p53-independent induction of p21 (WAF1/CIP1), reduction of cyclin B1 and G2/M arrest by the isoflavone genistein in human prostate carcinoma cells
p53-independent induction of p21 (WAF1/CIP1), reduction of cyclin B1 and G2/M arrest by the isoflavone genistein in human prostate carcinoma cells
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DOI：
10.1111/j.1349-7006.2000.tb00928.x
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发表时间：
2000-02-01
期刊：
影响因子：
--
通讯作者：
Zhang, LJ
中科院分区：
文献类型：
--
作者：
Choi, YH;Lee, WH;Zhang, LJ
染料木素。是一种天然的类异黄酮植物雌激素，是蛋白质酪氨酸激酶和DNA拓扑异构酶II活性的强抑制剂。染料木素已被证明具有抗癌增殖、分化和化学预防作用。在本研究中，我们探讨了染料木素抑制p53缺失的人前列腺癌细胞增殖的作用机制。染料木素对细胞生长增殖的抑制作用与细胞周期进程中的G2/M阻滞有关，同时显著抑制细胞周期蛋白B1和诱导Cdk抑制剂p21 （WAFI/CIP1）以p53不依赖的方式表达。在染料木素处理细胞后，p21与Cdk2和Cdc2结合增加，Cdc2和Cdk2激酶活性显著降低，而Cdk2和Cdc2的表达没有变化。染料木黄酮还诱导了p21启动子报告结构的激活，利用了与p53结合位点不同的序列。对p21启动子缺失结构的分析表明，对染料木黄酮的反应可能定位于转录起始位点附近的300个碱基对。这些数据表明染料木素可能具有很强的抗癌作用，这种作用可能与诱导p21有关，p21抑制Cdks和相关细胞周期蛋白的阈值激酶活性，导致细胞周期进程中的G2/M阻滞。
Genistein. a natural isoflavonoid phytoestrogen, is a strong inhibitor of protein tyrosine kinase and DNA topoisomerase II activities. Genistein has been shown to have anticancer proliferation, differentiation and chemopreventive effects. In the present study, we have addressed the mechanism of action by which genistein suppressed the proliferation of p53-null human prostate carcinoma cells. Genistein significantly inhibited the cell growth, which effect was reversible, and induced dendrite-like structure, The inhibitory effects of genistein on cell growth proliferation were associated with a G2/M arrest in cell cycle progression concomitant with a marked inhibition of cyclin B1 and an induction of Cdk inhibitor p21 (WAFI/CIP1) in a p53-independent manner. Following genistein treatment of cells, an increased binding of p21 with Cdk2 and Cdc2 paralleled a significant decrease in Cdc2 and Cdk2 kinase activity with no change in Cdk2 and Cdc2 expression. Genistein also induced the activation of a p21 promoter reporter construct, utilizing a sequence distinct from the p53-binding site, Analysis of deletion constructs of the p21 promoter indicated that the response to genistein could be localized to the 300 base pairs proximal to the transcription start site. These data suggest that genistein may exert a strong anticarcinogenic effect, and that this effect possibly involves an induction of p21, which inhibits the threshold kinase activities of Cdks and associated cyclins, leading to a G2/M arrest in the cell cycle progression.