Cdc37 enhances proliferation and is necessary for normal human prostate epithelial cell survival.
Cdc37 enhances proliferation and is necessary for normal human prostate epithelial cell survival.
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发表时间：
2003-08
期刊：
影响因子：
11.2
通讯作者：
S. Schwarze;Vivian X. Fu;D. Jarrard
中科院分区：
文献类型：
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作者：
S. Schwarze;Vivian X. Fu;D. Jarrard
Cdc37 是一种共伴侣蛋白，它将几种未成熟的客户激酶招募到 Hsp90 中以进行正确折叠。 Cdc37 上调是局部人类前列腺癌中常见的早期事件。尽管小鼠体内的靶向过度表达会导致前列腺上皮细胞增生，但 Cdc37 失调对人类前列腺细胞的影响尚不清楚。在这项研究中，我们使用独特的人类模型系统检查了 Cdc37 在正常前列腺上皮细胞生长调节中的作用。我们证明 Cdc37 过度表达会促进增殖，而 Cdc37 功能的丧失会抑制生长并导致细胞凋亡。随着 Cdc37 表达的增加，Cdc37 客户通路的分子分析表明 Raf-1 活性增强、Cdk4 水平升高以及细胞周期蛋白依赖性激酶抑制剂 p16/CDKN2 的表达减少。为了进一步研究这些下游途径，在人前列腺上皮细胞中选择性诱导 Raf-1 或 Cdk4 活性增强。 Raf-1 激活抑制增殖并产生扩大、扁平的形态。然而，使用细胞周期蛋白 D1 过表达诱导 Cdk4 活性足以促进增殖。这些数据表明 Cdc37 诱导增殖并且对于人类前列腺上皮细胞的存活至关重要。细胞分裂和存活的这些改变可能对早期前列腺癌的发生和进展很重要。
Cdc37 is a co-chaperone protein that recruits several immature client kinases to Hsp90 for proper folding. Cdc37 up-regulation is a common early event in localized human prostate cancer. Although targeted overexpression in mice leads to prostate epithelial cell hyperplasia, the effect of Cdc37 dysregulation in human prostate cells is unclear. In this study, we examine the role of Cdc37 in the growth regulation of normal prostate epithelial cells using a unique human model system. We demonstrate that Cdc37 overexpression drives proliferation, whereas loss of Cdc37 function arrests growth and leads to apoptosis. With increased Cdc37 expression, molecular analysis of Cdc37 client pathways demonstrates enhanced Raf-1 activity, greater Cdk4 levels, and reduced expression of the cyclin-dependent kinase inhibitor p16/CDKN2. To further investigate these downstream pathways, enhanced Raf-1 or Cdk4 activities were selectively induced in human prostate epithelial cells. Raf-1 activation inhibited proliferation and generated an enlarged, flattened morphology. Induction of Cdk4 activity using cyclin D1 overexpression, however, was sufficient to promote proliferation. These data indicate that Cdc37 induces proliferation and is critical for survival in human prostate epithelial cells. These alterations in cell division and survival may be important in the development and progression of early prostate cancer.