Nuclear PTEN-mediated growth suppression is independent of Akt down-regulation
Nuclear PTEN-mediated growth suppression is independent of Akt down-regulation
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DOI：
10.1128/mcb.25.14.6211-6224.2005
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发表时间：
2005-07-01
影响因子：
5.3
通讯作者：
Yung, WKA
中科院分区：
文献类型：
--
作者：
Liu, JL;Sheng, XY;Yung, WKA
肿瘤抑制基因 PTEN 是一种磷酸肌醇磷酸酶，在多种人类肿瘤中会因缺失和/或突变而失活。野生型 PTEN 在正常细胞的细胞质和细胞核中表达，在分化或静息细胞中优先定位于核。为了阐明 PTEN 的亚细胞定位与其生物学活性之间的关系，我们构建了不同的 PTEN 突变体，将 PTEN 蛋白靶向不同的亚细胞区室。我们的数据表明，PTEN (Delta PDZB) 突变体与 G129R 磷酸酶突变体的亚细胞定位模式与野生型 PTEN 没有区别。相比之下，Myr-PTEN 突变体与细胞膜的关联性增强。我们发现核 PTEN 单独能够抑制 U251MG 细胞中的贴壁依赖性生长并促进 G(1) 阻滞，而不抑制 Akt 活性。核区室特异性 PTEN 诱导的生长抑制依赖于具有功能性脂质磷酸酶结构域。此外，p70S6K 的下调至少部分是通过以不依赖 Akt 的方式激活 AMP 激活的蛋白激酶来介导的。引入 Akt 组成型活性突变体 Akt-DD 仅部分挽救了核 PTEN 介导的生长抑制。我们的集体结果提供了第一个直接证据，证明 PTEN 可以通过不依赖于 Akt 的信号通路促进 G 生长停滞。
The tumor suppressor gene PTEN is a phosphoinositide phosphatase that is inactivated by deletion and/or mutation in diverse human tumors. Wild-type PTEN is expressed both in the cytoplasm and nucleus in normal cells, with a preferential nuclear localization in differentiated or resting cells. To elucidate the relationship between PTEN's subcellular localization and its biologic activities, we constructed different PTEN mutants that targeted PTEN protein into different subcellular compartments. Our data show that the subcellular localization patterns of a PTEN (Delta PDZB) mutant versus a G129R phosphatase mutant were indistinguishable from those of wild-type PTEN. In contrast, the Myr-PTEN mutant demonstrated an enhanced association with the cell membrane. We found that nuclear PTEN alone is capable of suppressing anchorage-independent growth and facilitating G(1) arrest in U251MG cells without inhibiting Akt activity. Nuclear compartment-specific PTEN-induced growth suppression is dependent on possessing a functional lipid phosphatase domain. In addition, the down-regulation of p70S6K could be mediated, at least in part, through activation of AMP-activated protein kinase in an Akt-independent fashion. Introduction of a constitutively active mutant of Akt, Akt-DD, only partially rescues nuclear PTEN-mediated growth suppression. Our collective results provide the first direct evidence that PTEN can contribute to G, growth arrest through an Akt-independent signaling pathway.