keyword
MENU ▼
Read by QxMD icon Read
search

Egln

keyword
https://www.readbyqxmd.com/read/27832958/hypoxia-inducible-factor-prolyl-4-hydroxylase-inhibition-in-cardiometabolic-diseases
#1
REVIEW
Peppi Koivunen, Raisa Serpi, Elitsa Y Dimova
Hypoxia-inducible factor prolyl 4-hydroxylases (HIF-P4Hs, also called PHDs and EglNs) are enzymes that act as cellular oxygen sensors. They are the main downregulators of the hypoxia-inducible factor (HIF). HIF-P4Hs can be targeted with small molecule inhibitors, which stabilize HIF under normoxia and initiate the hypoxia response. Such inhibitors are in phase 2 and 3 clinical trials for the treatment of anemia due to their ability to induce erythropoietin and iron metabolism genes. Recent data suggest that HIF-P4H inhibition has a therapeutic role beyond anemia in cardiac ischemia, obesity and metabolic dysfunction, and atherosclerosis...
November 8, 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/27525289/the-2-oxoglutarate-analog-3-oxoglutarate-decreases-normoxic-hypoxia-inducible-factor-1%C3%AE-in-cancer-cells-induces-cell-death-and-reduces-tumor-xenograft-growth
#2
Peppi Koivunen, Stuart M Fell, Wenyun Lu, Joshua D Rabinowitz, Andrew L Kung, Susanne Schlisio
The cellular response to hypoxia is primarily regulated by the hypoxia-inducible factors (HIFs). HIF-1α is also a major mediator of tumor physiology, and its abundance is correlated with therapeutic resistance in a broad range of cancers. Accumulation of HIF-1α under hypoxia is mainly controlled by the oxygen-sensing HIF prolyl 4-hydroxylases (EGLNs, also known as PHDs). Here, we identified a high level of normoxic HIF-1α protein in various cancer cell lines. EGLNs require oxygen and 2-oxoglutarate for enzymatic activity...
2016: Hypoxia
https://www.readbyqxmd.com/read/27368101/paracrine-induction-of-hif-by-glutamate-in-breast-cancer-egln1-senses-cysteine
#3
Kimberly J Briggs, Peppi Koivunen, Shugeng Cao, Keriann M Backus, Benjamin A Olenchock, Hetalben Patel, Qing Zhang, Sabina Signoretti, Gary J Gerfen, Andrea L Richardson, Agnieszka K Witkiewicz, Benjamin F Cravatt, Jon Clardy, William G Kaelin
The HIF transcription factor promotes adaptation to hypoxia and stimulates the growth of certain cancers, including triple-negative breast cancer (TNBC). The HIFα subunit is usually prolyl-hydroxylated by EglN family members under normoxic conditions, causing its rapid degradation. We confirmed that TNBC cells secrete glutamate, which we found is both necessary and sufficient for the paracrine induction of HIF1α in such cells under normoxic conditions. Glutamate inhibits the xCT glutamate-cystine antiporter, leading to intracellular cysteine depletion...
June 30, 2016: Cell
https://www.readbyqxmd.com/read/26612615/catalytic-independent-inhibition-of-ciap1-mediated-rip1-ubiquitination-by-egln3
#4
Jian Fu
EGLN3 belongs to the EGLN family of prolyl hydroxylases that are able to catalyze the hydroxylation of proteins such as the α subunits of hypoxia-inducible factor. We and others have shown that EGLN3 negatively regulates the canonical NFκB pathway. Mechanistically, we demonstrated that EGLN3 inhibits ubiquitination of IKKγ (the regulatory subunit of IκB kinase complex) which is vitally important for NFκB activation. Polyubiquitination of the RIP1 (receptor-interacting protein 1) kinase is important for NFκB activation triggered by tumor necrosis factor α...
