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Article: D-2-hydroxyglutarate produced by mutant Idh1 perturbs collagen maturation and basement membrane function

TitleD-2-hydroxyglutarate produced by mutant Idh1 perturbs collagen maturation and basement membrane function
Authors
KeywordsBrain hemorrhage
Basement membrane
Oxidative stress
Metabolism
Collagen biosynthesis
Angiogenesis
Issue Date2012
Citation
Genes and Development, 2012, v. 26, n. 18, p. 2038-2049 How to Cite?
AbstractIsocitrate 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.
Persistent Identifierhttp://hdl.handle.net/10722/292725
ISSN
2023 Impact Factor: 7.5
2023 SCImago Journal Rankings: 5.015
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorSasaki, Masato-
dc.contributor.authorKnobbe, Christiane B.-
dc.contributor.authorItsumi, Momoe-
dc.contributor.authorElia, Andrew J.-
dc.contributor.authorHarris, Isaac S.-
dc.contributor.authorChio, Iok In Christine-
dc.contributor.authorCairns, Rob A.-
dc.contributor.authorMccracken, Susan-
dc.contributor.authorWakeham, Andrew-
dc.contributor.authorHaight, Jillian-
dc.contributor.authorTen, Annick You-
dc.contributor.authorSnow, Bryan-
dc.contributor.authorUeda, Takeshi-
dc.contributor.authorInoue, Satoshi-
dc.contributor.authorYamamoto, Kazuo-
dc.contributor.authorKo, Myunggon-
dc.contributor.authorRao, Anjana-
dc.contributor.authorYen, Katharine E.-
dc.contributor.authorSu, Shinsan M.-
dc.contributor.authorMak, Tak Wah-
dc.date.accessioned2020-11-17T14:57:05Z-
dc.date.available2020-11-17T14:57:05Z-
dc.date.issued2012-
dc.identifier.citationGenes and Development, 2012, v. 26, n. 18, p. 2038-2049-
dc.identifier.issn0890-9369-
dc.identifier.urihttp://hdl.handle.net/10722/292725-
dc.description.abstractIsocitrate 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.-
dc.languageeng-
dc.relation.ispartofGenes and Development-
dc.subjectBrain hemorrhage-
dc.subjectBasement membrane-
dc.subjectOxidative stress-
dc.subjectMetabolism-
dc.subjectCollagen biosynthesis-
dc.subjectAngiogenesis-
dc.titleD-2-hydroxyglutarate produced by mutant Idh1 perturbs collagen maturation and basement membrane function-
dc.typeArticle-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1101/gad.198200.112-
dc.identifier.pmid22925884-
dc.identifier.pmcidPMC3444730-
dc.identifier.scopuseid_2-s2.0-84866480031-
dc.identifier.volume26-
dc.identifier.issue18-
dc.identifier.spage2038-
dc.identifier.epage2049-
dc.identifier.eissn1549-5477-
dc.identifier.isiWOS:000308975900006-
dc.identifier.f1000717954201-
dc.identifier.issnl0890-9369-

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