Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha.
Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha.
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DOI：
10.1126/science.1170944
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发表时间：
2009-04-10
期刊：
影响因子：
--
通讯作者：
Xiong Y
中科院分区：
文献类型：
--
作者：
Zhao S;Lin Y;Xu W;Jiang W;Zha Z;Wang P;Yu W;Li Z;Gong L;Peng Y;Ding J;Lei Q;Guan KL;Xiong Y
在某些人类脑肿瘤中，在某些人脑肿瘤中出现了编码等异急塞脱氢酶1（IDH1）的杂合突变，但是它们在肿瘤发育中的机械作用尚不清楚。 - 型IDH1活性通过催化无效的异二聚体的形成。产物，α-酮戊二酸（α-kg），并增加了缺氧诱导因子亚基HIF-1α的水平，这是一种转录因子，当氧气较低并且其稳定性受HIF的调节时，可促进肿瘤生长。 -1α水平通过α-kg衍生物可逆。肿瘤抑制剂当突变灭活时，通过诱导HIF-1途径会导致肿瘤发生。
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.
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DOI：
10.1016/0005-2744(76)90180-7
发表时间：
1976-01-01
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA
影响因子：
--
作者：
INGEBRETSEN, OC
通讯作者：
INGEBRETSEN, OC
DOI：
10.1126/science.1164382
发表时间：
2008-09-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Parsons DW;Jones S;Zhang X;Lin JC;Leary RJ;Angenendt P;Mankoo P;Carter H;Siu IM;Gallia GL;Olivi A;McLendon R;Rasheed BA;Keir S;Nikolskaya T;Nikolsky Y;Busam DA;Tekleab H;Diaz LA Jr;Hartigan J;Smith DR;Strausberg RL;Marie SK;Shinjo SM;Yan H;Riggins GJ;Bigner DD;Karchin R;Papadopoulos N;Parmigiani G;Vogelstein B;Velculescu VE;Kinzler KW
通讯作者：
Kinzler KW
影响因子：
4.8
作者：
Soundar, S;Danek, BL;Colman, RF
通讯作者：
Colman, RF
人胞质 NADP 依赖性异柠檬酸脱氢酶的结构揭示了一种新的自我调节活性机制
影响因子：
4.8
作者：
Xu, X;Zhao, JY;Ding, JP
通讯作者：
Ding, JP
影响因子：
5.3
作者：
MacKenzie, Elaine D.;Selak, Mary A.;Gottlieb, Eyal
通讯作者：
Gottlieb, Eyal