February 2016: Cellular Signalling
https://www.readbyqxmd.com/read/25381339/18f-faza-pet-imaging-response-tracks-the-reoxygenation-of-tumors-in-mice-upon-treatment-with-the-mitochondrial-complex-i-inhibitor-bay-87-2243
#5
Edwin Chang, Hongguang Liu, Kerstin Unterschemmann, Peter Ellinghaus, Shuanglong Liu, Volker Gekeler, Zhen Cheng, Dietmar Berndorff, Sanjiv S Gambhir
PURPOSE: We describe a noninvasive PET imaging method that monitors early therapeutic efficacy of BAY 87-2243, a novel small-molecule inhibitor of mitochondrial complex I as a function of hypoxia-inducible factor-1α (HIF1α) activity. EXPERIMENTAL DESIGN: Four PET tracers [(18)F-FDG, (18)F-Fpp(RGD)2, (18)F-FLT, and (18)F-FAZA] were assessed for uptake into tumor xenografts of drug-responsive (H460, PC3) or drug-resistant (786-0) carcinoma cells. Mice were treated with BAY 87-2243 or vehicle...
January 15, 2015: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/24990963/prolyl-hydroxylation-by-egln2-destabilizes-foxo3a-by-blocking-its-interaction-with-the-usp9x-deubiquitinase
#6
Xingnan Zheng, Bo Zhai, Peppi Koivunen, Sandra J Shin, Gang Lu, Jiayun Liu, Christoph Geisen, Abhishek A Chakraborty, Javid J Moslehi, David M Smalley, Xin Wei, Xian Chen, Zhengming Chen, Justine M Beres, Jing Zhang, Jen Lan Tsao, Mitchell C Brenner, Yuqing Zhang, Cheng Fan, Ronald A DePinho, Jihye Paik, Steven P Gygi, William G Kaelin, Qing Zhang
The three EglN prolyl hydroxylases (EglN1, EglN2, and EglN3) regulate the stability of the HIF transcription factor. We recently showed that loss of EglN2, however, also leads to down-regulation of Cyclin D1 and decreased cell proliferation in a HIF-independent manner. Here we report that EglN2 can hydroxylate FOXO3a on two specific prolyl residues in vitro and in vivo. Hydroxylation of these sites prevents the binding of USP9x deubiquitinase, thereby promoting the proteasomal degradation of FOXO3a. FOXO transcription factors can repress Cyclin D1 transcription...
July 1, 2014: Genes & Development
https://www.readbyqxmd.com/read/24842922/elevated-testosterone-levels-during-rat-pregnancy-cause-hypersensitivity-to-angiotensin-ii-and-attenuation-of-endothelium-dependent-vasodilation-in-uterine-arteries
#7
Vijayakumar Chinnathambi, Chellakkan S Blesson, Kathleen L Vincent, George R Saade, Gary D Hankins, Chandra Yallampalli, Kunju Sathishkumar
Elevated testosterone levels increase maternal blood pressure and decrease uterine blood flow in pregnancy, resulting in abnormal perinatal outcomes. We tested whether elevated testosterone alters uterine artery adaptations during pregnancy, and whether these alterations depend on endothelium-derived factors such as nitric oxide, endothelium-derived hyperpolarizing factor, and prostacyclin, or endothelium-independent mechanisms such as angiotensin II (Ang-II). Pregnant Sprague-Dawley rats were injected with vehicle (n=20) or testosterone propionate (0...
August 2014: Hypertension
https://www.readbyqxmd.com/read/24637263/acute-hypoxia-produces-a-superoxide-burst-in-cells
#8
Pablo Hernansanz-Agustín, Alicia Izquierdo-Álvarez, Francisco J Sánchez-Gómez, Elena Ramos, Tamara Villa-Piña, Santiago Lamas, Anna Bogdanova, Antonio Martínez-Ruiz
Oxygen is a key molecule for cell metabolism. Eukaryotic cells sense the reduction in oxygen availability (hypoxia) and trigger a series of cellular and systemic responses to adapt to hypoxia, including the optimization of oxygen consumption. Many of these responses are mediated by a genetic program induced by the hypoxia-inducible transcription factors (HIFs), regulated by a family of prolyl hydroxylases (PHD or EGLN) that use oxygen as a substrate producing HIF hydroxylation. In parallel to these oxygen sensors modulating gene expression within hours, acute modulation of protein function in response to hypoxia is known to occur within minutes...
