Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha
- PMID: 19359588
- PMCID: PMC3251015
- DOI: 10.1126/science.1170944
Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha
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.
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Comment in
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Cancer. Puzzling patterns of predisposition.Science. 2009 Apr 10;324(5924):192-4. doi: 10.1126/science.1173362. Science. 2009. PMID: 19359573 No abstract available.
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