E2F activity is biphasically regulated by androgens in LNCaP cells
E2F activity is biphasically regulated by androgens in LNCaP cells
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DOI：
10.1006/bbrc.2001.4738
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发表时间：
2001-04-27
影响因子：
3.1
通讯作者：
Heyns, W
中科院分区：
文献类型：
--
作者：
Hofman, K;Swinnen, JV;Heyns, W
雄激素对LNCaP细胞的增殖产生独特的双相剂量依赖性影响，LNCaP细胞是研究雄激素对前列腺癌细胞影响的广泛使用的模型。低浓度的雄激素刺激增殖，但高浓度抑制增殖并诱导分化标志物的强表达。为了更深入地了解这些变化背后的分子机制，我们研究了宽浓度范围的合成雄激素R1881对几个细胞周期和分化相关参数的影响。已知可促进LNCaP细胞增殖的低浓度（0.1 nM）可诱导视网膜母细胞瘤蛋白磷酸化增加，同时伴有E2 F-1蛋白水平和E2 F活性增加以及E2 F靶基因产物E2 F-1和细胞周期蛋白A表达增加。高浓度的R1881（10 nM）诱导分化标志物前列腺特异性抗原的强烈表达。视网膜母细胞瘤蛋白大量低磷酸化，导致低E2 F活性和低浓度的E2 F-1和细胞周期蛋白A mRNA。最后，p27（Kip 1）蛋白质强烈增加，但p27（Kip 1）mRNA没有增加。这些结果表明LNCaP增殖对雄激素的双相剂量反应密切反映在Rb磷酸化、E2 F活性和p27（Kip 1）蛋白表达中。(C)北京：科学出版社.
Androgens exert a peculiar biphasic dose-dependent influence on the proliferation of LNCaP cells, a widely used model to study androgen effects on prostate cancer cells. Low concentrations of androgen stimulate proliferation, but high concentrations inhibit proliferation and induce strong expression of differentiation markers. In order to gain more insight into the molecular mechanisms that underlie these changes we studied the influence of a wide concentration range of the synthetic androgen R1881 on several cell cycle- and differentiation-related parameters. Low concentrations (0.1 nM), known to promote LNCaP cell proliferation, induce an increase of Retinoblastoma protein phosphorylation, accompanied by an increase of E2F-1 protein levels and E2F activity and by increased expression of the E2F-target gene products E2F-1 and cyclin A. High concentrations of R1881 (10 nM) induce strong expression of the differentiation marker prostate-specific antigen. Retinoblastoma protein is largely hypophosphorylated, resulting in low E2F activity and low concentrations of E2F-1 and cyclin A mRNA. Finally, there is a strong increase of p27(Kip1) protein, but not of p27(Kip1) mRNA. These results indicate that the biphasic dose response of LNCaP proliferation to androgen is closely reflected in Rb phosphorylation, E2F activity and p27(Kip1) protein expression. (C) 2001 Academic Press.