Glioma-Derived Mutations in IDH1 Dominantly Inhibit IDH1 Catalytic Activity and Induce HIF-1α
By Shimin Zhao, Yan Lin, W. Xu, Wenqing Jiang, Zhengyu Zha, Pu Wang, Wei Yu, Zhiqiang Li, Lingling Gong, Yingjie Peng and 4 more. Science, 2009
1,115 citations recorded by the source corpus.
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, α-ketoglutarate (α-KG), and increases the levels of hypoxia-inducible factor subunit HIF-1α, a transcription factor that facilitates tumor growth when oxygen is low and whose stability is regulated by α-KG. The rise in HIF-1α levels was reversible by an α-KG derivative. HIF-1α 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.
Subfields: Cancer Research, Genetics, Oncology
View Paper: https://www.semanticscholar.org/paper/d165fc3a8197de2929076dfa8026e305a30b0ece
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In Cancer Research
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- Craig B. Thompson
- Sophia Y. Lunt
- Navdeep S. Chandel
- Ralph J. Deberardinis
- W. Kaelin
In Genetics
- M. V. Vander Heiden
- H. Ohgaki
- P. Kleihues
- Craig B. Thompson
- Sophia Y. Lunt
- Guido Reifenberger
- Takuya Watanabe
- S. Nobusawa
In Oncology
- M. V. Vander Heiden
- Arkaitz Carracedo
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- Ping Gao
- C. V. Dang
- Craig B. Thompson
- Y. Xiong
- W. Kaelin
Citations in the corpus
- HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. (2013, neutral): “…by protein phosphatase 1 regulatory subunit 3C (PPP1R3C). verts α -ketoglutarate into D-2-hydroxyglutarate, which stimulates prolyl hydroxylase activity and results in decreased HIF-α protein levels (94), which contrasts with earlier reports of increased HIF-α levels in IDH-mutant cells (95).”
- The oncometabolite 2‐hydroxyglutarate inhibits histone lysine demethylases (2011, background): “HIF is stabilized in IDH-associated gliomas; this has been proposed to be a consequence of intracellular depletion of 2OG following IDH loss of function (Zhao et al, 2009).”
- Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. (2011, positive): “IDH1 mutations always involve only one allele, but expression of the mutant enzyme has been reported to act as a dominant inhibitor of normal IDH1 provided by the remaining allele (Zhao et al 2009).”
- The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate (2010, background): “Therefore, it has been proposed that mutant IDH1 can act as a dominant negative against wild-type IDH1 function, resulting in a decrease in cytosolic a-ketoglutarate levels and leading to an indirect activation of the HIF-1a pathway (Zhao et al., 2009).”
- Oncometabolite 2-Hydroxyglutarate Is a Competitive Inhibitor of α-Ketoglutarate-Dependent Dioxygenases (2011, positive): “We previously showed that mutant IDH1 retains its ability to associate with wild-type subunit and forms a catalytic inactive heterodimer, leading to the dominant inhibition of wild-type IDH1 (Zhao et al., 2009).”
- Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012, background): “The heterozygous nature of the mutations was then explained awaywith the report that IDH1mutants can dominantly inhibit the wild-type IDH1 in cells (Zhao et al., 2009).”