Identification of a novel inactivating mutation in Isocitrate Dehydrogenase 1 (IDH1-R314C) in a high grade astrocytoma
| Autor: | Remco J. Molenaar, Krissie Lenting, Jan Schepens, Cornelis J.F. Van Noorden, Anna C. Navis, Nil A. Schubert, William P.J. Leenders, Wiljan Hendriks, Hanka Venselaar, Bastiaan B J Tops, Stefan Pusch, Kiek Verrijp, Pieter Wesseling, Arno van Rooij, Sanne A. M. van Lith, Ron A. Wevers |
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| Přispěvatelé: | Cell Biology and Histology, Graduate School, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, CCA -Cancer Center Amsterdam, Pathology, CCA - Cancer biology |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Heterozygote Isocitrates IDH1 Mutant Astrocytoma Biology Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9] IDH2 Article Glutarates Mice 03 medical and health sciences Cell Line Tumor Journal Article Animals Humans Epigenetics General chemistry.chemical_classification Binding Sites Multidisciplinary Base Sequence Brain Neoplasms HEK 293 cells Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] Molecular biology Isocitrate Dehydrogenase Cytosol HEK293 Cells 030104 developmental biology Isocitrate dehydrogenase Enzyme Biochemistry chemistry Mutation Neoplasm Grading Protein Multimerization Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19] NADP |
| Zdroj: | Scientific Reports, 6. Nature Publishing Group Scientific Reports, 6 Scientific reports, 6. Nature Publishing Group van Lith, S A M, Navis, A C, Lenting, K, Verrijp, K, Schepens, J T G, Hendriks, W J A J, Schubert, N A, Venselaar, H, Wevers, R A, van Rooij, A, Wesseling, P, Molenaar, R J, van Noorden, C J F, Pusch, S, Tops, B & Leenders, W P J 2016, ' Identification of a novel inactivating mutation in Isocitrate Dehydrogenase 1 (IDH1-R314C) in a high grade astrocytoma ', Scientific Reports, vol. 6 . https://doi.org/10.1038/srep30486 Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/srep30486 |
| Popis: | The majority of low-grade and secondary high-grade gliomas carry heterozygous hotspot mutations in cytosolic isocitrate dehydrogenase 1 (IDH1) or the mitochondrial variant IDH2. These mutations mostly involve Arg132 in IDH1 and Arg172 or Arg140 in IDH2. Whereas IDHs convert isocitrate to alpha-ketoglutarate (α-KG) with simultaneous reduction of NADP+ to NADPH, these IDH mutants reduce α-KG to D-2-hydroxyglutarate (D-2-HG) while oxidizing NADPH. D-2-HG is a proposed oncometabolite, acting via competitive inhibition of α-KG-dependent enzymes that are involved in metabolism and epigenetic regulation. However, much less is known about the implications of the metabolic stress, imposed by decreased α-KG and NADPH production, for tumor biology. We here present a novel heterozygous IDH1 mutation, IDH1R314C, which was identified by targeted next generation sequencing of a high grade glioma from which a mouse xenograft model and a cell line were generated. IDH1R314C lacks isocitrate-to-α-KG conversion activity due to reduced affinity for NADP+ and differs from the IDH1R132 mutants in that it does not produce D-2-HG. Because IDH1R314C is defective in producing α-KG and NADPH, without concomitant production of the D-2-HG, it represents a valuable tool to study the effects of IDH1-dysfunction on cellular metabolism in the absence of this oncometabolite. |
| Databáze: | OpenAIRE |
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