Link Wolfgang, Rosado Aranzazu, Fominaya Jesus, Thomas James E, Carnero Amancio
Experimental Therapeutics Program, Centro Nacional de Investigaciones Oncologicas, Melchor Fernandez Almagro, 3, 28029 Madrid, Spain.
J Cell Biochem. 2005 Aug 1;95(5):979-89. doi: 10.1002/jcb.20479.
Phosphoinositide 3'-kinases (PI3Ks) constitute a family of lipid kinases implicated in signal transduction through tyrosine kinase receptors and heterotrimeric G protein-linked receptors. PI3Ks are heterodimers made up of four different 110-kDa catalytic subunits (p110alpha, p110beta, p110gamma, and p110delta) and a smaller regulatory subunit. Despite a clear implication of PI3Ks in survival signaling, the contribution of the individual PI3K isoforms has not been elucidated. To address this issue, we generated Rat1 fibroblasts that co-express c-Myc and membrane targeted derivates of the different p110 isoforms. Here we present data for the first time showing that activation of PI3-kinase signaling through membrane localization of p110beta, p110gamma, and p110delta protects c-Myc overexpressing Rat1 fibroblasts from apoptosis caused by serum deprivation like it has been described for p110alpha. Expression of each p110 isoform reduces significantly caspase-3 like activity in this apoptosis model. Decreased caspase-3 activity correlates with the increase in Akt phosphorylation in cells that contain one of the myristoylated p110 isoforms. p110 isoform-mediated protection from cell death was abrogated upon expression of a kinase-negative version of Akt.
磷酸肌醇3'-激酶（PI3Ks）是一类脂质激酶，参与通过酪氨酸激酶受体和异源三聚体G蛋白偶联受体的信号转导。PI3Ks是由四个不同的110 kDa催化亚基（p110α、p110β、p110γ和p110δ）和一个较小的调节亚基组成的异二聚体。尽管PI3Ks在生存信号传导中有着明确的作用，但各个PI3K亚型的具体贡献尚未阐明。为了解决这个问题，我们构建了共表达c-Myc和不同p110亚型的膜靶向衍生物的Rat1成纤维细胞。在此，我们首次展示的数据表明，通过p110β、p110γ和p110δ的膜定位激活PI3-激酶信号传导可保护过表达c-Myc的Rat1成纤维细胞免受血清剥夺引起的凋亡，就像p110α的情况一样。在这个凋亡模型中，每个p110亚型的表达都显著降低了类似caspase-3的活性。caspase-3活性的降低与含有一种肉豆蔻酰化p110亚型的细胞中Akt磷酸化的增加相关。当表达激酶阴性版本的Akt时，p110亚型介导的细胞死亡保护作用被消除。
