PRL activates the cyclin D1 promoter via the Jak2/Stat pathway.
PRL activates the cyclin D1 promoter via the Jak2/Stat pathway.
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DOI：
10.1210/mend.16.4.0817
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发表时间：
2002-04
影响因子：
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通讯作者：
J. L. Brockman;M. Schroeder;L. Schuler
中科院分区：
文献类型：
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作者：
J. L. Brockman;M. Schroeder;L. Schuler
PRL促进乳腺细胞的生长和分化，这对乳腺癌和正常发育都有影响。我们的数据表明，PRL显着增加乳腺癌细胞的增殖。PRL也增加细胞周期蛋白D1水平的2倍，这可以被放线菌素D抑制，表明细胞周期蛋白D1的转录增加是重要的。使用一个定义的中国仓鼠卵巢细胞模型系统，我们证明，PRL治疗后的细胞周期蛋白D1启动子-荧光素酶结构的活性增加。此外，这种启动子活性的增加主要由Jak 2/Stat 5信号通路介导。细胞周期蛋白D1启动子包含两个PRL诱导的Stat结合（GAS位点）的共有序列。Stat与远端GAS位点结合的破坏破坏了PRL诱导的启动子活性，而近端位点的破坏则没有影响。我们已经通过EMSA表明，PRL诱导Stat 5a和5 b结合到远端GAS位点，并且免疫沉淀和随后的PRL处理细胞的核提取物的Western分析表明，Stat 5a和5 b可以在该系统中作为异二聚体相互作用。这些数据表明，细胞周期蛋白D1可能是一个目标基因PRL在正常的小叶肺泡发育，以及在乳腺癌的发展和/或进展。
PRL promotes cell growth and differentiation in the mammary gland, which has implications for breast cancer as well as normal development. Our data demonstrate that PRL significantly increases proliferation of mammary carcinoma cells. PRL also increases cyclin D1 levels 2-fold, which can be inhibited by actinomycin D, suggesting that transcriptional increases in cyclin D1 are important. Using a defined Chinese hamster ovary cell model system, we demonstrate that the activity of a cyclin D1 promoter-luciferase construct increases after PRL treatment. Furthermore, this increase in promoter activity is predominantly mediated by the Jak2/Stat5 signaling pathway. The cyclin D1 promoter contains two consensus sequences for PRL-induced Stat binding (GAS sites). Disruption of Stat binding to the distal GAS site destroys PRL-induced promoter activity, whereas disruption of the proximal site has no effect. We have shown by EMSA that PRL induces Stat5a and 5b to bind to the distal GAS site, and immunoprecipitation and subsequent Western analysis of nuclear extracts from PRL-treated cells indicate that Stat5a and 5b can interact as a heterodimer in this system. These data suggest that cyclin D1 may be a target gene for PRL in normal lobuloalveolar development, as well as in the development and/or progression of mammary cancer.