Insights into The Function and Regulation of Jumonji C Lysine Demethylases as Hypoxic Responsive Enzymes

2020 ◽  
Vol 21 (7) ◽  
pp. 642-654
Author(s):  
Anand Chopra ◽  
Hemanta Adhikary ◽  
William G. Willmore ◽  
Kyle K. Biggar
Keyword(s):  
Catalytic Mechanism ◽  
Hypoxia Inducible Factor ◽  
Low Oxygen ◽  
Hypoxic Response ◽  
Protein Targets ◽  
Nonhistone Protein ◽  
Oxygen Sensitive ◽  
Demethylase Activity ◽  
Hypoxic Tumor

Cellular responses to hypoxia (low oxygen) are governed by oxygen sensitive signaling pathways. Such pathways, in part, are controlled by enzymes with oxygen-dependent catalytic activity, of which the role of prolyl 4-hydroxylases has been widely reviewed. These enzymes inhibit hypoxic response by inducing the oxygen-dependent degradation of hypoxia-inducible factor 1α, the master regulator of the transcriptional hypoxic response. Jumonji C domain-containing lysine demethylases are similar enzymes which share the same oxygen-dependent catalytic mechanism as prolyl 4- hydroxylases. Traditionally, the role of lysine demethylases has been studied in relation to demethylation activity against histone substrates, however, within the past decade an increasing number of nonhistone protein targets have been revealed, some of which have a key role in survival in the hypoxic tumor microenvironment. Within this review, we highlight the involvement of methyllysine in the hypoxic response with a focus on the HIF signaling pathway, the regulation of demethylase activity by oxygen, and provide insights into notable areas of future hypoxic demethylase research.

scholarly journals Translating the Hypoxic Response—the Role of HIF Protein Translation in the Cellular Response to Low Oxygen

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 114 ◽  
Author(s):  
Iglika G. Ivanova ◽  
Catherine V. Park ◽  
Niall S. Kenneth
Keyword(s):  
Cellular Response ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Protein Translation ◽  
Low Oxygen ◽  
Translation Rate ◽  
Hypoxic Response ◽  
Oxygen Sensitive ◽  
Multicellular Organisms

Hypoxia-Inducible Factors (HIFs) play essential roles in the physiological response to low oxygen in all multicellular organisms, while their deregulation is associated with human diseases. HIF levels and activity are primarily controlled by the availability of the oxygen-sensitive HIFα subunits, which is mediated by rapid alterations to the rates of HIFα protein production and degradation. While the pathways that control HIFα degradation are understood in great detail, much less is known about the targeted control of HIFα protein synthesis and what role this has in controlling HIF activity during the hypoxic response. This review will focus on the signalling pathways and RNA binding proteins that modulate HIFα mRNA half-life and/or translation rate, and their contribution to hypoxia-associated diseases.

scholarly journals Hypoxia-Inducible Factor in Thyroid Carcinoma

2011 ◽  
Vol 2011 ◽  
pp. 1-17 ◽  
Author(s):  
Natalie Burrows ◽  
Muhammad Babur ◽  
Julia Resch ◽  
Kaye J. Williams ◽  
Georg Brabant
Keyword(s):  
Thyroid Carcinoma ◽  
Potential Role ◽  
Hypoxia Inducible Factor ◽  
Current Data ◽  
Low Oxygen ◽  
Expression Of Genes ◽  
Mitogen Activated Protein ◽  
Growth Factor Signalling ◽  
Pi3k Signalling

Intratumoural hypoxia (low oxygen tension) is associated with aggressive disease and poor prognosis. Hypoxia-inducible factor-1 is a transcription factor activated by hypoxia that regulates the expression of genes that promote tumour cell survival, progression, metastasis, and resistance to chemo/radiotherapy. In addition to hypoxia, HIF-1 can be activated by growth factor-signalling pathways such as the mitogen-activated protein kinases- (MAPK-) and phosphatidylinositol-3-OH kinases- (PI3K-) signalling cascades. Mutations in these pathways are common in thyroid carcinoma and lead to enhanced HIF-1 expression and activity. Here, we summarise current data that highlights the potential role of both hypoxia and MAPK/PI3K-induced HIF-1 signalling in thyroid carcinoma progression, metastatic characteristics, and the potential role of HIF-1 in thyroid carcinoma response to radiotherapy. Direct or indirect targeting of HIF-1 using an MAPK or PI3K inhibitor in combination with radiotherapy may be a new potential therapeutic target to improve the therapeutic response of thyroid carcinoma to radiotherapy and reduce metastatic burden.

