Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic
Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic
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DOI：
10.1073/pnas.0408864102
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发表时间：
2005-01-18
影响因子：
11.1
通讯作者：
Vogt, PK
中科院分区：
文献类型：
--
作者：
Kang, SY;Bader, AG;Vogt, PK
编码磷脂酰肌醇3-激酶（P13-激酶）信号通路组分的基因突变在人类癌症中很常见。最近在许多人类肿瘤的PlK 3CA基因中发现的非随机体细胞突变表明了突变酶的致癌作用。我们已经确定了三种最常见的P13激酶突变的生长调节和信号传导特性：E542 K，E545 K和H1047 R。在鸡胚成纤维细胞中表达，所有三种突变体都以高效率诱导致癌转化。这种转化能力与体外激酶测定中的催化活性升高相关。mu转化的细胞显示Akt、p70 S6激酶和4 E结合蛋白1的组成性磷酸化。S6激酶和4 E结合蛋白1的磷酸化受雷帕霉素（TOR）激酶靶点的调节，并影响蛋白质合成速率。TOR的抑制剂雷帕霉素强烈干扰由P13-激酶突变体诱导的细胞转化，表明TOR及其下游靶标是转化过程的重要组成部分。致癌转化活性使得突变的P13-激酶蛋白有希望成为小分子抑制剂的靶点，可以开发成有效的和高度特异性的抗癌药物。
Mutations in genes that encode components of the phosphatidylinositol 3-kinase (Pl3-kinase) signaling pathway are common in human cancer. The recent discovery of nonrandom somatic mutations in the PlK3CA gene of many human tumors suggests an oncogenic role for the mutated enzyme. We have determined the growth-regulatory and signaling properties of the three most frequently observed Pl3-kinase mutations: E542K, E545K, and H1047R. Expressed in chicken embryo fibroblasts, all three mutants induce oncogenic transformation with high efficiency. This transforming ability is correlated with elevated catalytic activity in in vitro kinase assays. The mutant-transformed cells show constitutive phosphorylation of Akt, of p70 S6 kinase, and of the 4E-binding protein 1. Phosphorylation of S6 kinase and of 4E-binding protein 1 is regulated by the target of rapamycin (TOR) kinase and affects rates of protein synthesis. The inhibitor of TOR, rapamycin, strongly interferes with cellular transformation induced by the Pl3-kinase mutants, suggesting that the TOR and its downstream targets are essential components of the transformation process. The oncogenic transforming activity makes the mutated Pl3-kinase proteins promising targets for small molecule inhibitors that could be developed into effective and highly specific anticancer drugs.