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Samah Nassereddine, Coen J Lap, Faysal Haroun, Imad Tabbara
For decades, researchers have looked into the pathophysiology of acute myeloid leukemia (AML). With the advances in molecular techniques, the two-hit hypothesis was replaced by a multi-hit model, which also emphasizes the importance of aberrant epigenetic regulation in the pathogenesis of AML. IDH1 and IDH2 are two isoforms of isocitrate dehydrogenase that perform crucial roles in cellular metabolism. Somatic mutations in either of these two genes impart a neomorphic enzymatic activity upon the encoded enzymes resulting in the ability to convert α-ketoglutarate (αKG) into the oncometabolite R2-hydroxyglutarate (R2-HG), which can competitively inhibit multiple αKG-dependent dioxygenases...
December 2017: Annals of Hematology
Yanqing Huang, Daniel Lin, Cullen M Taniguchi
Hypoxia acts as an important regulator of physiological and pathological processes. Hypoxia inducible factors (HIFs) are the central players involved in the cellular adaptation to hypoxia and are regulated by oxygen sensing EGLN prolyl hydroxylases. Hypoxia affects many aspects of cellular growth through both redox effects and through the stabilization of HIFs. The HIF isoforms likely have differential effects on tumor growth via alteration of metabolism, growth, and self-renewal and are likely highly context-dependent...
October 13, 2017: Science China. Life Sciences
William G Kaelin
Mammalian cells sense changes in oxygen and transduce that information into adaptive changes in gene expression using a conserved pathway that converges on the heterodimeric transcription factor called hypoxia-inducible factor (HIF), which contains a labile alpha subunit and a stable beta subunit. In the presence of oxygen, the alpha subunit is hydroxylated on one (or both) of two highly conserved prolyl residues by an Egg-Laying Defective Nine (EglN) [also called Prolyl Hydroxylase Domain (PHD)] dioxygenase, which recruits an ubiquitin ligase complex containing the VHL tumor suppressor gene product...
2017: Transactions of the American Clinical and Climatological Association
Mircea Ivan, William G Kaelin
The EGLN (also called PHD) prolyl hydroxylase enzymes and their canonical targets, the HIFα subunits, represent the core of an ancient oxygen-monitoring machinery used by metazoans. In this review, we highlight recent progress in understanding the overlapping versus specific roles of EGLN enzymes and HIF isoforms and discuss how feedback loops based on recently identified noncoding RNAs introduce additional layers of complexity to the hypoxic response. Based on novel interactions identified upstream and downstream of EGLNs, an integrated network connecting oxygen-sensing functions to metabolic and signaling pathways is gradually emerging with broad therapeutic implications...
June 15, 2017: Molecular Cell
Erin V McGillick, Sandra Orgeig, Beth J Allison, Kirsty L Brain, Youguo Niu, Nozomi Itani, Katie L Skeffington, Andrew D Kane, Emilio A Herrera, Dino A Giussani, Janna L Morrison
KEY POINTS: Chronic fetal hypoxaemia is a common pregnancy complication associated with intrauterine growth restriction that may influence respiratory outcome at birth. We investigated the effect of maternal chronic hypoxia for a month in late gestation on signalling pathways regulating fetal lung maturation and the transition to air-breathing at birth using isobaric hypoxic chambers without alterations to maternal food intake. Maternal chronic hypoxia in late gestation increases fetal lung expression of genes regulating hypoxia signalling, lung liquid reabsorption and surfactant maturation, which may be an adaptive response in preparation for the successful transition to air-breathing at birth...
July 1, 2017: Journal of Physiology
Linli Zhang, Shan Peng, Xiangpeng Dai, Wenjian Gan, Xin Nie, Wenyi Wei, Guoqing Hu, Jianping Guo
EglN prolyl hydroxylases, a family of oxygen-sensing enzymes, hydroxylate distinct proteins to modulate diverse physiopathological signals. Aberrant regulations of EglNs result in multiple human diseases, including cancer. Different from EglN1 which function largely depends on the role of hypoxia-induce factor alpha (HIFα) in tumors, the functional significance and the upstream regulatory mechanisms of EglN2, especially in prostate cancer setting, remain largely unclear. Here, we demonstrated that dysregulation of EglN2 facilitated prostate cancer growth both in cells and in vivo...
April 1, 2017: Cancer Letters
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...
December 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
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
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
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
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
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
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
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
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
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
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
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
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
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
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