Department of Biochemistry, Purdue University, West Lafayette, IN, USA.
Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, USA.
Oncogene. 2018 Feb 8;37(6):810-820. doi: 10.1038/onc.2017.379. Epub 2017 Oct 23.
Although Numb is well-recognized as a cell-fate determinant in stem/progenitor cells, accumulating evidence supports that Numb also has a critical role in adult tissues and cancers, in particular, in the context of regulation of tumor suppressor p53. Herein, we identified Numb as a novel substrate of Polo-like kinase 1 (Plk1). Of significance, we showed that Plk1-mediated phosphorylation of Numb leads to its enhanced proteasomal degradation and impaired Numb/p53 pathway, thus providing another mechanism how Plk1 antagonizes p53 during DNA damage response. In addition, the novel phosphorylation event identified by us further supports the notion that post-translational modifications of Numb uncouple Numb from p53 and lead to p53 destabilization. Finally, our data generated from both human cancer cell lines and mouse xenograft model showed that cancer cells carrying the unphosphorylated form of Numb by Plk1 are more sensitive to doxorubicin, a classical chemotherapeutic drug. Therefore, our work may provide future strategies for improving the efficacy of chemotherapy by targeting Numb phosphorylation by Plk1.
虽然 Numb 被公认为干细胞/祖细胞中的细胞命运决定因子，但越来越多的证据表明，Numb 也在成人组织和癌症中发挥着关键作用，特别是在调节肿瘤抑制因子 p53 的背景下。本文中，我们鉴定 Numb 是 Polo 样激酶 1 (Plk1) 的一个新底物。重要的是，我们表明 Plk1 介导的 Numb 磷酸化导致其增强的蛋白酶体降解和受损的 Numb/p53 通路，从而提供了 Plk1 在 DNA 损伤反应中拮抗 p53 的另一种机制。此外，我们鉴定的新磷酸化事件进一步支持了这样一种观点，即 Numb 的翻译后修饰使其与 p53 分离，并导致 p53 不稳定。最后，我们从人癌细胞系和小鼠异种移植模型中获得的数据表明，携带 Plk1 未磷酸化形式的 Numb 的癌细胞对阿霉素（一种经典的化疗药物）更为敏感。因此，我们的工作可能为通过靶向 Plk1 对 Numb 的磷酸化来提高化疗效果提供未来的策略。
