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Science 324 (5924): 261-265

Copyright © 2009 by the American Association for the Advancement of Science

Glioma-Derived Mutations in IDH1 Dominantly Inhibit IDH1 Catalytic Activity and Induce HIF-1{alpha}

Shimin Zhao,1,2 Yan Lin,1* Wei Xu,1,2* Wenqing Jiang,1,2* Zhengyu Zha,1 Pu Wang,1,2 Wei Yu,1,2 Zhiqiang Li,4 Lingling Gong,5 Yingjie Peng,6 Jianping Ding,6 Qunying Lei,1,3 Kun-Liang Guan,1,3,7{dagger} Yue Xiong1,2,8{dagger}

Abstract: 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-1{alpha}, a transcription factor that facilitates tumor growth when oxygen is low and whose stability is regulated by {alpha}-KG. The rise in HIF-1{alpha} levels was reversible by an {alpha}-KG derivative. HIF-1{alpha} 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.

1 Molecular and Cell Biology Laboratory, Institute of Biomedical Sciences, Fudan University, 130 Dong-An Road, Shanghai 200032, China.
2 School of Life Sciences, Fudan University, 220 Han-Dan Road, Shanghai 200433, China.
3 Department of Biological Chemistry, School of Medicine, Fudan University, 130 Dong-An Road, Shanghai 200032, China.
4 Department of Neurosurgery, Zhongnan Hospital, Wuhan University, Wuhan 430071, China.
5 Department of Pathology, Zhongnan Hospital, Wuhan University, Wuhan 430071, China.
6 State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China.
7 Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
8 Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC 27599, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: kuguan{at} (K.-L.G.); yxiong{at} (Y.X.)

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H. Carter, S. Chen, L. Isik, S. Tyekucheva, V. E. Velculescu, K. W. Kinzler, B. Vogelstein, and R. Karchin (2009)
Cancer Res. 69, 6660-6667
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CANCER: Puzzling Patterns of Predisposition.
P. J. Pollard and P. J. Ratcliffe (2009)
Science 324, 192-194
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