Li D M, Sun H
Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15406-11. doi: 10.1073/pnas.95.26.15406.
PTEN/MMAC1/TEP1 is a tumor suppressor that possesses intrinsic phosphatase activity. Deletions or mutations of its encoding gene are associated with a variety of human cancers. However, very little is known about the molecular mechanisms by which this important tumor suppressor regulates cell growth. Here, we show that PTEN expression potently suppressed the growth and tumorigenicity of human glioblastoma U87MG cells. The growth suppression activity of PTEN was mediated by its ability to block cell cycle progression in the G1 phase. Such an arrest correlated with a significant increase of the cell cycle kinase inhibitor p27(KIP1) and a concomitant decrease in the activities of the G1 cyclin-dependent kinases. PTEN expression also led to the inhibition of Akt/protein kinase B, a serine-threonine kinase activated by the phosphatidylinositol 3-kinase (PI 3-kinase) signaling pathway. In addition, the effect of PTEN on p27(KIP1) and the cell cycle can be mimicked by treatment of U87MG cells with LY294002, a selective inhibitor of PI 3-kinase. Taken together, our studies suggest that the PTEN tumor suppressor modulates G1 cell cycle progression through negatively regulating the PI 3-kinase/Akt signaling pathway, and one critical target of this signaling process is the cyclin-dependent kinase inhibitor p27(KIP1).
PTEN/MMAC1/TEP1是一种具有内在磷酸酶活性的肿瘤抑制因子。其编码基因的缺失或突变与多种人类癌症相关。然而，对于这种重要的肿瘤抑制因子调节细胞生长的分子机制却知之甚少。在此，我们表明PTEN的表达能有效抑制人胶质母细胞瘤U87MG细胞的生长和致瘤性。PTEN的生长抑制活性是通过其阻断G1期细胞周期进程的能力介导的。这种停滞与细胞周期激酶抑制剂p27（KIP1）的显著增加以及G1期细胞周期蛋白依赖性激酶活性的相应降低相关。PTEN的表达还导致对Akt/蛋白激酶B的抑制，Akt/蛋白激酶B是一种由磷脂酰肌醇3激酶（PI 3激酶）信号通路激活的丝氨酸 - 苏氨酸激酶。此外，用PI 3激酶的选择性抑制剂LY294002处理U87MG细胞可模拟PTEN对p27（KIP1）和细胞周期的影响。综上所述，我们的研究表明，PTEN肿瘤抑制因子通过负调节PI 3激酶/Akt信号通路来调节G1期细胞周期进程，并且该信号传导过程的一个关键靶点是细胞周期蛋白依赖性激酶抑制剂p27（KIP1）。
