Burns Timothy F, Fei Peiwen, Scata Kimberly A, Dicker David T, El-Deiry Wafik S
Laboratory of Molecular Oncology and Cell Cycle Regulation, Howard Hughes Medical Institute, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Mol Cell Biol. 2003 Aug;23(16):5556-71. doi: 10.1128/MCB.23.16.5556-5571.2003.
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.
在人类肿瘤细胞中，p53缺失会使其对抗微管药物敏感，但人们对其在有丝分裂过程中的作用却知之甚少。我们已将Polo样激酶家族成员血清诱导激酶（Snk/Plk2）鉴定为一种新的p53靶基因。Snk/Plk2诱变表明，其激酶活性受其C末端负调控。在有丝分裂毒物紫杉醇（泰素）或诺考达唑存在的情况下，通过小干扰RNA（siRNA）介导使Snk/Plk2沉默，显著增加了细胞凋亡，这与赋予紫杉醇敏感性的p53突变类似。此外，我们已证明，面对纺锤体损伤时，因Snk/Plk2沉默导致的细胞凋亡发生在有丝分裂细胞中，而非进展到类似G1期但未分裂的细胞中。由于针对Snk/Plk2的siRNA促进了紫杉醇处理的有丝分裂细胞的死亡，我们设想存在一个有丝分裂检查点，其中p53依赖的Snk/Plk2激活可防止纺锤体损伤后发生有丝分裂灾难。最后，这些研究表明，破坏Snk/Plk2可能在使紫杉醇耐药肿瘤敏感化方面具有治疗价值。