June 2014: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/23683440/selective-small-molecule-probes-for-the-hypoxia-inducible-factor-hif-prolyl-hydroxylases
#9
Rasheduzzaman Chowdhury, José Ignacio Candela-Lena, Mun Chiang Chan, David Jeremy Greenald, Kar Kheng Yeoh, Ya-Min Tian, Michael A McDonough, Anthony Tumber, Nathan R Rose, Ana Conejo-Garcia, Marina Demetriades, Sinnakaruppan Mathavan, Akane Kawamura, Myung Kyu Lee, Freek van Eeden, Christopher W Pugh, Peter J Ratcliffe, Christopher J Schofield
The hypoxia inducible factor (HIF) system is central to the signaling of low oxygen (hypoxia) in animals. The levels of HIF-α isoforms are regulated in an oxygen-dependent manner by the activity of the HIF prolyl-hydroxylases (PHD or EGLN enzymes), which are Fe(II) and 2-oxoglutarate (2OG) dependent oxygenases. Here, we describe biochemical, crystallographic, cellular profiling, and animal studies on PHD inhibitors including selectivity studies using a representative set of human 2OG oxygenases. We identify suitable probe compounds for use in studies on the functional effects of PHD inhibition in cells and in animals...
July 19, 2013: ACS Chemical Biology
https://www.readbyqxmd.com/read/23630074/what-a-difference-a-hydroxyl-makes-mutant-idh-r-2-hydroxyglutarate-and-cancer
#10
REVIEW
Julie-Aurore Losman, William G Kaelin
Mutations in metabolic enzymes, including isocitrate dehydrogenase 1 (IDH1) and IDH2, in cancer strongly implicate altered metabolism in tumorigenesis. IDH1 and IDH2 catalyze the interconversion of isocitrate and 2-oxoglutarate (2OG). 2OG is a TCA cycle intermediate and an essential cofactor for many enzymes, including JmjC domain-containing histone demethylases, TET 5-methylcytosine hydroxylases, and EglN prolyl-4-hydroxylases. Cancer-associated IDH mutations alter the enzymes such that they reduce 2OG to the structurally similar metabolite (R)-2-hydroxyglutarate [(R)-2HG]...
April 15, 2013: Genes & Development
https://www.readbyqxmd.com/read/23393090/-r-2-hydroxyglutarate-is-sufficient-to-promote-leukemogenesis-and-its-effects-are-reversible
#11
Julie-Aurore Losman, Ryan E Looper, Peppi Koivunen, Sungwoo Lee, Rebekka K Schneider, Christine McMahon, Glenn S Cowley, David E Root, Benjamin L Ebert, William G Kaelin
Mutations in IDH1 and IDH2, the genes coding for isocitrate dehydrogenases 1 and 2, are common in several human cancers, including leukemias, and result in overproduction of the (R)-enantiomer of 2-hydroxyglutarate [(R)-2HG]. Elucidation of the role of IDH mutations and (R)-2HG in leukemogenesis has been hampered by a lack of appropriate cell-based models. Here, we show that a canonical IDH1 mutant, IDH1 R132H, promotes cytokine independence and blocks differentiation in hematopoietic cells. These effects can be recapitulated by (R)-2HG, but not (S)-2HG, despite the fact that (S)-2HG more potently inhibits enzymes, such as the 5'-methylcytosine hydroxylase TET2, that have previously been linked to the pathogenesis of IDH mutant tumors...
March 29, 2013: Science
https://www.readbyqxmd.com/read/23324380/hypoxia-inducible-factor-prolyl-4-hydroxylases-common-and-specific-roles
#12
REVIEW
Johanna Myllyharju, Peppi Koivunen
Hypoxia-inducible transcription factor (HIF), an αβ dimer, is the key inducer of hypoxia-responsive genes that operate both during normal development and pathological processes in association with decreased oxygen availability. The products of HIF target genes function in, e.g., hematopoiesis, angiogenesis, iron transport, glucose utilization, resistance to oxidative stress, cell proliferation, survival and apoptosis, extracellular matrix homeostasis, and tumorigenesis and metastasis. HIF is accumulated in hypoxia, whereas it is rapidly degraded in normoxic cells...
