Distinct signaling pathways mediate stimulation of cell cycle progression and prevention of apoptotic cell death by estrogen in rat pituitary tumor PR1 cells
Distinct signaling pathways mediate stimulation of cell cycle progression and prevention of apoptotic cell death by estrogen in rat pituitary tumor PR1 cells
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DOI：
10.1091/mbc.e03-05-0303
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发表时间：
2003-12-01
影响因子：
3.3
通讯作者：
Weisz, A
中科院分区：
文献类型：
--
作者：
Caporali, S;Imai, M;Weisz, A
雌激素通过基因组和基因组外途径的相互作用控制靶细胞的生长和活力，尚未阐明。在这里，我们表明，在大鼠垂体瘤PR 1细胞的细胞增殖和生存的差异调节雌激素的证据。皮科至飞摩尔浓度的17 β-雌二醇（E2）足以促进PR 1细胞增殖，而需要纳摩尔浓度的17 β-雌二醇（E2）来防止在不存在激素的情况下在这些细胞中以高速率发生的细胞死亡。内源性（PRL）或转染的雌激素反应基因的激活发生在相同的，更高浓度的E2需要促进细胞存活，而刺激细胞周期蛋白D3的表达和DNA合成发生在较低的E2浓度。类似地，纯抗雌激素ICI 182，780抑制雌激素反应元件依赖性反式激活和细胞死亡比细胞周期蛋白-cdk活性、G（1）-S转换或DNA合成速率更有效。在抗雌激素处理和/或雌激素剥夺的细胞中，死亡主要是由于细胞凋亡。雌激素诱导的细胞存活，而不是E2依赖的细胞周期进程，可以通过c-Src激酶抑制剂或通过阻断丝裂原活化蛋白激酶激酶/细胞外信号调节激酶信号通路来阻止。这些数据表明，两个可区分的雌激素信号通路在PR 1细胞中共存，其特征在于不同的功能和对激素和抗激素的敏感性。
Estrogens control cell growth and viability in target cells via an interplay of genomic and extragenomic pathways not yet elucidated. Here, we show evidence that cell proliferation and survival are differentially regulated by estrogen in rat pituitary tumor PR1 cells. Pico- to femtomolar concentrations of 17beta-estradiol (E2) are sufficient to foster PR1 cell proliferation, whereas nanomolar concentrations of the same are needed to prevent cell death that occurs at a high rate in these cells in the absence of hormone. Activation of endogenous (PRL) or transfected estrogen-responsive genes occurs at the same, higher concentrations of E2 required to promote cell survival, whereas stimulation of cyclin D3 expression and DNA synthesis occur at lower E2 concentrations. Similarly, the pure antiestrogen ICI 182,780 inhibits estrogen response element-dependent trans-activation and cell death more effectively than cyclin-cdk activity, G(1)-S transition, or DNA synthesis rate. In antiestrogen-treated and/or estrogen-deprived cells, death is due predominantly to apoptosis. Estrogen-induced cell survival, but not E2-dependent cell cycle progression, can be prevented by an inhibitor of c-Src kinase or by blockade of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase signaling pathway. These data indicate the coexistence of two distinguishable estrogen signaling pathways in PR1 cells, characterized by different functions and sensitivity to hormones and antihormones.