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首页> 外文期刊>Cellular Signalling >The extracellular-regulated protein kinase 5(ERK5)promotes cell proliferation through the down-regulation of inhibitors of cyclin dependent protein kinases(CDKs)
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The extracellular-regulated protein kinase 5(ERK5)promotes cell proliferation through the down-regulation of inhibitors of cyclin dependent protein kinases(CDKs)

机译：细胞外调节蛋白激酶5（ERK5）通过下调细胞周期蛋白依赖性蛋白激酶（CDKs）抑制剂促进细胞增殖

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摘要

Activation of the extracellular-regulated protein kinase 5(ERK5)has been associated with mitogenic signal transduction. However, conflicting findings have challenged the idea that ERK5 is a critical regulator of cell proliferation. We have addressed this issue by testing the effect of the conditional loss of ERK5 in primary fibroblasts. We have discovered that ERK5 suppressed the expression of the cyclin dependent protein kinase(CDKs)inhibitors, p21 and p27, by decreasing mRNA and protein stability, respectively. As a result, low level CDK2 activity detected in ERK5-deficient cells correlated with a defect in G1 to S phase transition of the cell cycle. Similarly, we found that the malignant MDA-MB-231 human breast cancer cell line was dependent on ERK5 to proliferate. We propose that ERK5 blocks p21 expression in MDA-MB-231 cells via a mechanism that implicates c-Myc-dependent transcriptional regulation of the miR-17-92 cluster. Together with evidence that cancer patients with poor prognosis display a high level of expression of components of the ERK5 signaling pathway, these findings support the hypothesis that ERK5 can be a potential target for cancer therapy.
机译：细胞外调节蛋白激酶5（ERK5）的激活与有丝分裂信号转导有关。然而，矛盾的发现挑战了ERK5是细胞增殖的关键调节剂的观点。我们已经通过测试有条件的ERK5在原代成纤维细胞中丢失的影响解决了这个问题。我们已经发现ERK5分别通过降低mRNA和蛋白质稳定性来抑制细胞周期蛋白依赖性蛋白激酶（CDKs）抑制剂p21和p27的表达。结果，在ERK5缺陷型细胞中检测到的低水平CDK2活性与细胞周期的G1至S相转变中的缺陷有关。同样，我们发现恶性MDA-MB-231人乳腺癌细胞系依赖于ERK5增殖。我们建议，ERK5通过牵连c-Myc依赖的miR-17-92簇转录调控机制来阻断MDA-MB-231细胞中的p21表达。连同预后不良的癌症患者显示ERK5信号通路的高水平表达的证据一起，这些发现支持了ERK5可能成为癌症治疗潜在靶点的假设。

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