April 2013: Biological Chemistry
https://www.readbyqxmd.com/read/23151668/dual-action-inhibitors-of-hif-prolyl-hydroxylases-that-induce-binding-of-a-second-iron-ion
#13
Kar Kheng Yeoh, Mun Chiang Chan, Armin Thalhammer, Marina Demetriades, Rasheduzzaman Chowdhury, Ya-Min Tian, Ineke Stolze, Luke A McNeill, Myung Kyu Lee, Esther C Y Woon, Mukram M Mackeen, Akane Kawamura, Peter J Ratcliffe, Jasmin Mecinović, Christopher J Schofield
Inhibition of the hypoxia-inducible factor (HIF) prolyl hydroxylases (PHD or EGLN enzymes) is of interest for the treatment of anemia and ischemia-related diseases. Most PHD inhibitors work by binding to the single ferrous ion and competing with 2-oxoglutarate (2OG) co-substrate for binding at the PHD active site. Non-specific iron chelators also inhibit the PHDs, both in vitro and in cells. We report the identification of dual action PHD inhibitors, which bind to the active site iron and also induce the binding of a second iron ion at the active site...
February 7, 2013: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/22611156/treatment-of-erythropoietin-deficiency-in-mice-with-systemically-administered-sirna
#14
William Querbes, Roman L Bogorad, Javid Moslehi, Jamie Wong, Amy Y Chan, Elena Bulgakova, Satya Kuchimanchi, Akin Akinc, Kevin Fitzgerald, Victor Koteliansky, William G Kaelin
Anemia linked to a relative deficiency of renal erythropoietin production is a significant cause of morbidity and medical expenditures in the developed world. Recombinant erythropoietin is expensive and has been linked to excess cardiovascular events. Moreover, some patients become refractory to erythropoietin because of increased production of factors such as hepcidin. During fetal life, the liver, rather than the kidney, is the major source of erythropoietin. In the present study, we show that it is feasible to reactivate hepatic erythropoietin production and suppress hepcidin levels using systemically delivered siRNAs targeting the EglN prolyl hydroxylases specifically in the liver, leading to improved RBC production in models of anemia caused by either renal insufficiency or chronic inflammation with enhanced hepcidin production...
August 30, 2012: Blood
https://www.readbyqxmd.com/read/22348009/hif-independent-regulation-of-thioredoxin-reductase-1-contributes-to-the-high-levels-of-reactive-oxygen-species-induced-by-hypoxia
#15
Salvador Naranjo-Suarez, Bradley A Carlson, Petra A Tsuji, Min-Hyuk Yoo, Vadim N Gladyshev, Dolph L Hatfield
Cellular adaptation to hypoxic conditions mainly involves transcriptional changes in which hypoxia inducible factors (HIFs) play a critical role. Under hypoxic conditions, HIF protein is stabilized due to inhibition of the activity of prolyl hydroxylases (EGLNs). Because the reaction carried out by these enzymes uses oxygen as a co-substrate it is generally accepted that the hypoxic inhibition of EGLNs is due to the reduction in oxygen levels. However, several studies have reported that hypoxic generation of mitochondrial reactive oxygen species (ROS) is required for HIF stabilization...
2012: PloS One
https://www.readbyqxmd.com/read/22343896/transformation-by-the-r-enantiomer-of-2-hydroxyglutarate-linked-to-egln-activation
#16
Peppi Koivunen, Sungwoo Lee, Christopher G Duncan, Giselle Lopez, Gang Lu, Shakti Ramkissoon, Julie A Losman, Päivi Joensuu, Ulrich Bergmann, Stefan Gross, Jeremy Travins, Samuel Weiss, Ryan Looper, Keith L Ligon, Roel G W Verhaak, Hai Yan, William G Kaelin
The identification of succinate dehydrogenase (SDH), fumarate hydratase (FH) and isocitrate dehydrogenase (IDH) mutations in human cancers has rekindled the idea that altered cellular metabolism can transform cells. Inactivating SDH and FH mutations cause the accumulation of succinate and fumarate, respectively, which can inhibit 2-oxoglutarate (2-OG)-dependent enzymes, including the EGLN prolyl 4-hydroxylases that mark the hypoxia inducible factor (HIF) transcription factor for polyubiquitylation and proteasomal degradation...
