CDK2 is a target for retinoic acid-mediated growth inhibition in MCF-7 human breast cancer cells.
CDK2 is a target for retinoic acid-mediated growth inhibition in MCF-7 human breast cancer cells.
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DOI：
10.1210/mend.11.9.9977
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发表时间：
1997-08
影响因子：
--
通讯作者：
C. Teixeira;M. A. Christine Pratt
中科院分区：
文献类型：
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作者：
C. Teixeira;M. A. Christine Pratt
维甲酸（RA）对乳腺癌细胞生长的抑制作用与细胞周期G1期的细胞积累有关。我们研究了RA对MCF-7人乳腺癌细胞中细胞周期调节蛋白表达和活性的影响。流式细胞术分析显示，RA处理的MCF-7细胞在48 h时处于S期的细胞百分比下降，在72 h时最大。RA处理的细胞中视网膜母细胞瘤蛋白（pRb）的磷酸化部分降低，同时视网膜母细胞瘤蛋白水平下降。细胞周期蛋白D1转录物的表达在48小时后降低，细胞周期蛋白依赖性激酶2 (cdk2) mRNA水平在处理后8小时内下降，随后细胞周期蛋白D1和cdk2蛋白水平下降。RA不影响cdk4和cdc2的信息和蛋白水平。虽然cdk4活性在对照和RA处理的细胞中相似，但cdk2活性在暴露于RA的48小时内开始下降，并在72小时后急剧下降。这种降低的活性与cdk2磷酸化降低有关。cdk2活性的降低发生在ra介导的cdk抑制剂p21和p27水平升高的情况下。然而，从ra处理的细胞和对照细胞的混合裂解物中检测cdk2显示，ra处理的细胞具有cdk2抑制活性。我们的研究结果表明，RA通过抑制cdk2 mRNA和蛋白的产生以及降低cdk2活性来抑制MCF-7细胞的细胞周期进程。
Retinoic acid (RA) inhibition of breast cancer cell growth is associated with an accumulation of cells in G1 phase of the cell cycle. We have investigated the effects of RA on the expression and activity of cell cycle-regulatory proteins in MCF-7 human breast cancer cells. Flow cytometry analysis of MCF-7 cells treated with RA revealed a decrease in the percentage of cells in S phase by 48 h, which was maximal by 72 h. Phosphorylation of the retinoblastoma protein (pRb) was partially reduced in RA-treated cells accompanied by a decrease in the level of retinoblastoma protein. Expression of the cyclin D1 transcript was reduced by 48 h and cyclin-dependent kinase 2 (cdk2) mRNA levels declined within 8 h posttreatment followed by a decrease in cyclin D1 and cdk2 protein levels. Message and protein levels of cdk4 and cdc2 were not affected by RA. While cdk4 activity was similar in control and RA-treated cells, cdk2 activity began to decrease within 48 h of exposure to RA and was profoundly reduced after 72 h. This reduced activity was associated with decreased phosphorylation of cdk2. The decrease in cdk2 activity occurred in the absence of RA-mediated increases in the levels of the cdk inhibitors p21 and p27. However, assays of cdk2 from pooled lysates from RA-treated and control cells showed that RA-treated cells contain a cdk2-inhibitory activity. Our results show that RA inhibits cell cycle progression of MCF-7 cells by inhibiting cdk2 mRNA and protein production and by decreasing cdk2 activity.