An R132H mutation in isocitrate dehydrogenase 1 enhances p21 expression and inhibits phosphorylation of retinoblastoma protein in glioma cells.
An R132H mutation in isocitrate dehydrogenase 1 enhances p21 expression and inhibits phosphorylation of retinoblastoma protein in glioma cells.
复制标题
DOI：
10.2176/nmc.oa2012-0409
复制
发表时间：
2013
影响因子：
1.9
通讯作者：
Watanabe E
中科院分区：
文献类型：
--
作者：
Miyata S;Urabe M;Gomi A;Nagai M;Yamaguchi T;Tsukahara T;Mizukami H;Kume A;Ozawa K;Watanabe E
在脑肿瘤中具有R132 H突变的胞质异柠檬酸脱氢酶1（IDH 1）失去其催化异柠檬酸生成α-酮戊二酸（α-KG）的酶活性，并获得新的活性，从而将α-KG转化为2-羟基戊二酸。IDH 1突变诱导三羧酸循环中间产物的下调和脂质代谢的上调。固醇调节元件结合蛋白（SREBPs）不仅调节胆固醇和脂肪酸的合成，还调节使细胞周期停止在G1的acyclin依赖性激酶抑制剂p21。在这里，我们表明，SREBP上调U87人胶质母细胞瘤细胞转染IDH 1 R132 H表达质粒。针对SREBP 1的小干扰核糖核酸（siRNA）特异性降低了p21信使RNA（mRNA）水平，而不依赖于p53通路。在表达IDH 1 R132 H的U87细胞中，视网膜母细胞瘤（Rb）蛋白的磷酸化也降低。我们认为IDH 1突变诱导的代谢变化通过SREBP 1增强p21表达并抑制Rb的磷酸化，这减缓了细胞周期的进展，并可能与IDH 1突变的胶质瘤的非侵袭性特征相关。
Cytosolic isocitrate dehydrogenase 1 (IDH1) with an R132H mutation in brain tumors loses its enzymatic activity for catalyzing isocitrate to α-ketoglutarate (α-KG) and acquires new activity whereby it converts α-KG to 2-hydroxyglutarate. The IDH1 mutation induces down-regulation of tricarboxylic acid cycle intermediates and up-regulation of lipid metabolism. Sterol regulatory element-binding proteins (SREBPs) regulate not only the synthesis of cholesterol and fatty acids but also acyclin-dependent kinase inhibitor p21 that halts the cell cycle at G1. Here we show that SREBPs were up-regulated in U87 human glioblastoma cells transfected with an IDH1R132H-expression plasmid. Small interfering ribonucleic acid (siRNA) for SREBP1 specifically decreased p21 messenger RNA (mRNA) levels independent of the p53 pathway. In IDH1R132H-expressing U87 cells, phosphorylation of Retinoblastoma (Rb) protein also decreased. We propose that metabolic changes induced by the IDH1 mutation enhance p21 expression via SREBP1 and inhibit phosphorylation of Rb, which slows progressionof the cell cycle and may be associated with non-aggressive features of gliomas with an IDH1 mutation.