Silencing of the novel p53 target gene Snk/Plk2 leads to mitotic catastrophe in paclitaxel (Taxol)-exposed cells
Silencing of the novel p53 target gene Snk/Plk2 leads to mitotic catastrophe in paclitaxel (Taxol)-exposed cells
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DOI：
10.1128/mcb.23.16.5556-5571.2003
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发表时间：
2003-08-01
影响因子：
5.3
通讯作者：
El-Deiry, WS
中科院分区：
文献类型：
--
作者：
Burns, TF;Fei, PW;El-Deiry, WS
p53的缺失使人肿瘤细胞对抗微管药物敏感，但对其在有丝分裂中的作用知之甚少。我们已经确定了Polo样激酶家族成员血清诱导激酶（Snk/Plk 2）作为一种新的p53靶基因。Snk/Plk 2突变表明其激酶活性受其C末端负调控。小干扰RNA（siRNA）介导的Snk/Plk 2沉默在有丝分裂毒药紫杉醇（紫杉醇）或诺考达唑的存在下显着增加细胞凋亡，类似于p53突变，赋予紫杉醇敏感性。此外，我们已经证明，由于沉默的Snk/Plk 2在面对纺锤体损伤的细胞凋亡发生在有丝分裂细胞，而不是在细胞已经发展到G（1）样状态没有分裂。由于针对Snk/Plk 2的siRNA促进了有丝分裂中紫杉醇处理的细胞的死亡，我们设想了一个有丝分裂检查点，其中Snk/Plk 2的p53依赖性激活防止了纺锤体损伤后的有丝分裂灾难。最后，这些研究表明，Snk/Plk 2的破坏可能在致敏紫杉醇耐药肿瘤中具有治疗价值。
Loss of p53 sensitizes to antimicrotubule agents in human tumor cells, but little is known about its role during mitosis. We have identified the Polo-like kinase family member serum inducible kinase (Snk/Plk2) as a novel p53 target gene. Snk/Plk2 mutagenesis demonstrated that its kinase activity is negatively regulated by its C terminus. Small interfering RNA (siRNA) -mediated Snk/Plk2 silencing in the presence of the mitotic poisons paclitaxel (Taxol) or nocodazole significantly increased apoptosis, similar to p53 mutations, which confer paclitaxel sensitivity. Furthermore, we have demonstrated that the apoptosis due to silencing of Snk/Plk2 in the face of spindle damage occurs in mitotic cells and not in cells that have progressed to a G(1)-like state without dividing. Since siRNA directed against Snk/Plk2 promoted death of paclitaxel-treated cells in mitosis, we envision a mitotic checkpoint wherein p53-dependent activation of Snk/Plk2 prevents mitotic catastrophe following spindle damage. Finally, these studies suggest that disruption of Snk/Plk2 may be of therapeutic value in sensitizing paclitaxel-resistant tumors.