PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3,4,5,-trisphosphate and Akt protein kinase B signaling pathway
PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3,4,5,-trisphosphate and Akt protein kinase B signaling pathway
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DOI：
10.1073/pnas.96.11.6199
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发表时间：
1999-05-25
影响因子：
11.1
通讯作者：
Wu, H
中科院分区：
文献类型：
--
作者：
Sun, H;Lesche, R;Wu, H
为了研究PTEN介导的肿瘤抑制的分子基础，我们通过在胚胎干（ES）细胞中同源重组将无效突变引入小鼠Pten基因。Pten（-/-）ES细胞表现出增加的生长速率，并且即使在没有血清的情况下也能增殖。缺乏PTEN功能的ES细胞也显示提前进入S期。这种加速的G（1）/S转换伴随着p27（KIP 1）的下调，KIP 1是G（1）细胞周期蛋白依赖性激酶的主要抑制剂。ES细胞和胚胎成纤维细胞中PTEN的失活导致磷脂酰肌醇3激酶产物3，4，5-三磷酸磷脂酰肌醇水平升高。因此，PTEN缺陷导致Akt/蛋白激酶B的磷酸化和活化的剂量依赖性增加，Akt/蛋白激酶B是磷脂酰肌醇3激酶信号传导途径的充分表征的靶标。Akt激活增加Bad磷酸化并促进Pten（-/-）细胞存活。我们的研究表明，PTEN调节磷脂酰肌醇3，4，5，-三磷酸和Akt信号通路，从而调节两个关键的细胞过程：细胞周期进程和细胞存活。
To investigate the molecular basis of PTEN-mediated tumor suppression, we introduced a null mutation into the mouse Pten gene by homologous recombination in embryonic stem (ES) cells. Pten(-/-) ES cells exhibited an increased growth rate and proliferated even in the absence of serum. ES cells lacking PTEN function also displayed advanced entry into S phase. This accelerated G(1)/S transition was accompanied by down-regulation of p27(KIP1), a major inhibitor for G(1) cyclin-dependent kinases. Inactivation of PTEN in ES cells and in embryonic fibroblasts resulted in elevated levels of phosphatidylinositol 3,4,5,-trisphosphate, a product of phosphatidylinositol 3 kinase. Consequently, PTEN deficiency led to dosage-dependent increases in phosphorylation and activation of Akt/protein kinase B, a well-characterized target of the phosphatidylinositol 3 kinase signaling pathway. Akt activation increased Bad phosphorylation and promoted Pten(-/-) cell survival. Our studies suggest that PTEN regulates the phosphatidylinositol 3,4,5,-trisphosphate and Akt signaling pathway and consequently modulates two critical cellular processes: cell cycle progression and cell survival.