BCR/ABL regulates expression of the cyclin-dependent kinase inhibitor p27Kip1 through the phosphatidylinositol 3-kinase/AKT pathway
BCR/ABL regulates expression of the cyclin-dependent kinase inhibitor p27Kip1 through the phosphatidylinositol 3-kinase/AKT pathway
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DOI：
10.1074/jbc.m007291200
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发表时间：
2000-12-15
影响因子：
4.8
通讯作者：
Griffin, JD
中科院分区：
文献类型：
--
作者：
Gesbert, F;Sellers, WR;Griffin, JD
细胞周期检查点的失调是人类癌症中几乎普遍的异常，并且最常见的是由于肿瘤抑制基因如Rb、p53或p16（INK 4a）的功能丧失突变。在这项研究中，我们证明，BCR/ABL抑制一个关键的细胞周期抑制剂，p27（Kip 1）的表达，通过信号转导途径，涉及磷脂酰肌醇3-激酶（PI 3 K）。p27（Kip 1）是一种广泛表达的cdk 2抑制剂，cdk 2是一种调节进入S期的必需细胞周期激酶。我们通过两种不同的方法证明了造血细胞中p27（Kip 1）的减少是直接由于BCR/ABL。首先，四环素调控的启动子诱导BCR/ABL与p27（Kip 1）的可逆下调有关。第二，用Abl酪氨酸激酶抑制剂STI 571抑制BCR/ABL激酶活性迅速增加p27（Kipl）水平。PI 3 K抑制剂LY-294002阻断BCR/ABL诱导p27（Kip 1）下调的能力，并抑制BCR/ABL诱导的进入S期。丝氨酸/苏氨酸激酶AKT/蛋白激酶B是PI 3 K的已知下游靶标。发现AKT的激活突变体的瞬时表达降低了p27（Kip 1）的表达，即使当PI 3 K被LY-294002抑制时。p27（Kip 1）的调节机制主要与蛋白质的稳定性有关，因为蛋白酶体活性的抑制增加了BCR/ABL转化细胞中p27（Kip 1）的水平，而p27转录的变化很小。总体而言，这些数据与BCR/ABL通过PI 3 K/AKT抑制p27（Kip 1）蛋白水平，导致加速进入S期的模型一致。这种活性可能部分解释了先前的研究，这些研究表明，PI 3 K的活化是体外和体内BCR/ABL对造血细胞进行最佳转化所必需的。
Deregulation of cell cycle checkpoints is an almost universal abnormality in human cancers and is most often due to loss-of-function mutations of tumor suppressor genes such as Rb, p53, or p16(INK4a). In this study, we demonstrate that BCR/ABL inhibits the expression of a key cell cycle inhibitor, p27(Kip1), by signaling through a pathway involving phosphatidylinositol 3-kinase (PI3K). p27(Kip1) is a widely expressed inhibitor of cdk2, an essential cell cycle kinase regulating entry into S phase. We demonstrate that the decrease of p27(Kip1) is directly due to BCR/ABL in hematopoietic cells by two different approaches. First, induction of BCR/ABL by a tetracycline-regulated promoter is associated with a reversible down-regulation of p27(Kip1). Second, inhibition of BCR/ABL kinase activity with the Abl tyrosine kinase inhibitor STI571 rapidly increases p27(Kip1) levels. The PI3K inhibitor LY-294002 blocks the ability of BCR/ABL to induce p27(Kip1) down-regulation and inhibits BCR/ ABL-induced entry into S phase. The serine/threonine kinase AKT/protein kinase B is a known downstream target of PI3K. Transient expression of an activated mutant of AKT was found to decrease expression of p27(Kip1), even when PI3K was inhibited by LY-294002. The mechanism of p27(Kip1) regulation is primarily related to protein stability, since inhibition of proteasome activity increased p27(Kip1) levels in BCR/ABL-transformed cells, whereas very little change in p27 transcription was found. Overall, these data are consistent with a model in which BCR/ABL suppresses p27(Kip1) protein levels through PI3K/AKT, leading to accelerated entry into S phase. This activity is likely to explain in part previous studies showing that activation of PI3K was required for optimum transformation of hematopoietic cells by BCR/ABL in vitro and in vivo.