Plk1 regulates liver tumor cell death by phosphorylation of TAp63
Plk1 regulates liver tumor cell death by phosphorylation of TAp63
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DOI：
10.1038/onc.2009.216
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发表时间：
2009-10-15
期刊：
影响因子：
8
通讯作者：
Kamijo, T.
中科院分区：
文献类型：
--
作者：
Komatsu, S.;Takenobu, H.;Kamijo, T.
我们以前发现Plk 1通过其直接磷酸化抑制p53/p73活性。在这项研究中，我们研究了Plk 1在调节p53家族成员TAp 63中的功能作用，从而控制肝肿瘤细胞的凋亡细胞死亡。免疫沉淀和体外pull-down实验表明，p63通过DNA结合区与Plk 1的激酶结构域结合。体外激酶活性测定表明，p63在反式激活（TA）结构域的Ser-52处被Plk 1磷酸化。Plk 1通过磷酸化降低TAp 63蛋白的稳定性，抑制TAp 63诱导的细胞死亡。此外，在p53突变的肝肿瘤细胞中Plk 1敲低反式激活p53家族下游效应物，p21（Cip 1/WAF 1）和14-3-3 sigma，并诱导凋亡性细胞死亡。Plk 1/p63的双重敲低减弱了Plk 1敲低诱导的凋亡性细胞死亡和反式激活。有趣的是，与非SP组分细胞相比，Plk 1和p63在肝肿瘤细胞的侧群（SP）组分中高度表达，表明Plk 1/TAp 63在肿瘤起始SP组分细胞中控制细胞死亡的重要性。因此，Plk 1通过磷酸化控制TAp 63，并调节肝肿瘤细胞的凋亡性细胞死亡。Plk 1/TAp 63有可能成为肝肿瘤治疗的分子靶点。Oncogene（2009）28，3631-3641; doi：10.1038/onc.2009.216; 2009年8月10日在线发表
We previously found that Plk1 inhibited the p53/p73 activity through its direct phosphorylation. In this study, we investigated the functional role of Plk1 in modulating the p53 family member TAp63, resulting in the control of apoptotic cell death in liver tumor cells. Immunoprecipitation and in vitro pull-down assay showed that p63 binds to the kinase domain of Plk1 through its DNA-binding region. in vitro kinase assay indicated that p63 is phosphorylated by Plk1 at Ser-52 of the transactivating (TA) domain. Plk1 decreased the protein stability of TAp63 by its phosphorylation and suppressed TAp63-induced cell death. Furthermore, Plk1 knockdown in p53-mutated liver tumor cells transactivated p53 family downstream effectors, PUMA, p21(Cip1/WAF1) and 14-3-3 sigma, and induced apoptotic cell death. Double knockdown of Plk1/p63 attenuated Plk1 knockdown-induced apoptotic cell death and transactivation. Intriguingly, both Plk1 and p63 are highly expressed in the side population (SP) fraction of liver tumor cells compared to non-SP fraction cells, suggesting the significance of Plk1/TAp63 in the control of cell death in tumor-initiating SP fraction cells. Thus, Plk1 controls TAp63 by its phosphorylation and regulates apoptotic cell death in liver tumor cells. Plk1/TAp63 may be a suitable candidate as a molecular target of liver tumor treatments. Oncogene (2009) 28, 3631-3641; doi: 10.1038/onc.2009.216; published online 10 August 2009