Abstract
Heterozygous mutations in the gene encoding isocitrate dehydrogenase-1 (IDH1) occur in certain human brain tumors, but their mechanistic role in tumor development is unknown. We have shown that tumor-derived IDH1 mutations impair the enzyme's affinity for its substrate and dominantly inhibit wild-type IDH1 activity through the formation of catalytically inactive heterodimers. Forced expression of mutant IDH1 in cultured cells reduces formation of the enzyme product, alpha-ketoglutarate (alpha-KG), and increases the levels of hypoxia-inducible factor subunit HIF-1alpha, a transcription factor that facilitates tumor growth when oxygen is low and whose stability is regulated by alpha-KG. The rise in HIF-1alpha levels was reversible by an alpha-KG derivative. HIF-1alpha levels were higher in human gliomas harboring an IDH1 mutation than in tumors without a mutation. Thus, IDH1 appears to function as a tumor suppressor that, when mutationally inactivated, contributes to tumorigenesis in part through induction of the HIF-1 pathway.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adolescent
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Adult
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Aged
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Astrocytoma / genetics
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Astrocytoma / metabolism
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Biocatalysis
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Brain Neoplasms / genetics*
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Brain Neoplasms / metabolism
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Cell Line
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Child
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Female
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Gene Expression Regulation, Neoplastic
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Genes, Tumor Suppressor
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Glioblastoma / genetics
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Glioblastoma / metabolism
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Glioma / genetics*
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Glioma / metabolism
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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Isocitrate Dehydrogenase / chemistry
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Isocitrate Dehydrogenase / genetics*
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Isocitrate Dehydrogenase / metabolism*
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Ketoglutaric Acids / metabolism
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Male
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Middle Aged
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Mutant Proteins / chemistry
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Mutant Proteins / metabolism
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Oligodendroglioma / genetics
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Oligodendroglioma / metabolism
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Oxalates / pharmacology
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Protein Multimerization
Substances
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Ketoglutaric Acids
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Mutant Proteins
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Oxalates
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oxalomalic acid
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Isocitrate Dehydrogenase