Retinoic acid-mediated G1 arrest is associated with induction of p27Kip1 and inhibition of cyclin-dependent kinase 3 in human lung squamous carcinoma CH27 cells
Retinoic acid-mediated G1 arrest is associated with induction of p27Kip1 and inhibition of cyclin-dependent kinase 3 in human lung squamous carcinoma CH27 cells
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DOI：
10.1006/excr.2000.4933
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发表时间：
2000-08-01
影响因子：
3.7
通讯作者：
Chang, CD
中科院分区：
文献类型：
--
作者：
Hsu, SL;Hsu, JW;Chang, CD
类维生素a是预防和治疗包括肺癌在内的几种人类恶性肿瘤的有前途的药物。本研究探讨了维甲酸（RA）对人肺鳞癌CH27细胞生长的影响及其调控机制。在这里，我们报道了RA介导G1期剂量和时间依赖性生长停滞，伴随着p27（Kip1）的上调和周期蛋白依赖性激酶3 （Cdk3）和p21（CIP1/Waf1）蛋白的下调。此外，ra诱导的CH27细胞生长停滞还与视黄酸受体β (RAR β)增加和c-Myc表达减少有关。然而，RA对CH27细胞中细胞周期蛋白A、D1、D3、E或H的水平没有影响，也没有影响Cdk2、Cdk4、Cdk5、CDk6、Cdk7、p16（Ink4A）、p15（Ink4B）、p53或pRb蛋白的水平。cyclin- cdk复合物的激酶活性评估显示，RA增加了CH27细胞中p27（Kip1）的表达，导致cyclin A/Cdk2激酶活性显著降低，cyclin E/Cdk2激酶活性略有降低，而对cyclin D/Cdk4和cyclin D/Cdk6活性无影响。此外，与激酶活性降低相一致的是细胞周期蛋白a结合的p27（Kip1）的急剧增加。这些结果表明，p27（Kip1）水平的增加及其与细胞周期蛋白A的结合，以及Cdk3蛋白表达的减少，是细胞周期调节剂的强有力的候选物，该调节剂可以阻止ha处理的CH27细胞进入S期，延长G1期并抑制DNA合成。(C) 2000年学术出版社。
Retinoids are promising agents for the prevention and treatment of several human malignancies including lung cancer. In this study, the effect of retinoic acid (RA) on cell growth and the mechanism of growth modulation were examined in human lung squamous carcinoma CH27 cells. Here we report that RA mediated the dose-and time dependent growth arrest in G1 phase, accompanied by the up-regulation of p27(Kip1) and the downregulation of the cyclin-dependent kinase 3 (Cdk3) and p21(CIP1/Waf1) proteins. Furthermore, RA-induced growth arrest of CH27 cells was also associated with increased retinoic acid receptor beta (RAR beta) and reduced c-Myc expression. However, RA had no effect on the levels of cyclins A, D1, D3, E, or H, or on Cdk2, Cdk4, Cdk5, CDk6, Cdk7, p16(Ink4A), p15(Ink4B), p53, or pRb proteins in CH27 cells. Evaluation of the kinase activity of cyclin-Cdk complexes showed that RA increases p27(Kip1) expression in CH27 cells leading to markedly reduced cyclin A/Cdk2 kinase activity and slightly reduced cyclin E/Cdk2 kinase activity, with no effect on cyclin D/Cdk4 and cyclin D/Cdk6 activities. Moreover, coincident with the decrease in kinase activity was a drastic increase in cyclin A-bound p27(Kip1). These results suggest that increases in the levels of p27(Kip1) and its binding to cyclin A, as well as reduction of Cdk3 protein expression, are strong candidates for the cell cycle regulator that prevents the entry into the S phase in HA-treated CH27 cells, with prolongation of G1 phase and inhibition of DNA synthesis. (C) 2000 Academic Press.