2-hydroxyglutarate production, but not dominant negative function, is conferred by glioma-derived NADP-dependent isocitrate dehydrogenase mutations.
2-hydroxyglutarate production, but not dominant negative function, is conferred by glioma-derived NADP-dependent isocitrate dehydrogenase mutations.
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DOI：
10.1371/journal.pone.0016812
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发表时间：
2011-02-04
期刊：
影响因子：
3.7
通讯作者：
Yan H
中科院分区：
文献类型：
--
作者：
Jin G;Reitman ZJ;Spasojevic I;Batinic-Haberle I;Yang J;Schmidt-Kittler O;Bigner DD;Yan H
神经胶质瘤通常在细胞质NADP+依赖性异柠檬酸脱氢酶（IDH 1）或线粒体NADP+依赖性异柠檬酸脱氢酶（IDH 2）中含有突变。在神经胶质瘤患者中，在IDH 1 R132或IDH 2 R172处出现几种不同的氨基酸取代。遗传学证据表明，这些突变共享一个共同的功能增益，但目前尚不清楚是否共享的功能是显性负活性，（R）-2-羟基戊二酸（2 HG）的新形态生产，或两者兼而有之。我们通过共沉淀显示，五种癌症衍生的IDH 1 R132突变体结合IDH 1-WT，但三种癌症衍生的IDH 2 R172突变体与IDH 2-WT的结合最小。在哺乳动物细胞裂解物中，在生理（40 µM）异柠檬酸浓度下，没有突变体显性负性降低异柠檬酸脱氢酶活性。与此相反，所有这些突变体赋予细胞高10至100倍的2 HG产生，并且与没有IDH突变的神经胶质瘤组织相比，含有IDH 1 R132或IDH 2 R172突变的神经胶质瘤组织含有高水平的2 HG（54.4对0.1 mg 2 HG/g蛋白质）。与WT IDH 1或IDH 2的结合或显性抑制不是IDH 1和IDH 2突变的共有特征，因此在癌症中不太可能是重要的。获得产生2 HG的酶活性是IDH 1和IDH 2突变的共同特征，这一事实表明这是这些突变体在驱动癌症发病机制中的重要功能。
Gliomas frequently contain mutations in the cytoplasmic NADP+-dependent isocitrate dehydrogenase (IDH1) or the mitochondrial NADP+-dependent isocitrate dehydrogenase (IDH2). Several different amino acid substitutions recur at either IDH1 R132 or IDH2 R172 in glioma patients. Genetic evidence indicates that these mutations share a common gain of function, but it is unclear whether the shared function is dominant negative activity, neomorphic production of (R)-2-hydroxyglutarate (2HG), or both. We show by coprecipitation that five cancer-derived IDH1 R132 mutants bind IDH1-WT but that three cancer-derived IDH2 R172 mutants exert minimal binding to IDH2-WT. None of the mutants dominant-negatively lower isocitrate dehydrogenase activity at physiological (40 µM) isocitrate concentrations in mammalian cell lysates. In contrast to this, all of these mutants confer 10- to 100-fold higher 2HG production to cells, and glioma tissues containing IDH1 R132 or IDH2 R172 mutations contain high levels of 2HG compared to glioma tissues without IDH mutations (54.4 vs. 0.1 mg 2HG/g protein). Binding to, or dominant inhibition of, WT IDH1 or IDH2 is not a shared feature of the IDH1 and IDH2 mutations, and thus is not likely to be important in cancer. The fact that the gain of the enzymatic activity to produce 2HG is a shared feature of the IDH1 and IDH2 mutations suggests that this is an important function for these mutants in driving cancer pathogenesis.
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DOI：
10.1016/j.bbrc.2010.06.125
发表时间：
2010-07-30
影响因子：
3.1
作者：
Lopez, Giselle Y.;Reitman, Zachary J.;Yan, Hai
通讯作者：
Yan, Hai
影响因子：
50.3
作者：
Ward PS;Patel J;Wise DR;Abdel-Wahab O;Bennett BD;Coller HA;Cross JR;Fantin VR;Hedvat CV;Perl AE;Rabinowitz JD;Carroll M;Su SM;Sharp KA;Levine RL;Thompson CB
通讯作者：
Thompson CB
影响因子：
64.8
作者：
通讯作者：
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DOI：
10.1126/science.1170944
发表时间：
2009-04-10
期刊：
Science (New York, N.Y.)
影响因子：
--
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
通讯作者：
Xiong Y
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
通讯作者：
Melnick A