KLF5 Promotes Breast Cell Survival Partially through Fibroblast Growth Factor-binding Protein 1-pERK-mediated Dual Specificity MKP-1 Protein Phosphorylation and Stabilization
KLF5 Promotes Breast Cell Survival Partially through Fibroblast Growth Factor-binding Protein 1-pERK-mediated Dual Specificity MKP-1 Protein Phosphorylation and Stabilization
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DOI：
10.1074/jbc.m808919200
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发表时间：
2009-06-19
影响因子：
4.8
通讯作者：
Chen, Ceshi
中科院分区：
文献类型：
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作者：
Liu, Rong;Zheng, Han-Qiu;Chen, Ceshi
Krupple样转录因子5（KLF 5）是一种锌指转录因子，在多种癌症中促进细胞存活和肿瘤发生。KLF 5的高表达水平已被证明与较短的乳腺癌患者生存期相关。然而，KLF 5在乳腺癌中的作用及其作用机制尚不清楚。在这项研究中，我们发现，KLF 5敲低小干扰RNA在两个乳腺细胞系，MCF 10A和BT 20，诱导凋亡。有趣的是，一种促存活磷酸酶，双特异性丝裂原活化蛋白激酶磷酸酶1（MKP-1），通过KLF 5消融下调。因此，KLF 5过表达增加了Hs 578 T和MCF 7中MKP-1蛋白的表达。我们进一步发现，MKP-1是KLF 5促进乳腺细胞存活所必需的。然而，MKP-1不是KLF 5直接转录靶点，因为MKP-1 mRNA水平不受KLF 5调节。通过放线菌酮追踪实验，我们发现KLF 5通过激活ERK信号通路减少MKP-1蛋白的降解。药理学抑制剂U 0126对pERK的抑制特异性阻断KLF 5诱导的MKP-1磷酸化和稳定化。此外，ERK的组成性激活的组成性激活MEK 1拯救KLF 5耗竭诱导的MKP-1下调。因此，磷酸化缺陷型MKP-1突变体不能被KLF 5稳定。最后，KLF 5激活ERK很可能是通过乳腺细胞中的KLF 5直接靶基因FGF-BP。这些发现表明，KLF 5是一种促生存因子，部分通过pERK介导的MKP-1磷酸化和稳定化促进乳腺细胞存活。KLF 5-FGF-BP-pERK-MKP-1信号轴可能为浸润性乳腺癌提供新的治疗靶点。
Krupple-like transcription factor 5 (KLF5) is a zinc-finger transcription factor promoting cell survival and tumorigenesis in multiple cancers. A high expression level of KLF5 has been shown to be associated with shorter breast cancer patient survival. However, the role of KLF5 and mechanism of KLF5 actions in breast cancer remain unclear. In this study, we found that KLF5 knockdown by small interfering RNA in two breast cell lines, MCF10A and BT20, induces apoptosis. Interestingly, a pro-survival phosphatase, dual specificity mitogen-activated protein kinase phosphatase 1 (MKP-1), is down-regulated by KLF5 ablation. Consistently, KLF5 overexpression increases the MKP-1 protein expression in Hs578T and MCF7. We further found that MKP-1 is essential and sufficient for KLF5 to promote breast cell survival. However, MKP-1 is not a KLF5 direct transcription target because the MKP-1 mRNA level is not regulated by KLF5. By cycloheximide chase assays, we found that KLF5 decreases MKP-1 protein degradation via activating the ERK signaling. Inhibition of pERK by the pharmacological inhibitor U0126 specifically blocks KLF5-induced MKP-1 phosphorylation and stabilization. Additionally, constitutive activation of ERK by constitutively activated MEK1 rescues the KLF5 depletion-induced MKP-1 down-regulation. Consistently, the phosphorylation-deficient MKP-1 mutant cannot be stabilized by KLF5. Finally, the activation of ERK by KLF5 is very likely through the KLF5 direct target gene FGF-BP in breast cells. These findings suggest that KLF5 is a pro-survival factor that promotes breast cell survival partially through pERK-mediated MKP-1 phosphorylation and stabilization. The KLF5-FGF-BP-pERK-MKP-1 signaling axis may provide new therapeutic targets for invasive breast cancer.