IDH1 Arg-132 mutant promotes tumor formation through down-regulating p53
IDH1 Arg-132 mutant promotes tumor formation through down-regulating p53
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IDH1 Arg-132突变体通过下调p53促进肿瘤形成
DOI：
10.1074/jbc.ra117.001385
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发表时间：
2018-06-22
影响因子：
4.8
通讯作者：
Li, Qinxi
中科院分区：
文献类型：
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作者：
Jiang, Bin;Zhao, Wentao;Li, Qinxi
抗凋亡和不受控制的增殖是癌细胞的两个标志。p53对于由广泛的应激触发的细胞凋亡是至关重要的，并且是肿瘤转化的众所周知的看门人。在这里，我们表明，致癌IDH 1 R132 H/R132 Q突变体强烈抑制p53的表达，这种效果是由于2-HG的生产。从机制上讲，2-羟基戊二酸（2-HG）稳定缺氧诱导因子-2 α，进而激活miR-380- 5 p的表达，miR-380- 5 p是一种针对p53表达的特征性microRNA。p53的拯救表达可抑制IDH 1 R132 Q小鼠胚胎成纤维细胞的增殖速率，并削弱阿霉素诱导凋亡的抵抗力。此外，p53蛋白水平与人神经胶质瘤样品中的IDH 1 R132 H水平负相关。因此，我们的研究结果揭示了新的光p53是如何下调2-HG和p53介导的细胞凋亡的损害有助于IDH 1突变体驱动的肿瘤发生。
Resistance to apoptosis and uncontrolled proliferation are two hallmarks of cancer cells. p53 is crucial for apoptosis triggered by a broad range of stresses and a well-known gatekeeper for neoplastic transformation. Here we show that oncogenic IDH1 R132H/R132Q mutants robustly inhibit p53 expression and such an effect is attributed to 2-HG production. Mechanistically, 2-hydroxyglutarate (2-HG) stabilizes hypoxia-inducible factor-2α, which in turn activates the expression of miR-380-5p, a characterized microRNA against p53 expression. Rescue expression of p53 can inhibit the proliferation rate and impair the resistance of apoptosis induced by doxorubicin in IDH1 R132Q mouse embryonic fibroblast cells. Furthermore, p53 protein levels correlates negatively with IDH1 R132H levels in human glioma samples. Our results thus shed a new light on how p53 is down-regulated by 2-HG and suggests that impairment of p53-mediated apoptosis contributes to the tumorigenesis driven by IDH1 mutants.