Up-regulation of circadian clock gene Period 2 in the prostate mesenchymal cells during flutamide-induced apoptosis
Up-regulation of circadian clock gene Period 2 in the prostate mesenchymal cells during flutamide-induced apoptosis
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DOI：
10.1007/s11010-009-0238-7
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发表时间：
2010-02
影响因子：
4.3
通讯作者：
Kaoru Yoshida;Pei-jian He;N. Yamauchi;S. Hashimoto;M. Hattori
中科院分区：
文献类型：
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作者：
Kaoru Yoshida;Pei-jian He;N. Yamauchi;S. Hashimoto;M. Hattori
雄激素调节前列腺的正常发育和生理功能。在这里，我们研究了雄激素和雄激素受体（AR）拮抗剂对大鼠前列腺间充质细胞（PMCs）的时钟核心基因周期2（Per 2）的昼夜节律振荡的调制。用基因表达实时监测系统分析了昼夜节律振荡，使用转基因大鼠与mousePer 2启动子融合的不稳定的荧光素酶（Per 2-dLuc）报告基因。昼夜节律振荡，免疫荧光和雄激素反应元件（ARE）-荧光素酶报告基因分析表明，昼夜节律钟是可操作的，AR蛋白是在体外PMC的功能。雄激素如睾酮（T）和双氢睾酮（DHT）对融合细胞的Per 2-dLuc 1昼夜节律振荡没有任何影响。FL处理后，PER 2蛋白在细胞核和细胞质中均有明显的积累，并在Per 2-dLucoscillations的第一个高峰期定位于细胞核和细胞质。同时，FL处理增加凋亡细胞死亡。总的来说，本研究表明，一个时钟基因Per 2是上调PMC在FL诱导的凋亡细胞死亡。因此，Per 2基因表达的昼夜节律振荡可能与PMC的细胞状态如凋亡性细胞死亡密切相关。
Androgen regulates the proper development and physiological function of the prostate. Here, we investigated the modulation of androgen and androgen receptor (AR) antagonist on circadian oscillations of a clock core genePeriod 2(Per2) in rat prostate mesenchymal cells (PMCs). Circadian oscillations were analyzed with the real-time monitoring system of gene expression using transgenic rats introduced with mousePer2promoter fused to a destabilized luciferase (Per2-dLuc) reporter gene. Analyses of circadian oscillations, immunofluorescence, and androgen response element (ARE)-luciferase reporter assay revealed that circadian clocks are operative and the AR protein is functional in PMCs in vitro. Androgen such as testosterone (T) and dihydrotestosterone (DHT) did not cause any changes in circadianPer2-dLucoscillations of confluent cells. Conversely, flutamide (FL) up-regulated the amplitude of circadianPer2-dLucoscillations in a dose-dependent manner, whereas T antagonized the action of FL. The PER2 protein was markedly accumulated by FL treatment and localized in both the nucleus and cytoplasm during the first peak period of circadianPer2-dLucoscillations. Simultaneously, FL treatment increased apoptotic cell death. Collectively, the present study demonstrates that a clock genePer2is up-regulated in PMCs during FL-induced apoptotic cell death. Thus, circadian oscillations of Per2 gene expression may be closely linked to the cellular states of PMCs such as apoptotic cell death.