The oncogenic properties of mutant p110alpha and p110beta phosphatidylinositol 3-kinases in human mammary epithelial cells.
The oncogenic properties of mutant p110alpha and p110beta phosphatidylinositol 3-kinases in human mammary epithelial cells.
复制标题
DOI：
--
复制
发表时间：
2005
影响因子：
11.1
通讯作者：
Jean J. Zhao;Zhenning Liu;Li Wang;Eyoung Shin;M. Loda;T. Roberts
中科院分区：
文献类型：
--
作者：
Jean J. Zhao;Zhenning Liu;Li Wang;Eyoung Shin;M. Loda;T. Roberts
编码IA类磷脂酰肌醇3-激酶（PI3Ks）p110 α亚基的PIK3CA基因在人类肿瘤中经常发生突变。编码p110 β的PIK3CB基因（唯一的其他广泛表达的IA类PI3K）的突变尚未报道。我们比较了人乳腺上皮细胞系统中p110 α和p110 β突变形式的生化活性和转化潜力。p110 α的两个最常见的肿瘤衍生等位基因H1047 R和E545 K有效地激活PI3 K信号传导。表达这些等位基因的人乳腺上皮细胞在软琼脂中有效生长，并在裸鼠体内形成原位肿瘤。我们还研究了p110 α中的第三类突变，即p85结合域中的突变。一个代表性的肿瘤来源的p85结合结构域突变体R38 H显示适度减少的p85结合和弱激活的PI3 K/Akt信号传导。相反，缺失整个p85结合结构域的突变体有效地激活PI3K信号。当我们在p110 β中构建与p110 α的E545K等位基因同源的突变时，所得到的p110 β突变体仅被弱激活，并允许最小的软琼脂生长。然而，p110 β与c-Src的膜锚的基因融合在软琼脂和原位裸鼠试验中都具有高度活性和转化性。因此，虽然在p110 β的相应位点引入p110 α的激活突变未能使该酶在人类细胞中致癌，但其他突变可能激活β亚型的可能性仍然存在。
The PIK3CA gene encoding the p110alpha subunit of Class IA phosphatidylinositol 3-kinases (PI3Ks) is frequently mutated in human tumors. Mutations in the PIK3CB gene encoding p110beta, the only other widely expressed Class IA PI3K, have not been reported. We compared the biochemical activity and transforming potential of mutant forms of p110alpha and p110beta in a human mammary epithelial cell system. The two most common tumor-derived alleles of p110alpha, H1047R and E545K, potently activated PI3K signaling. Human mammary epithelial cells expressing these alleles grew efficiently in soft agar and as orthotopic tumors in nude mice. We also examined a third class of mutations in p110alpha, those in the p85-binding domain. A representative tumor-derived p85-binding-domain mutant R38H showed modestly reduced p85 binding and weakly activated PI3K/Akt signaling. In contrast, a deletion mutant lacking the entire p85-binding domain efficiently activated PI3K signaling. When we constructed in p110beta a mutation homologous to the E545K allele of p110alpha, the resulting p110beta mutant was only weakly activated and allowed minimal soft-agar growth. However, a gene fusion of p110beta with the membrane anchor from c-Src was highly active and transforming in both soft-agar and orthotopic nude mouse assays. Thus, although introduction of activating mutations from p110alpha at the corresponding sites in p110beta failed to render the enzyme oncogenic in human cells, the possibility remains that other mutations might activate the beta isoform.