scholarly journals Differential signal pathway activation and 5-HT function: the role of gut enterochromaffin cells as oxygen sensors

2012 ◽  
Vol 303 (10) ◽  
pp. G1164-G1173 ◽  
Author(s):  
Martin Haugen ◽  
Rikard Dammen ◽  
Bernhard Svejda ◽  
Bjorn I. Gustafsson ◽  
Roswitha Pfragner ◽  
...  
Keyword(s):  
Tryptophan Hydroxylase ◽  
Cell Model ◽  
Hypoxia Inducible Factor ◽  
Mechanical Stretch ◽  
Renilla Luciferase ◽  
Low Oxygen ◽  
Differential Signal ◽  
Oxygen Levels ◽  
Ec Cells

The chemomechanosensory function of the gut enterochromaffin (EC) cell enables it to respond to dietary agents and mechanical stretch. We hypothesized that the EC cell, which also sensed alterations in luminal or mucosal oxygen level, was physiologically sensitive to fluctuations in O2. Given that low oxygen levels induce 5-HT production and secretion through a hypoxia inducible factor 1α (HIF-1α)-dependent pathway, we also hypothesized that increasing O2would reduce 5-HT production and secretion. Isolated normal EC cells as well as the well-characterized EC cell model KRJ-I were used to examine HIF signaling (luciferase-assays), hypoxia transcriptional response element (HRE)-mediated transcription (PCR), signaling pathways (Western blot), and 5-HT release (ELISA) during exposure to different oxygen levels. Normal EC cells and KRJ-I cells express HIF-1α, and transient transfection with Renilla luciferase under HRE control identified a hypoxia-mediated pathway in these cells. PCR confirmed activation of HIF-downstream targets, GLUT1, IGF2, and VEGF under reduced O2levels (0.5%). Reducing O2also elevated 5-HT secretion (2–3.2-fold) as well as protein levels of HIF-1α (1.7–3-fold). Increasing O2to 100% inhibited HRE-mediated signaling, transcription, reduced 5-HT secretion, and significantly lowered HIF-1α levels (∼75% of control). NF-κB signaling was also elevated during hypoxia (1.2–1.6-fold), but no significant changes were noted in PKA/cAMP. We concluded that gut EC cells are oxygen responsive, and alterations in O2levels differentially activate HIF-1α and tryptophan hydroxylase 1, as well as NF-κB signaling. This results in alterations in 5-HT production and secretion and identifies that the chemomechanosensory role of EC cells extends to oxygen sensing.

scholarly journals Regeneration in Spinal Disease: Therapeutic Role of Hypoxia-Inducible Factor-1 Alpha in Regeneration of Degenerative Intervertebral Disc

2021 ◽  
Vol 22 (10) ◽  
pp. 5281
Author(s):  
Jin-Woo Kim ◽  
Neunghan Jeon ◽  
Dong-Eun Shin ◽  
So-Young Lee ◽  
Myongwhan Kim ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Structural Changes ◽  
Hypoxia Inducible Factor ◽  
Low Oxygen ◽  
Hypoxia Inducible Factor 1 ◽  
Metabolic Activities ◽  
Cartilaginous Endplate ◽  
Ivd Degeneration ◽  
Complex Joint

