Bombesin regulates cyclin D1 expression through the early growth response protein Egr-1 in prostate cancer cells.
Bombesin regulates cyclin D1 expression through the early growth response protein Egr-1 in prostate cancer cells.
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DOI：
10.1158/0008-5472.can-05-1830
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发表时间：
2005-11
期刊：
影响因子：
11.2
通讯作者：
D. Xiao;D. Chinnappan;R. Pestell;C. Albanese;H. Weber
中科院分区：
文献类型：
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作者：
D. Xiao;D. Chinnappan;R. Pestell;C. Albanese;H. Weber
我们之前的研究表明丝裂原激活蛋白激酶（MAPK）通路的激活参与了铃蟾肽诱导的前列腺癌细胞增殖。 Cyclin D1 是参与细胞周期从 G1 期进入 S 期的关键调节因子，从而有助于细胞增殖。大多数情况下，有丝分裂原刺激的细胞周期蛋白 D1 表达归因于细胞外信号调节激酶 (ERK) 激活。在这里，我们发现铃蟾肽诱导 DU-145 前列腺癌细胞中 mRNA 和蛋白质水平上的人细胞周期蛋白 D1 表达。突变分析表明，铃蟾肽增强的细胞周期蛋白 D1 转录需要核蛋白与人细胞周期蛋白 D1 启动子的 -143 至 -105 区域结合，该区域包含转录因子 Sp-1 和早期生长反应蛋白 (Egr-1) 的结合位点。 Do novo 蛋白质合成是铃蟾肽诱导的细胞周期蛋白 D1 表达所必需的。进一步的研究表明 Egr-1 在铃蟾肽刺激下被诱导。 Egr-1 表达的诱导及其与细胞周期蛋白 D1 启动子的结合对于铃蟾肽增强的细胞周期蛋白 D1 转录至关重要。使用 MEK1 抑制剂 PD98059 或显性失活 Ras 突变体 RasN17 抑制 MAPK 通路，消除了铃蟾肽诱导的细胞周期蛋白 D1 激活。综上所述，铃蟾肽诱导的前列腺癌细胞中的 cyclin D1 表达是通过 Egr-1 激活以及 Egr-1 通过 MAPK 途径激活与 cyclin D1 启动子的 Egr-1/Sp1 基序相互作用介导的。这些发现代表了一种通过直接调节前列腺癌细胞周期来依赖铃蟾肽刺激有丝分裂的新机制。
Our previous studies indicate that the activation of mitogen-activated protein kinase (MAPK) pathway is involved in bombesin-induced cell proliferation in prostate cancer cells. Cyclin D1 is a critical regulator involved in cell cycle progression through the G1 phase into the S phase, thereby contributing to cell proliferation. Mostly, mitogen-stimulated expression of cyclin D1 is attributed to the extracellular signal-regulated kinase (ERK) activation. Here, we found that bombesin induced human cyclin D1 expression on both mRNA and protein levels in DU-145 prostate cancer cells. Mutational analyses showed that bombesin-enhanced cyclin D1 transcription required the binding of nuclear proteins to the -143 to -105 region of the human cyclin D1 promoter, which contains binding sites for transcription factors Sp-1 and early growth response protein (Egr-1). Do novo protein synthesis was requisite for bombesin-induced cyclin D1 expression. Further studies showed Egr-1 was induced upon bombesin stimulation. The induction of Egr-1 expression and its binding to the cyclin D1 promoter were essential for bombesin-enhanced cyclin D1 transcription. Inhibition of MAPK pathway with either the MEK1 inhibitor PD98059 or a dominant-negative Ras mutant, RasN17, abolished bombesin-induced cyclin D1 activation. Taken together, bombesin-induced cyclin D1 expression in prostate cancer cells is mediated by Egr-1 activation and the interaction of Egr-1 with the Egr-1/Sp1 motif of the cyclin D1 promoter through the activation of MAPK pathway. These findings represent a novel mechanism of bombesin-dependent stimulation of mitogenesis by regulating directly the cell cycle in prostate cancer.