Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation.
Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation.
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DOI：
10.1038/nature10898
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发表时间：
2012-02-15
期刊：
影响因子：
64.8
通讯作者：
Kaelin, William G., Jr.
中科院分区：
文献类型：
--
作者：
Koivunen, Peppi;Lee, Sungwoo;Duncan, Christopher G.;Lopez, Giselle;Lu, Gang;Ramkissoon, Shakti;Losman, Julie A.;Joensuu, Paivi;Bergmann, Ulrich;Gross, Stefan;Travins, Jeremy;Weiss, Samuel;Looper, Ryan;Ligon, Keith L.;Verhaak, Roel G. W.;Yan, Hai;Kaelin, William G., Jr.
人类癌症中琥珀酸脱氢酶（SDH）、富马酸水合酶（FH）和异柠檬酸脱氢酶（IDH）突变的鉴定重新点燃了改变细胞代谢可以转化细胞的想法。失活SDH和FH突变分别引起琥珀酸和富马酸的积累，这可以抑制2-酮戊二酸（2-OG）依赖性酶，包括标记HIF转录因子的EglN脯氨酰4-羟化酶，用于多泛素化和蛋白酶体降解。不适当的HIF激活被怀疑有助于SDH缺陷型和FH缺陷型肿瘤的发病机制，但在某些其他情况下可以抑制肿瘤生长。IDH 1和IDH 2催化异柠檬酸和2-OG的相互转化，在人类脑肿瘤和白血病中经常发生突变。所得突变体显示将2-OG转化为2-羟基戊二酸的R-对映体（R-2 HG）的新变体能力。在这里，我们表明，R-2 HG，而不是S-2 HG，刺激EglN活性，导致HIF水平降低，这增强了人类星形胶质细胞的增殖和软琼脂生长。
The identification of succinate dehydrogenase (SDH), fumarate hydratase (FH), and isocitrate dehydrogenase (IDH) mutations in human cancers has rekindled the idea that altered cellular metabolism can transform cells. Inactivating SDH and FH mutations cause the accumulation of succinate and fumarate, respectively, which can inhibit 2-oxoglutarate (2-OG)-dependent enzymes, including the EglN prolyl 4-hydroxylases that mark the HIF transcription factor for polyubiquitylation and proteasomal degradation . Inappropriate HIF activation is suspected of contributing to the pathogenesis of SDH-defective and FH-defective tumors but can suppress tumor growth in some other contexts. IDH1 and IDH2, which catalyze the interconversion of isocitrate and 2-OG, are frequently mutated in human brain tumors and leukemias. The resulting mutants display the neomorphic ability to convert 2-OG to the R-enantiomer of 2-hydroxyglutarate (R-2HG) . Here we show that R-2HG, but not S-2HG, stimulates EglN activity leading to diminished HIF levels, which enhances the proliferation and soft agar growth of human astrocytes.
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影响因子：
3.7
作者：
Jin G;Reitman ZJ;Spasojevic I;Batinic-Haberle I;Yang J;Schmidt-Kittler O;Bigner DD;Yan H
通讯作者：
Yan H
影响因子：
64.8
作者：
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影响因子：
50.3
作者：
Figueroa ME;Abdel-Wahab O;Lu C;Ward PS;Patel J;Shih A;Li Y;Bhagwat N;Vasanthakumar A;Fernandez HF;Tallman MS;Sun Z;Wolniak K;Peeters JK;Liu W;Choe SE;Fantin VR;Paietta E;Löwenberg B;Licht JD;Godley LA;Delwel R;Valk PJ;Thompson CB;Levine RL;Melnick A
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Melnick A
影响因子：
14.9
作者：
Benita Y;Kikuchi H;Smith AD;Zhang MQ;Chung DC;Xavier RJ
通讯作者：
Xavier RJ
影响因子：
9.9
作者：
Moroni, I;Bugiani, M;Uziel, G
通讯作者：
Uziel, G