes and natural killer cells, while stimulating the infiltration and activity of regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. Targeting Hypoxia-Inducible Factors or their target gene products may restore anticancer immunity and improve the response to immunotherapies.
-
the role of hypoxia inducible Factors in carotid body patho physiology
The Journal of Physiology, 2018Co-Authors: Gregg L Semenza, Nanduri R. PrabhakarAbstract:Hypoxia-Inducible Factors mediate adaptive responses to reduced O2 availability. In patients with obstructive sleep apnoea, repeated episodes of hypoxaemia and reoxygenation (intermittent hypoxia) are sensed by the carotid body (CB). The ensuing CB chemosensory reflex activates the sympathetic nervous system and increased secretion of catecholamines by the adrenal medulla, resulting in hypertension and breathing abnormalities. In the CB, intermittent hypoxia induces the formation of reactive oxygen species (ROS) and increased intracellular Ca2+ levels, which drive increased expression of Hypoxia-Inducible factor (HIF) 1α and a decrease in the levels of HIF-2α. Intermittent hypoxia increases HIF-1α-dependent expression of Nox2, encoding the pro-oxidant enzyme NADPH oxidase 2, and decreased HIF-2α-dependent expression of Sod2, encoding the anti-oxidant enzyme superoxide dismutase 2. These changes in gene expression drive persistently elevated ROS levels in the CB, brainstem, and adrenal medulla that are required for the development of hypertension and breathing abnormalities. The ROS generated by dysregulated HIF activity in the CB results in oxidation and inhibition of haem oxygenase 2, and the resulting reduction in the levels of carbon monoxide leads to increased hydrogen sulfide production, triggering glomus cell depolarization. Thus, the pathophysiology of obstructive sleep apnoea involves the dysregulation of O2 -regulated transcription Factors, gasotransmitters, and sympathetic outflow that affects blood pressure and breathing.
-
Maintenance of redox homeostasis by Hypoxia-Inducible Factors.
Redox biology, 2017Co-Authors: Debangshu Samanta, Gregg L SemenzaAbstract:Oxidative phosphorylation enables cells to generate the large amounts of ATP required for development and maintenance of multicellular organisms. However, under conditions of reduced O2 availability, electron transport becomes less efficient, leading to increased generation of superoxide anions. Hypoxia-Inducible Factors switch cells from oxidative to glycolytic metabolism, to reduce mitochondrial superoxide generation, and increase the synthesis of NADPH and glutathione, in order to maintain redox homeostasis under hypoxic conditions.
-
hypoxia inducible Factors regulate pluripotency factor expression by znf217 and alkbh5 mediated modulation of rna methylation in breast cancer cells
Oncotarget, 2016Co-Authors: Chuanzhao Zhang, Debangshu Samanta, Ivan Chen, Haiquan Lu, Edward Gabrielson, Gregg L SemenzaAbstract:// Chuanzhao Zhang 1,2 , Wanqing Iris Zhi 3 , Haiquan Lu 1,9 , Debangshu Samanta 1,9 , Ivan Chen 1,9 , Edward Gabrielson 3,4 and Gregg L. Semenza 1,3,5,6,7,8,9 1 Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA 2 Department of General Surgery, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China 3 Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA 4 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA 5 Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA 6 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA 7 Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA 8 Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA 9 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA Correspondence to: Gregg L. Semenza, email: // Keywords : breast cancer stem cells; hypoxia; metastasis; N 6 -methyladenosine; pluripotency Factors Received : August 02, 2016 Accepted : August 12, 2016 Published : August 31, 2016 Abstract Exposure of breast cancer cells to hypoxia increases the percentage of breast cancer stem cells (BCSCs), which are required for tumor initiation and metastasis, and this response is dependent on the activity of Hypoxia-Inducible Factors (HIFs). We previously reported that exposure of breast cancer cells to hypoxia induces the ALKBH5-mediated demethylation of N 6 -methyladenosine (m 6 A) in NANOG mRNA leading to increased expression of NANOG, which is a pluripotency factor that promotes BCSC specification. Here we report that exposure of breast cancer cells to hypoxia also induces ZNF217-dependent inhibition of m 6 A methylation of mRNAs encoding NANOG and KLF4, which is another pluripotency factor that mediates BCSC specification. Although hypoxia induced the BCSC phenotype in all breast-cancer cell lines analyzed, it did so through variable induction of pluripotency Factors and ALKBH5 or ZNF217. However, in every breast cancer line, the hypoxic induction of pluripotency factor and ALKBH5 or ZNF217 expression was HIF-dependent. Immunohistochemistry revealed that expression of HIF-1α and ALKBH5 was concordant in all human breast cancer biopsies analyzed. ALKBH5 knockdown in MDA-MB-231 breast cancer cells significantly decreased metastasis from breast to lungs in immunodeficient mice. Thus, HIFs stimulate pluripotency factor expression and BCSC specification by negative regulation of RNA methylation.
