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.
Figures




Comment in
-
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.
Similar articles
-
Analysis of isocitrate dehydrogenase 1 mutation in 97 patients with glioma.J Mol Neurosci. 2012 Jul;47(3):442-7. doi: 10.1007/s12031-011-9681-5. Epub 2011 Nov 24. J Mol Neurosci. 2012. PMID: 22113362
-
Enrichment of branched chain amino acid transaminase 1 correlates with multiple biological processes and contributes to poor survival of IDH1 wild-type gliomas.Aging (Albany NY). 2021 Jan 20;13(3):3645-3660. doi: 10.18632/aging.202328. Epub 2021 Jan 20. Aging (Albany NY). 2021. PMID: 33493139 Free PMC article.
-
[Mutation of isocitrate dehydrogenase gene in Chinese patients with glioma].Zhonghua Bing Li Xue Za Zhi. 2013 May;42(5):292-8. doi: 10.3760/cma.j.issn.0529-5807.2013.05.002. Zhonghua Bing Li Xue Za Zhi. 2013. PMID: 24004584 Chinese.
-
Glioma-derived mutations in IDH: from mechanism to potential therapy.Biochem Biophys Res Commun. 2010 Jun 25;397(2):127-30. doi: 10.1016/j.bbrc.2010.05.115. Epub 2010 May 27. Biochem Biophys Res Commun. 2010. PMID: 20510884 Review.
-
Isocitrate dehydrogenase mutations in gliomas.Neuro Oncol. 2016 Jan;18(1):16-26. doi: 10.1093/neuonc/nov136. Epub 2015 Jul 16. Neuro Oncol. 2016. PMID: 26188014 Free PMC article. Review.
Cited by
-
What do we know about IDH1/2 mutations so far, and how do we use it?Acta Neuropathol. 2013 May;125(5):621-36. doi: 10.1007/s00401-013-1106-9. Epub 2013 Mar 20. Acta Neuropathol. 2013. PMID: 23512379 Free PMC article. Review.
-
Metabolic Rewiring in Radiation Oncology Toward Improving the Therapeutic Ratio.Front Oncol. 2021 May 10;11:653621. doi: 10.3389/fonc.2021.653621. eCollection 2021. Front Oncol. 2021. PMID: 34041023 Free PMC article. Review.
-
Aberrant HIF1- α and SIX-1 Expression is Associated with Poor Prognosis in Acute Myeloid Leukemia Patients with Isocitrate Dehydrogenase 1 Mutations.Cancer Control. 2024 Jan-Dec;31:10732748241271714. doi: 10.1177/10732748241271714. Cancer Control. 2024. PMID: 39110525 Free PMC article.
-
Disabling Uncompetitive Inhibition of Oncogenic IDH Mutations Drives Acquired Resistance.Cancer Discov. 2023 Jan 9;13(1):170-193. doi: 10.1158/2159-8290.CD-21-1661. Cancer Discov. 2023. PMID: 36222845 Free PMC article.
-
Recent advances in the molecular understanding of glioblastoma.J Neurooncol. 2012 May;108(1):11-27. doi: 10.1007/s11060-011-0793-0. Epub 2012 Jan 20. J Neurooncol. 2012. PMID: 22270850 Free PMC article. Review.
References
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Molecular Biology Databases
Research Materials
Miscellaneous