Cancer-specific mutations in PIK3CA are oncogenic in vivo
Cancer-specific mutations in PIK3CA are oncogenic in vivo
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DOI：
10.1073/pnas.0510857103
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发表时间：
2006-01-31
影响因子：
11.1
通讯作者：
Vogt, PK
中科院分区：
文献类型：
--
作者：
Bader, AG;Kang, SY;Vogt, PK
编码IA类磷脂酰肌醇3 - 激酶（PI3s）催化亚基p110α的PIK3CA基因在人类癌症中经常发生突变。突变的p110α蛋白在体外显示出酶功能增强，并且在细胞培养中具有致癌性。在此，我们表明p110α的三种常见突变体E542K、E545K和H1047R在体内具有致癌性。它们在鸡胚的绒毛尿囊膜中诱发肿瘤，并在动物体内引起血管肉瘤。这些肿瘤的特征是血管生成增加以及Akt通路的激活。雷帕霉素抑制剂RAD001可阻断由H1047R p110α突变体诱导的肿瘤生长。PIK3CA突变体在禽类中的体内致癌性有力地表明这些突变蛋白在人类恶性肿瘤中起着关键作用。
The PIK3CA gene, coding for the catalytic subunit p110 alpha of class IA phosphatidylinositol 3-kinases (PI3s), is frequently mutated in human cancer. Mutated p110 alpha proteins show a gain of enzymatic function in vitro and are oncogenic in cell culture. Here, we show that three prevalent mutants of p110 alpha, E542K, E545K, and H1047R, are oncogenic in vivo. They induce tumors in the chorioallantoic membrane of the chicken embryo and cause hemangiosarcomas in the animal. These tumors are marked by increased angiogenesis and an activation of the Akt pathway. The target of rapamycin inhibitor RAD001 blocks tumor growth induced by the H1047R p110 alpha mutant. The in vivo oncogenicity of PIK3CA mutants in an avian species strongly suggests a critical role for these mutated proteins in human malignancies.