-
the hypoxic tumor microenvironment a driving force for breast cancer progression
Biochimica et Biophysica Acta, 2016Co-Authors: Gregg L SemenzaAbstract:Intratumoral hypoxia is a common finding in breast cancer and is associated with a significantly increased risk of metastasis and patient mortality. Hypoxia-Inducible Factors activate the transcription of a large battery of genes encoding proteins that promote primary tumor vascularization and growth, stromal cell recruitment, extracellular matrix remodeling, premetastatic niche formation, cell motility, local tissue invasion, extravasation at sites of metastasis, and maintenance of the cancer stem cell phenotype that is required to generate secondary tumors. Recent preclinical studies suggest that the combination of cytotoxic chemotherapy with drugs that inhibit Hypoxia-Inducible Factors may improve outcome for women with triple-negative breast cancer. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza.
Karl H Plate - One of the best experts on this subject based on the ideXlab platform.
-
up regulation of hypoxia inducible Factors hif 1alpha and hif 2alpha under normoxic conditions in renal carcinoma cells by von hippel lindau tumor suppressor gene loss of function
Oncogene, 2000Co-Authors: Marion Krieg, Richard Haas, Hiltrud Brauch, Till Acker, Ingo Flamme, Karl H PlateAbstract:Up-regulation of Hypoxia-Inducible Factors HIF-1α and HIF-2α under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor suppressor gene loss of function
-
Up-regulation of Hypoxia-Inducible Factors HIF-1α and HIF-2α under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor suppressor gene loss of function
Oncogene, 2000Co-Authors: Marion Krieg, Richard Haas, Hiltrud Brauch, Till Acker, Ingo Flamme, Karl H PlateAbstract:Hypoxia induces transcription of a range of physiologically important genes including erythropoietin and vascular endothelial growth factor. The transcriptional activation is mediated by the Hypoxia-Inducible factor-1 (HIF-1), a heterodimeric member of the basic helix–loop–helix PAS family, composed of α and β subunits. HIF-1α shares 48 per cent identity with the recently identified HIF-2α protein that is also stimulated by hypoxia. In a previous study of hemangioblastomas, the most frequent manifestation of hereditary von Hippel-Lindau disease (VHL), we found elevated levels of vascular endothelial growth factor and HIF-2α mRNA in stromal cells of the tumors. Mutations of the VHL tumor suppressor gene are associated with a variety of tumors such as renal clear cell carcinomas (RCC). In this study, we analysed the expression of the Hypoxia-Inducible Factors HIF-1α and HIF-2α in a range of VHL wildtype and VHL deficient RCC cell lines. In the presence of functional VHL protein, HIF-1α mRNA levels are elevated, whereas HIF-2α mRNA expression is increased only in cells lacking a functional VHL gene product. On the protein levels, however, in VHL deficient cell lines, both HIF-α subunits are constitutively expressed, whereas re-introduction of a functional VHL gene restores the instability of HIF-1α and HIF-2α proteins under normoxic conditions. Moreover, immunohistochemical analyses of RCCs and hemangioblastomas demonstrate up-regulation of HIF-1α and HIF-2α in the tumor cells. The data presented here provide evidence for a role of the VHL protein in regulation of angiogenesis and erythropoiesis mediated by the HIF-1α and HIF-2α proteins.
Celeste M Simon - One of the best experts on this subject based on the ideXlab platform.
