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

作者：Shimin Zhao, Yan Lin, Wei Xu, Wenqing Jiang, Zhengyu Zha, Pu Wang, Wei Yu, Zhiqiang Li, Ling-Ling Gong, Yingjie Peng, Jianping Ding, Qun‐Ying Lei, Kun‐Liang Guan, Yue Xiong · 发表于：Science · 年份：2009 · DOI：10.1126/science.1170944 · 被引用次数：1116 · 研究领域：Cancer, Hypoxia, and Metabolism、Glioma Diagnosis and Treatment、Cancer-related Molecular Pathways

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.