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

• DOI: 10.1126/science.1170944
• Publication Date: 2009-04-09T21:44:49Z
• Authors: Shimin Zhao; Yan Lin; Wei Xu; Wenqing Jiang; Zhengyu Zha; Pu Wang; Wei Yu; Zhiqiang Li; Lingling Gong; Yingjie Peng; Jianping Ding; Qunying Lei; Kun-Liang Guan; Yue Xiong
• Keywords: Adult; Male; 0303 health sciences; Adolescent; Brain Neoplasms; Glioma; Astrocytoma; Middle Aged; Hypoxia-Inducible Factor 1, alpha Subunit; Isocitrate Dehydrogenase; Cell Line; Gene Expression Regulation, Neoplastic; 03 medical and health sciences; Biocatalysis; Humans; Ketoglutaric Acids; Female; Genes, Tumor Suppressor; Mutant Proteins; Child; Glioblastoma; Aged

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.