The intervertebral disc (IVD) is a complex joint structure comprising three primary components—namely, nucleus pulposus (NP), annulus fibrosus (AF), and cartilaginous endplate (CEP). The IVD retrieves oxygen from the surrounding vertebral body through CEP by diffusion and likely generates ATP via anaerobic glycolysis. IVD degeneration is characterized by a cascade of cellular, compositional, structural changes. With advanced age, pronounced changes occur in the composition of the disc extracellular matrix (ECM). NP and AF cells in the IVD possess poor regenerative capacity compared with that of other tissues. Hypoxia-inducible factor (HIF) is a master transcription factor that initiates a coordinated cellular cascade in response to a low oxygen tension environment, including the regulation of numerous enzymes in response to hypoxia. HIF-1α is essential for NP development and homeostasis and is involved in various processes of IVD degeneration process, promotes ECM in NP, maintains the metabolic activities of NP, and regulates dystrophic mineralization of NP, as well as angiogenesis, autophagy, and apoptosis during IVD degeneration. HIF-1α may, therefore, represent a diagnostic tool for early IVD degeneration and a therapeutic target for inhibiting IVD degeneration.

scholarly journals Hypoxia in cartilage: HIF-1α is essential for chondrocyte growth arrest and survival

2001 ◽  
Vol 15 (21) ◽  
pp. 2865-2876
Author(s):  
Ernestina Schipani ◽  
Heather E. Ryan ◽  
Susanna Didrickson ◽  
Tatsuya Kobayashi ◽  
Melissa Knight ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Growth Plate ◽  
Hypoxia Inducible Factor ◽  
Growth Arrest ◽  
Brdu Incorporation ◽  
Independent Manner ◽  
Hypoxic Response ◽  
Surrounding Areas

Breakdown or absence of vascular oxygen delivery is a hallmark of many common human diseases, including cancer, myocardial infarction, and stroke. The chief mediator of hypoxic response in mammalian tissues is the transcription factor hypoxia-inducible factor 1 (HIF-1), and its oxygen-sensitive component HIF-1α. A key question surrounding HIF-1α and the hypoxic response is the role of this transcription factor in cells removed from a functional vascular bed; in this regard there is evidence indicating that it can act as either a survival factor or induce growth arrest and apoptosis. To study more closely how HIF-1α functions in hypoxia in vivo, we used tissue-specific targeting to delete HIF-1α in an avascular tissue: the cartilaginous growth plate of developing bone. We show here the first evidence that the developmental growth plate in mammals is hypoxic, and that this hypoxia occurs in its interior rather than at its periphery. As a result of this developmental hypoxia, cells that lack HIF-1α in the interior of the growth plate die. This is coupled to decreased expression of the CDK inhibitor p57, and increased levels of BrdU incorporation in HIF-1α null growth plates, indicating defects in HIF-1α-regulated growth arrest occurs in these animals. Furthermore, we find that VEGF expression in the growth plate is regulated through both HIF-1α-dependent and -independent mechanisms. In particular, we provide evidence that VEGFexpression is up-regulated in a HIF-1α-independent manner in chondrocytes surrounding areas of cell death, and this in turn induces ectopic angiogenesis. Altogether, our findings have important implications for the role of hypoxic response and HIF-1α in development, and in cell survival in tissues challenged by interruption of vascular flow; they also illustrate the complexities of HIF-1α response in vivo, and they provide new insights into mechanisms of growth plate development.

scholarly journals HIF1-alpha expressing cells induce a hypoxic-like response in neighbouring cancer cells

2018 ◽  
Author(s):  
Hannah Harrison ◽  
Henry J Pegg ◽  
Jamie Thompson ◽  
Christian Bates ◽  
Paul Shore
Keyword(s):  
Cancer Cells ◽  
Cancer Progression ◽  
Hypoxia Inducible Factor ◽  
Experimental Models ◽  
Metastatic Progression ◽  
Low Oxygen ◽  
Hypoxic Response ◽  
Oxygen Levels ◽  
Mammosphere Formation ◽  
Cellular Environment