-
hypoxia inducible Factors and the response to hypoxic stress
Molecular Cell, 2010Co-Authors: Amar J Majmundar, Waihay J Wong, Celeste M SimonAbstract:Oxygen (O 2 ) is an essential nutrient that serves as a key substrate in cellular metabolism and bioenergetics. In a variety of physiological and pathological states, organisms encounter insufficient O 2 availability, or hypoxia. In order to cope with this stress, evolutionarily conserved responses are engaged. In mammals, the primary transcriptional response to hypoxic stress is mediated by the Hypoxia-Inducible Factors (HIFs). While canonically regulated by prolyl hydroxylase domain-containing enzymes (PHDs), the HIFα subunits are intricately responsive to numerous other Factors, including factor-inhibiting HIF1α (FIH1), sirtuins, and metabolites. These transcription Factors function in normal tissue homeostasis and impinge on critical aspects of disease progression and recovery. Insights from basic HIF biology are being translated into pharmaceuticals targeting the HIF pathway.
-
the role of oxygen availability in embryonic development and stem cell function
Nature Reviews Molecular Cell Biology, 2008Co-Authors: Celeste M Simon, Brian KeithAbstract:Low levels of oxygen (O2) occur naturally in developing embryos. Cells respond to their hypoxic microenvironment by stimulating several Hypoxia-Inducible Factors (and other molecules that mediate O2 homeostasis), which then coordinate the development of the blood, vasculature, placenta, nervous system and other organs. Furthermore, embryonic stem and progenitor cells frequently occupy hypoxic 'niches' and low O2 regulates their differentiation. Recent work has revealed an important link between Factors that are involved in regulating stem and progenitor cell behaviour and Hypoxia-Inducible Factors, which provides a molecular framework for the hypoxic control of differentiation and cell fate. These findings have important implications for the development of therapies for tissue regeneration and disease.
-
hypoxia inducible Factors stem cells and cancer
Cell, 2007Co-Authors: Brian Keith, Celeste M SimonAbstract:Regions of severe oxygen deprivation (hypoxia) arise in tumors due to rapid cell division and aberrant blood vessel formation. The Hypoxia-Inducible Factors (HIFs) mediate transcriptional responses to localized hypoxia in normal tissues and in cancers and can promote tumor progression by altering cellular metabolism and stimulating angiogenesis. Recently, HIFs have been shown to activate specific signaling pathways such as Notch and the expression of transcription Factors such as Oct4 that control stem cell self renewal and multipotency. As many cancers are thought to develop from a small number of transformed, self-renewing, and multipotent "cancer stem cells," these results suggest new roles for HIFs in tumor progression.
-
hypoxia inducible Factors central regulators of the tumor phenotype
Current Opinion in Genetics & Development, 2007Co-Authors: John D Gordan, Celeste M SimonAbstract:Low oxygen levels are a defining characteristic of solid tumors, and responses to hypoxia contribute substantially to the malignant phenotype. Hypoxia-induced gene transcription promotes characteristic tumor behaviors, including angiogenesis, invasion, metastasis, de-differentiation and enhanced glycolytic metabolism. These effects are mediated, at least in part, by targets of the Hypoxia-Inducible Factors (HIFs). The HIFs function as heterodimers comprising an oxygen-labile alpha-subunit and a stable beta-subunit also referred to as ARNT. HIF-1alpha and HIF-2alpha stimulate the expression of overlapping as well as unique transcriptional targets, and their induction can have distinct biological effects. New targets and novel mechanisms of dysregulation place the HIFs in an ever more central role in tumor biology and have led to development of pharmacological inhibitors of their activity.
Marion Krieg - One of the best experts on this subject based on the ideXlab platform.
