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

被引:938
作者
Zhao, Shimin [1 ,2 ]
Lin, Yan [1 ]
Xu, Wei [1 ,2 ]
Jiang, Wenqing [1 ,2 ]
Zha, Zhengyu [1 ]
Wang, Pu [1 ,2 ]
Yu, Wei [1 ,2 ]
Li, Zhiqiang [4 ]
Gong, Lingling [5 ]
Peng, Yingjie [6 ]
Ding, Jianping [6 ]
Lei, Qunying [1 ,3 ]
Guan, Kun-Liang [1 ,3 ,7 ,8 ]
Xiong, Yue [1 ,2 ,9 ]
机构
[1] Fudan Univ, Inst Biomed Sci, Mol & Cell Biol Lab, Shanghai 200032, Peoples R China
[2] Fudan Univ, Sch Life Sci, Shanghai 200433, Peoples R China
[3] Fudan Univ, Sch Med, Dept Biol Chem, Shanghai 200032, Peoples R China
[4] Wuhan Univ, Dept Neurosurg, Zhongnan Hosp, Wuhan 430071, Peoples R China
[5] Wuhan Univ, Dept Pathol, Zhongnan Hosp, Wuhan 430071, Peoples R China
[6] Chinese Acad Sci, Shanghai Inst Biol Sci, State Key Lab Mol Biol, Shanghai 200031, Peoples R China
[7] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA
[8] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA
[9] Univ N Carolina, Dept Biochem & Biophys, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA
关键词
DEPENDENT ISOCITRATE DEHYDROGENASE; MECHANISM; TUMORS;
D O I
10.1126/science.1170944
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:261 / 265
页数:5
相关论文
共 12 条
[1]   CELLULAR CONCENTRATIONS OF ENZYMES AND THEIR SUBSTRATES [J].
ALBE, KR ;
BUTLER, MH ;
WRIGHT, BE .
JOURNAL OF THEORETICAL BIOLOGY, 1990, 143 (02) :163-195
[2]   Analysis of the IDH1 codon 132 mutation in brain tumors [J].
Balss, Joerg ;
Meyer, Jochen ;
Mueller, Wolf ;
Korshunov, Andrey ;
Hartmann, Christian ;
von Deimling, Andreas .
ACTA NEUROPATHOLOGICA, 2008, 116 (06) :597-602
[3]   IDH1 Mutations at Residue p.R132 (IDH1R132) Occur Frequently in High-Grade Gliomas But Not in Other Solid Tumors [J].
Bleeker, Fonnet E. ;
Lamba, Simona ;
Leenstra, Sieger ;
Troost, Dirk ;
Hulsebos, Theo ;
Vandertop, W. Peter ;
Frattini, Milo ;
Molinari, Francesca ;
Knowles, Margaret ;
Cerrato, Aniello ;
Rodolfo, Monica ;
Scarpa, Aldo ;
Felicioni, Lara ;
Buttitta, Fiamma ;
Malatesta, Sara ;
Marchetti, Antonio ;
Bardelli, Alberto .
HUMAN MUTATION, 2009, 30 (01) :7-11
[4]   Malignant astrocytic glioma: genetics, biology, and paths to treatment [J].
Furnari, Frank B. ;
Fenton, Tim ;
Bachoo, Robert M. ;
Mukasa, Akitake ;
Stommel, Jayne M. ;
Stegh, Alexander ;
Hahn, William C. ;
Ligon, Keith L. ;
Louis, David N. ;
Brennan, Cameron ;
Chin, Lynda ;
DePinho, Ronald A. ;
Cavenee, Webster K. .
GENES & DEVELOPMENT, 2007, 21 (21) :2683-2710
[5]   MECHANISM OF INHIBITORY EFFECT OF GLYOXYLATE PLUS OXALOACETATE AND OXALOMALATE ON NADP-SPECIFIC ISOCITRATE DEHYDROGENASE [J].
INGEBRETSEN, OC .
BIOCHIMICA ET BIOPHYSICA ACTA, 1976, 452 (02) :302-309
[6]   Cell-permeating α-ketoglutarate derivatives alleviate pseudohypoxia in succinate dehydrogenase-deficient cells [J].
MacKenzie, Elaine D. ;
Selak, Mary A. ;
Tennant, Daniel A. ;
Payne, Lloyd J. ;
Crosby, Stuart ;
Frederiksen, Casper M. ;
Watson, David G. ;
Gottlieb, Eyal .
MOLECULAR AND CELLULAR BIOLOGY, 2007, 27 (09) :3282-3289
[7]   An integrated genomic analysis of human glioblastoma Multiforme [J].
Parsons, D. Williams ;
Jones, Sian ;
Zhang, Xiaosong ;
Lin, Jimmy Cheng-Ho ;
Leary, Rebecca J. ;
Angenendt, Philipp ;
Mankoo, Parminder ;
Carter, Hannah ;
Siu, I-Mei ;
Gallia, Gary L. ;
Olivi, Alessandro ;
McLendon, Roger ;
Rasheed, B. Ahmed ;
Keir, Stephen ;
Nikolskaya, Tatiana ;
Nikolsky, Yuri ;
Busam, Dana A. ;
Tekleab, Hanna ;
Diaz, Luis A., Jr. ;
Hartigan, James ;
Smith, Doug R. ;
Strausberg, Robert L. ;
Marie, Suely Kazue Nagahashi ;
Shinjo, Sueli Mieko Oba ;
Yan, Hai ;
Riggins, Gregory J. ;
Bigner, Darell D. ;
Karchin, Rachel ;
Papadopoulos, Nick ;
Parmigiani, Giovanni ;
Vogelstein, Bert ;
Velculescu, Victor E. ;
Kinzler, Kenneth W. .
SCIENCE, 2008, 321 (5897) :1807-1812
[8]   Evaluation of HIF-1 inhibitors as anticancer agents [J].
Semenza, Gregg L. .
DRUG DISCOVERY TODAY, 2007, 12 (19-20) :853-859
[9]   Identification by mutagenesis of arginines in the substrate binding site of the porcine NADP-dependent isocitrate dehydrogenase [J].
Soundar, S ;
Danek, BL ;
Colman, RF .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (08) :5606-5612
[10]   MULTIPLE NADPH-PRODUCING PATHWAYS CONTROL GLUTATHIONE (GSH) CONTENT IN RETINA [J].
WINKLER, BS ;
DESANTIS, N ;
SOLOMON, F .
EXPERIMENTAL EYE RESEARCH, 1986, 43 (05) :829-847