AbstractHypoxia stimulates metastasis in cancer and is linked to poor patient prognosis. In tumours, oxygen levels vary and hypoxic regions exist within a generally well-oxygenated tumour. However, whilst the heterogeneous environment is known to contribute to metastatic progression, little is known about the mechanism by which heterogeneic hypoxia contributes to cancer progression. This is largely because existing experimental models do not recapitulate the heterogeneous nature of hypoxia. The primary effector of the hypoxic response is the transcription factor Hypoxia inducible factor 1-alpha (HIF1-alpha). HIF1-alpha is stabilised in response to low oxygen levels in the cellular environment and its expression is seen in hypoxic regions throughout the tumour.We have developed a model system in which HIF1-alpha can be induced within a sub-population of cancer cells, thus enabling us to mimic the effects of heterogeneic HIF1-alpha expression.We show that induction of HIF1-alpha not only recapitulates elements of the hypoxic response in the induced cells but also results in significant changes in proliferation, gene expression and mammosphere formation within the HIF1-alpha negative population.These findings suggest that the HIF1-alpha expressing cells found within hypoxic regions are likely to contribute to the subsequent progression of a tumour by modifying the behaviour of cells in the non-hypoxic regions of the local micro-environment.

scholarly journals Hypoxic Regulation of Gene Transcription and Chromatin: Cause and Effect

2020 ◽  
Vol 21 (21) ◽  
pp. 8320
Author(s):  
Jessica D. Kindrick ◽  
David R. Mole
Keyword(s):  
Transcriptional Activation ◽  
Cellular Response ◽  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Transcriptional Response ◽  
Epigenetic Landscape ◽  
Low Oxygen ◽  
Epigenetic Modifiers ◽  
Oxygen Sensitive ◽  
Cell Type Specific

Cellular responses to low oxygen (hypoxia) are fundamental to normal physiology and to the pathology of many common diseases. Hypoxia-inducible factor (HIF) is central to this by enhancing the transcriptional activity of many hundreds of genes. The cellular response to HIF is cell-type-specific and is largely governed by the pre-existing epigenetic landscape. Prior to activation, HIF-binding sites and the promoters of HIF-target genes are already accessible, in contact with each other through chromatin looping and display markers of activity. However, hypoxia also modulates the epigenetic environment, both in parallel to and as a consequence of HIF activation. This occurs through a combination of oxygen-sensitive changes in enzyme activity, transcriptional activation of epigenetic modifiers, and localized recruitment to chromatin by HIF and activated RNApol2. These hypoxic changes in the chromatin environment may both contribute to and occur as a consequence of transcriptional regulation. Nevertheless, they have the capacity to both modulate and extend the transcriptional response to hypoxia.

scholarly journals Hypoxia-Inducible Factor 2 Regulates Hepatic Lipid Metabolism

2009 ◽  
Vol 29 (16) ◽  
pp. 4527-4538 ◽  
Author(s):  
Erinn B. Rankin ◽  
Jennifer Rha ◽  
Mary A. Selak ◽  
Travis L. Unger ◽  
Brian Keith ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lipid Metabolism ◽  
Hypoxia Inducible Factor ◽  
Hepatic Tissue ◽  
Low Oxygen ◽  
Hepatic Lipid Metabolism ◽  
Peripheral Tissues ◽  
Hepatic Lipid ◽  
Normal Hepatocyte ◽  
Oxygen Sensitive

ABSTRACT In mammals, the liver integrates nutrient uptake and delivery of carbohydrates and lipids to peripheral tissues to control overall energy balance. Hepatocytes maintain metabolic homeostasis by coordinating gene expression programs in response to dietary and systemic signals. Hepatic tissue oxygenation is an important systemic signal that contributes to normal hepatocyte function as well as disease. Hypoxia-inducible factors 1 and 2 (HIF-1 and HIF-2, respectively) are oxygen-sensitive heterodimeric transcription factors, which act as key mediators of cellular adaptation to low oxygen. Previously, we have shown that HIF-2 plays an important role in both physiologic and pathophysiologic processes in the liver. HIF-2 is essential for normal fetal EPO production and erythropoiesis, while constitutive HIF-2 activity in the adult results in polycythemia and vascular tumorigenesis. Here we report a novel role for HIF-2 in regulating hepatic lipid metabolism. We found that constitutive activation of HIF-2 in the adult results in the development of severe hepatic steatosis associated with impaired fatty acid β-oxidation, decreased lipogenic gene expression, and increased lipid storage capacity. These findings demonstrate that HIF-2 functions as an important regulator of hepatic lipid metabolism and identify HIF-2 as a potential target for the treatment of fatty liver disease.