-
up regulation of hypoxia inducible Factors hif 1alpha and hif 2alpha under normoxic conditions in renal carcinoma cells by von hippel lindau tumor suppressor gene loss of function
Oncogene, 2000Co-Authors: Marion Krieg, Richard Haas, Hiltrud Brauch, Till Acker, Ingo Flamme, Karl H PlateAbstract:Up-regulation of Hypoxia-Inducible Factors HIF-1α and HIF-2α under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor suppressor gene loss of function
-
Up-regulation of Hypoxia-Inducible Factors HIF-1α and HIF-2α under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor suppressor gene loss of function
Oncogene, 2000Co-Authors: Marion Krieg, Richard Haas, Hiltrud Brauch, Till Acker, Ingo Flamme, Karl H PlateAbstract:Hypoxia induces transcription of a range of physiologically important genes including erythropoietin and vascular endothelial growth factor. The transcriptional activation is mediated by the Hypoxia-Inducible factor-1 (HIF-1), a heterodimeric member of the basic helix–loop–helix PAS family, composed of α and β subunits. HIF-1α shares 48 per cent identity with the recently identified HIF-2α protein that is also stimulated by hypoxia. In a previous study of hemangioblastomas, the most frequent manifestation of hereditary von Hippel-Lindau disease (VHL), we found elevated levels of vascular endothelial growth factor and HIF-2α mRNA in stromal cells of the tumors. Mutations of the VHL tumor suppressor gene are associated with a variety of tumors such as renal clear cell carcinomas (RCC). In this study, we analysed the expression of the Hypoxia-Inducible Factors HIF-1α and HIF-2α in a range of VHL wildtype and VHL deficient RCC cell lines. In the presence of functional VHL protein, HIF-1α mRNA levels are elevated, whereas HIF-2α mRNA expression is increased only in cells lacking a functional VHL gene product. On the protein levels, however, in VHL deficient cell lines, both HIF-α subunits are constitutively expressed, whereas re-introduction of a functional VHL gene restores the instability of HIF-1α and HIF-2α proteins under normoxic conditions. Moreover, immunohistochemical analyses of RCCs and hemangioblastomas demonstrate up-regulation of HIF-1α and HIF-2α in the tumor cells. The data presented here provide evidence for a role of the VHL protein in regulation of angiogenesis and erythropoiesis mediated by the HIF-1α and HIF-2α proteins.
Ingo Flamme - One of the best experts on this subject based on the ideXlab platform.
-
up regulation of hypoxia inducible Factors hif 1alpha and hif 2alpha under normoxic conditions in renal carcinoma cells by von hippel lindau tumor suppressor gene loss of function
Oncogene, 2000Co-Authors: Marion Krieg, Richard Haas, Hiltrud Brauch, Till Acker, Ingo Flamme, Karl H PlateAbstract:Up-regulation of Hypoxia-Inducible Factors HIF-1α and HIF-2α under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor suppressor gene loss of function
-
Up-regulation of Hypoxia-Inducible Factors HIF-1α and HIF-2α under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor suppressor gene loss of function
Oncogene, 2000Co-Authors: Marion Krieg, Richard Haas, Hiltrud Brauch, Till Acker, Ingo Flamme, Karl H PlateAbstract:Hypoxia induces transcription of a range of physiologically important genes including erythropoietin and vascular endothelial growth factor. The transcriptional activation is mediated by the Hypoxia-Inducible factor-1 (HIF-1), a heterodimeric member of the basic helix–loop–helix PAS family, composed of α and β subunits. HIF-1α shares 48 per cent identity with the recently identified HIF-2α protein that is also stimulated by hypoxia. In a previous study of hemangioblastomas, the most frequent manifestation of hereditary von Hippel-Lindau disease (VHL), we found elevated levels of vascular endothelial growth factor and HIF-2α mRNA in stromal cells of the tumors. Mutations of the VHL tumor suppressor gene are associated with a variety of tumors such as renal clear cell carcinomas (RCC). In this study, we analysed the expression of the Hypoxia-Inducible Factors HIF-1α and HIF-2α in a range of VHL wildtype and VHL deficient RCC cell lines. In the presence of functional VHL protein, HIF-1α mRNA levels are elevated, whereas HIF-2α mRNA expression is increased only in cells lacking a functional VHL gene product. On the protein levels, however, in VHL deficient cell lines, both HIF-α subunits are constitutively expressed, whereas re-introduction of a functional VHL gene restores the instability of HIF-1α and HIF-2α proteins under normoxic conditions. Moreover, immunohistochemical analyses of RCCs and hemangioblastomas demonstrate up-regulation of HIF-1α and HIF-2α in the tumor cells. The data presented here provide evidence for a role of the VHL protein in regulation of angiogenesis and erythropoiesis mediated by the HIF-1α and HIF-2α proteins.