Androgen regulation of the cyclin-dependent kinase inhibitor p21 gene through an androgen response element in the proximal promoter.
Androgen regulation of the cyclin-dependent kinase inhibitor p21 gene through an androgen response element in the proximal promoter.
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DOI：
10.1210/mend.13.3.0254
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发表时间：
1999-03
影响因子：
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通讯作者：
S. Lu;Min Liu;Daniel E. Epner;S. Tsai;M. Tsai
中科院分区：
文献类型：
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作者：
S. Lu;Min Liu;Daniel E. Epner;S. Tsai;M. Tsai
雄激素对于生理上维持前列腺上皮细胞的完整性是必不可少的，而去势会导致细胞发生凋亡。为了研究雄激素依赖的细胞生长的分子机制，我们发现雄激素在mRNA和蛋白水平上上调细胞周期蛋白依赖性激酶抑制因子p21(WAF1、CIP1、SDI1、CAP20)基因的表达。核连续分析表明，雄激素在转录水平刺激内源性p21基因的表达。瞬时转基因实验表明，雄激素可以增强p21基因的2.4kb启动子的活性，该启动子与荧光素酶报告基因相连。这些结果表明，在2.4kb的启动子片段中包含一个可能的雄激素反应元件(ARE)，它介导雄激素反应以增强p21的转录。对该启动子的缺失分析表明，在p21基因启动子区域的-200bp处有一个功能性ARE(AGCACGCGAGGTTCC)。电泳迁移率改变分析进一步证明雄激素受体与该元件特异性结合。野生型ARE，但不是突变型ARE，赋予异源启动子雄激素反应性。雄激素对p21基因表达的上调提示，p21在前列腺上皮细胞中可能具有抗凋亡作用。然而，这一假设还需要在未来的实验中得到验证。
Androgen is essential for the physiological maintenance of the integrity of prostatic epithelial cells, and castration causes the cells to undergo apoptosis. To study the molecular mechanism of androgen-dependent cell growth, we showed that androgen up-regulates the expression of the cyclin-dependent kinase inhibitor p21 (WAF1, CIP1, SDI1, CAP20) gene at both the mRNA and protein levels. Nuclear run-on assays demonstrated that androgen stimulates endogenous p21 gene expression at the transcriptional level. Transient transfection experiments showed that androgen can enhance the activity of a 2.4-kb promoter of the p21 gene linked to a luciferase reporter. These results suggested that a putative androgen response element (ARE), which mediates androgen response to enhance the p21 transcription, is included in the 2.4-kb promoter fragment. Deletion analysis of the promoter revealed a functional ARE (AGCACGCGAGGTTCC) located at -200 bp of the p21 gene proximal to the promoter region. Electrophoretic mobility shift assay further demonstrated that the androgen receptor specifically binds to this element. Wild-type ARE, but not mutant ARE, confers androgen responsiveness to a heterologous promoter. The up-regulation of p21 gene expression by androgen suggests that p21 may have an antiapoptotic function in prostatic epithelial cells. However, this hypothesis will need to be tested in future experiments.