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Ko, Myunggon
Molecular Immunology & Cancer Epigenetics
Research Interests
  • TET proteins, DNA hydroxymethylation, oncogenesis, cancer stem cells, cancer therapy

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D-2-hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function

Cited 71 times inthomson ciCited 69 times inthomson ci
Title
D-2-hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function
Author
Sasaki, MasatoKnobbe, Christiane BItsumi, MomoeElia, Andrew JHarris, Isaac SChio, Iok In ChristineCairns, Rob AMcCracken, SusanWakeham, AndrewHaight, JillianTen, Annick YouSnow, BryanUeda, TakeshiInoue, SatoshiYamamoto, KazuoKo, Myung GonRao, AnjanaYen, Katharine ESu, Shinsan MMak, Tak Wah
Issue Date
2012-09
Publisher
COLD SPRING HARBOR LAB PRESS
Citation
GENES & DEVELOPMENT, v.26, no.18, pp.2038 - 2049
Abstract
Isocitrate dehydrogenase-1 (IDH1) R132 mutations occur in glioma, but their physiological significance is unknown. Here we describe the generation and characterization of brain-specific Idh1 R132H conditional knockin (KI) mice. Idh1 mutation results in hemorrhage and perinatal lethality. Surprisingly, intracellular reactive oxygen species (ROS) are attenuated in Idh1-KI brain cells despite an apparent increase in the NADP+/NADPH ratio. Idh1-KI cells also show high levels of D-2-hydroxyglutarate (D2HG) that are associated with inhibited prolyl-hydroxylation of hypoxia-inducible transcription factor-1α (Hif1α) and up-regulated Hif1α target gene transcription. Intriguingly, D2HG also blocks prolyl-hydroxylation of collagen, causing a defect in collagen protein maturation. An endoplasmic reticulum (ER) stress response induced by the accumulation of immature collagens may account for the embryonic lethality of these mutants. Importantly, D2HG-mediated impairment of collagen maturation also led to basement membrane (BM) aberrations that could play a part in glioma progression. Our study presents strong in vivo evidence that the D2HG produced by the mutant Idh1 enzyme is responsible for the above effects. © 2012 by Cold Spring Harbor Laboratory Press.
URI
https://scholarworks.unist.ac.kr/handle/201301/12563
URL
http://genesdev.cshlp.org/content/26/18/2038.long
DOI
10.1101/gad.198200.112
ISSN
0890-9369
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