原创力文档2-hydroxyglutarate production, but not dominant negative function, is conferred by glioma-derived nadp+-dependent isocitrate dehydrogenase mutations2-hydroxyglutarate生产,但不占主导地位的消极功能,赋予了glioma-derived辅酶ii +端依赖异柠檬酸脱氢酶突变.pdfVIP
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2-hydroxyglutarateproduction,butnotdominantnegativefunction,isconferredbyglioma-derivednadp-dependentisocitratedehydrogenasemutations2-hydroxyglutarate生产,但不占主导地位的消极功能,赋予了glioma-derived辅酶ii端依赖异柠檬酸脱氢酶突变
2-Hydroxyglutarate Production, but Not Dominant
Negative Function, Is Conferred by Glioma-Derived
NADP+-Dependent Isocitrate Dehydrogenase Mutations
1. 1. 2 3 4
Genglin Jin , Zachary J. Reitman , Ivan Spasojevic , Ines Batinic-Haberle , Jian Yang , Oleg Schmidt-
4 1 1
Kittler , Darell D. Bigner , Hai Yan *
1The Preston Robert Tisch Brain Tumor Center at Duke, Pediatric Brain Tumor Foundation Institute, and Department of Pathology, Duke University Medical Center,
Durham, North Carolina, United States of America, 2 Clinical Pharmacology Laboratory, Department of Medicine, Duke Comprehensive Cancer Center, Duke University
Medical Center, Durham, North Carolina, United States of America, 3 Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, United
States of America, 4 The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
Abstract
+
Background: Gliomas frequently contain mutations in the cytoplasmic NADP -dependent isocitrate dehydrogenase (IDH1)
or the mitochondrial NADP+-dependent isocitrate dehydrogenase (IDH2). Several different amino acid substitutions recur at
either IDH1 R132 or IDH2 R172 in glioma patients. Genetic evidence indicates that these mutations share a common gain of
function, but it is unclear whether the shared function is dominant negative activity, neomorphic production of (R)-2-
hydroxyglutarate (2HG), or both.
Methodology/Principal Findings: We show by coprecipitation that five cancer-derived IDH1 R132 mutants bind IDH1-WT
but that th
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