February 15, 2012: Nature
https://www.readbyqxmd.com/read/22089927/cancer-and-altered-metabolism-potential-importance-of-hypoxia-inducible-factor-and-2-oxoglutarate-dependent-dioxygenases
#17
REVIEW
W G Kaelin
Hypoxia-inducible factor (HIF) deregulation contributes to the Warburg effect. HIF consists of an unstable α subunit and a stable β subunit. In the presence of oxygen, HIFα becomes prolyl hydroxylated by members of the EglN (also called PHD) family, leading to its proteasomal degradation. Under hypoxic conditions, EglN activity is diminished and HIF levels rise. EglN1 is the primary HIF prolyl hydroxylase with EglN2 and EglN3 playing compensatory roles under certain conditions. EglN2 and EglN3 also appear to play HIF-independent roles in regulating cell proliferation and apoptosis, respectively...
2011: Cold Spring Harbor Symposia on Quantitative Biology
https://www.readbyqxmd.com/read/20959442/mutation-analysis-of-hif-prolyl-hydroxylases-phd-egln-in-individuals-with-features-of-phaeochromocytoma-and-renal-cell-carcinoma-susceptibility
#18
Dewi Astuti, Christopher J Ricketts, Rasheduzzaman Chowdhury, Michael A McDonough, Dean Gentle, Gail Kirby, Susanne Schlisio, Rajappa S Kenchappa, Bruce D Carter, William G Kaelin, Peter J Ratcliffe, Christopher J Schofield, Farida Latif, Eamonn R Maher
Germline mutations in the von Hippel-Lindau disease (VHL) and succinate dehydrogenase subunit B (SDHB) genes can cause inherited phaeochromocytoma and/or renal cell carcinoma (RCC). Dysregulation of the hypoxia-inducible factor (HIF) transcription factors has been linked to VHL and SDHB-related RCC; both HIF dysregulation and disordered function of a prolyl hydroxylase domain isoform 3 (PHD3/EGLN3)-related pathway of neuronal apoptosis have been linked to the development of phaeochromocytoma. The 2-oxoglutarate-dependent prolyl hydroxylase enzymes PHD1 (EGLN2), PHD2 (EGLN1) and PHD3 (EGLN3) have a key role in regulating the stability of HIF-α subunits (and hence expression of the HIF-α transcription factors)...
February 2011: Endocrine-related Cancer
https://www.readbyqxmd.com/read/20955552/hypoxia-dependent-sequestration-of-an-oxygen-sensor-by-a-widespread-structural-motif-can-shape-the-hypoxic-response-a-predictive-kinetic-model
#19
Bernhard Schmierer, Béla Novák, Christopher J Schofield
BACKGROUND: The activity of the heterodimeric transcription factor hypoxia inducible factor (HIF) is regulated by the post-translational, oxygen-dependent hydroxylation of its α-subunit by members of the prolyl hydroxylase domain (PHD or EGLN)-family and by factor inhibiting HIF (FIH). PHD-dependent hydroxylation targets HIFα for rapid proteasomal degradation; FIH-catalysed asparaginyl-hydroxylation of the C-terminal transactivation domain (CAD) of HIFα suppresses the CAD-dependent subset of the extensive transcriptional responses induced by HIF...
2010: BMC Systems Biology
https://www.readbyqxmd.com/read/20089853/prolyl-hydroxylase-egln3-regulates-skeletal-myoblast-differentiation-through-an-nf-kappab-dependent-pathway
#20
Jian Fu, Mark B Taubman
The egg-laying abnormal-9 (EGLN) prolyl hydroxylases have been shown to regulate the stability and thereby the activity of the alpha subunits of hypoxia-inducible factor (HIF) through its ability to catalyze their hydroxylation. We have previously shown that EGLN3 promotes differentiation of C2C12 skeletal myoblasts. However, the mechanism underlying this effect remains to be fully elucidated. Here, we report that exposure of C2C12 cells to dimethyl oxalylglycine (DMOG), desferrioxamine, and hypoxia, all inhibitors of prolyl hydroxylase activity, led to repression of C2C12 myogenic differentiation...
March 19, 2010: Journal of Biological Chemistry
keyword
keyword
73594
1
2
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read
×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"