Glioma-Derived Mutations in IDH1 Dominantly Inhibit IDH1 Catalytic Activity and Induce HIF-1α

• Published in: Science (American Association for the Advancement of Science) 2009-04, Vol.324 (5924), p.261-265
• Main Authors: Zhao, Shimin, Lin, Yan, Xu, Wei, Jiang, Wenqing, Zha, Zhengyu, Wang, Pu, Yu, Wei, Li, Zhiqiang, Gong, Lingling, Peng, Yingjie, Ding, Jianping, Lei, Qunying, Guan, Kun-Liang, Xiong, Yue
• Format: Article
• Language: English
• Subjects: Biochemistry; Biological and medical sciences; Catalytic activity; Cell growth; Cultured cells; Enzymes; Genetic mutation; Glioma; Hypoxia; Isocitrates; Medical sciences; Neurology; Tumors; Tumors of the nervous system. Phacomatoses
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1170944

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.