The role of Cdc25B in lung cancer progression

鉴于生长因子在启动和维持细胞增殖中的重要性，我们研究了它们对人癌细胞CDC25B蛋白表达的影响。在表皮生长因子或转化生长因子-α作用后1h内，肺癌细胞株A549细胞中CDC25B蛋白水平升高。CDC25B升高的一个功能后果是伴随着磷酸化的细胞周期蛋白依赖性激酶的降低。此外，EGFR受体选择性酪氨酸激酶抑制剂AG1478和丝裂原激活的激酶抑制剂U0126可阻断生长因子介导的CDc25B诱导。因此，表皮生长因子和转化生长因子-α似乎通过丝裂原活化蛋白激酶途径诱导细胞CDC25B。此外，CDC25B是雌激素受体(ER)的共同激活剂。由于内质网和生长因子信号通路之间存在潜在的相互作用，我们研究了β1对cdc25B表达和cdc25B-ERα相互作用的影响。HEG-β1诱导表达HER2/neu的A549细胞中的CDc25B蛋白水平，这种诱导作用可被HER2/neu酪氨酸激酶抑制剂AG879和β抑制剂U0126阻断。HEG-β1诱导无雌激素培养的乳腺癌细胞系MCF7细胞CDC25B-ERα相互作用呈浓度和时间依赖性增加。CDC25B-ERα相互作用的增强也可被AG879和U0126所阻断。因此，在激素剥夺条件下，HEG-β1诱导CDC25B的表达和ERα的共激活需要一个有活性的丝裂原活化蛋白激酶途径。

Given the importance of growth factors in initiating and sustaining cell proliferation, we examined their effects on Cdc25B protein expression inhuman cancer cells. Within 1h after epidermal growth factor(EGF) or transforming growth factor-α(TGF-α) treatment, Cdc25B protein levels increased in lung cancer cell line A549 cells. A functional consequence of elevated Cdc25B was implied by the concomitant decrease in phosphorylated cyclin dependent kinase. Moreover, the EGFR receptor-selective tyrosine kinase inhibitor AG1478 and mitogen activated kinase kinase inhibitor U0126 blocked growth factor-mediated Cdc25B induction. Thus, EGF and TGF-αappear to induce cellular Cdc25B through the mitogen-activated protein kinase pathway. Further, Cdc25B is a co-activator for the estrogen receptor(ER). Because of potential cross talk between the ER and growth factor signaling pathways, we examined the effects of heregulin (HEG)-β1 on Cdc25B expression and Cdc25B-ERα interactions. HEG-β1 induced Cdc25B protein levels in Her2/neu-expressing A549 cells and this Cdc25B induction by HEG-β1 was blocked by the HER2/neu tyrosine kinase inhibitor AG879 and the MEK inhibitor U0126. HEG-β1 caused a concentration-and time-dependent increase in Cdc25B-ERα interactions in breast cancer cell line MCF-7 cells grown in estrogenic substance-free medium. The increased Cdc25B-ERα interaction after HEG-β1 was also blocked by AG879 and U0126. Thus, HEG-β1 induction of Cdc25B expression and ERα co-activation under hormone deprivation require a competent mitogen-activated protein kinase pathway.