The DOI matches its Crossref record; 12 of the 12 references it cites were found in a registry or an index.
Glioma-Derived Mutations in IDH1 Dominantly Inhibit IDH1 Catalytic Activity and Induce HIF-1α
Open accessAbstract
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.
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“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).”
From The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases (2011) · cites this paper as Zhao et al, 2009
In the citing paper
“The IDH mutations occur at substrate-binding arginine residues (Arg 132 in IDH1; Arg 140 and Arg 172 in IDH2) and inactivate IDH for conversion of isocitrate to 2-oxoglutarate (2OG; Zhao et al, 2009).”
From The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases (2011) · cites this paper as Zhao et al, 2009
In the citing paper
“Overexpression of IDH1 Arg 132 mutants results in elevated HIFa levels (Zhao et al, 2009).”
From The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases (2011) · cites this paper as Zhao et al, 2009
In the citing paper
“The stability of HIF‐1α is regulated by α‐KG, and increasing α‐KG reduces the expression of HIF‐1α.”
From Hypoxia signaling in cancer: Implications for therapeutic interventions (2023) · cites this paper as [168]
In the citing paper
“Inhibiting the mitochondrial enzyme SDH during ischaemia by preloading tissues with the SDH inhibitor DMM prevented succinate accumulation during ischaemia and protected against tissue damage upon reperfusion150.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [150]
In the citing paper
“succinate accumulated during ischaemia and is then oxidised upon reperfusion to drive the mitochondrial superoxide formation that contributes to ischaemia-reperfusion (IR) injury150,151.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [150]
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Cites
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Metadata
- Authors
- Zhao, S., Lin, Y., Xu, W., Jiang, W., Zha, Z., Wang, P., Yu, W., Li, Z., Gong, L., Peng, Y., Ding, J., Lei, Q., Guan, K.-L., & Xiong, Y.
- Affiliations
- Shanghai Medical College of Fudan University (CN)
- Molecular and Cell Biology Laboratory, Institute of Biomedical Sciences, Fudan University, 130 Dong-An Road, Shanghai 200032, China.
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Lin, Yan
- Xu, Wei
- Jiang, Wenqing
- Guan, Kun-Liang
- Xiong, Yue
- ORCID
- Venue
- Science
- Published
- 2009-04-10
- Volume
- 324
- Issue
- 5924
- Pages
- 261-265
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC3251015
- OpenAlex
- W1964150693
- Cited by
- 1,119
- References
- 12
- Citations by year
- 2026: 24 · 2025: 27 · 2024: 43 · 2023: 36 · 2022: 50 · 2021: 62 · 2020: 58 · 2019: 54 · 2018: 63 · 2017: 71 · 2016: 57 · 2015: 71 · 2014: 74 · 2013: 90 · 2012: 84
- FWCI
- 37.70
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA068377)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- IDH1 mutation, isocitrate dehydrogenase, glioma, HIF-1α, alpha-ketoglutarate, heterodimer formation, tumor suppressor, hypoxia, carcinogenesis, brain tumors, enzyme activity
- MeSH terms
- Adolescent, Adult, Aged, Astrocytoma, Brain Neoplasms, Cell Line, Child, Female, Glioblastoma, Glioma, Humans, Isocitrate Dehydrogenase, Ketoglutaric Acids, Male, Middle Aged, Oligodendroglioma, Oxalates, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Mutant Proteins, Hypoxia-Inducible Factor 1, alpha Subunit, Biocatalysis, Protein Multimerization
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