scholarly journals C-terminal HSP90 Inhibitors Block the HSP90:HIF-1α Interaction and Inhibit the Cellular Hypoxic Response

2019 ◽  
Author(s):  
Nalin Kataria ◽  
Bernadette Kerr ◽  
Samantha S. Zaiter ◽  
Shelli McAlpine ◽  
Kristina M Cook
Keyword(s):  
Heat Shock ◽  
Heat Shock Response ◽  
Hypoxia Inducible Factor ◽  
Chemotherapy Resistance ◽  
Heat Shock Protein 90 ◽  
Low Oxygen ◽  
Hsp90 Inhibitors ◽  
Hypoxic Response ◽  
C Terminus ◽  
Shock Response

Hypoxia Inducible Factor (HIF) is a transcription factor activated by low oxygen, which is common in solid tumours. HIF controls the expression of genes involved in angiogenesis, chemotherapy resistance and metastasis. The chaperone HSP90 (Heat Shock Protein 90) stabilizes the subunit HIF-1α and prevents degradation. Previously identified HSP90 inhibitors bind to the N-terminal pocket of HSP90 which blocks binding to HIF-1α, and produces HIF-1α degradation. N-terminal inhibitors have failed in the clinic as single therapy treatments due in part because they induce a heat shock response, which increases chemotherapy resistance. SM molecules are HSP90 inhibitors that bind to the C-terminus and do not activate the heat shock response. The effects of C-terminal HSP90 inhibitors on HIF-1α are unreported. Herein we show that SM compounds block binding between HSP90 and HIF-1α, leading to HIF-1α degradation through the proteasome using the PHD/pVHL pathway in hypoxic conditions. The SM compounds decrease HIF-1α target gene expression at the mRNA and protein level under hypoxia in colorectal cancer cells, leading to cell death, without inducing a heat shock response. Our results suggest that targeting the C-terminus of HSP90 blocks the hypoxic response and may be an effective anti-cancer strategy.

scholarly journals Abnormal Sympathoadrenal Development and Systemic Hypotension in PHD3−/− Mice

2008 ◽  
Vol 28 (10) ◽  
pp. 3386-3400 ◽  
Author(s):  
Tammie Bishop ◽  
Denis Gallagher ◽  
Alberto Pascual ◽  
Craig A. Lygate ◽  
Joseph P. de Bono ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Hypoxia Inducible Factor ◽  
Systemic Blood Pressure ◽  
Target Tissue ◽  
Cervical Ganglion ◽  
Oxygen Sensitive ◽  
Hif Prolyl Hydroxylase ◽  
Number Of Cells

ABSTRACT Cell culture studies have implicated the oxygen-sensitive hypoxia-inducible factor (HIF) prolyl hydroxylase PHD3 in the regulation of neuronal apoptosis. To better understand this function in vivo, we have created PHD3 −/− mice and analyzed the neuronal phenotype. Reduced apoptosis in superior cervical ganglion (SCG) neurons cultured from PHD3 −/− mice is associated with an increase in the number of cells in the SCG, as well as in the adrenal medulla and carotid body. Genetic analysis by intercrossing PHD3 −/− mice with HIF-1a +/− and HIF-2a +/− mice demonstrated an interaction with HIF-2α but not HIF-1α, supporting the nonredundant involvement of a PHD3-HIF-2α pathway in the regulation of sympathoadrenal development. Despite the increased number of cells, the sympathoadrenal system appeared hypofunctional in PHD3 −/− mice, with reduced target tissue innervation, adrenal medullary secretory capacity, sympathoadrenal responses, and systemic blood pressure. These observations suggest that the role of PHD3 in sympathoadrenal development extends beyond simple control of cell survival and organ mass, with functional PHD3 being required for proper anatomical and physiological integrity of the system. Perturbation of this interface between developmental and adaptive signaling by hypoxic, metabolic, or other stresses could have important effects on key sympathoadrenal functions, such as blood pressure regulation.

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