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Cyclin-dependent kinase 1-mediated phosphorylation of YES links mitotic arrest and apoptosis during antitubulin chemotherapy

机译：细胞周期蛋白依赖性激酶1介导磷酸化抗胰岛素化疗期间的链接丝分裂钝化钝化术和细胞凋亡

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摘要

YES is a member of the SRC family kinase (SFK) group of non-receptor tyrosine kinases, which are implicated in multiple key cellular processes involved in oncogenesis. Antitubulin agents have been widely used as chemotherapeutics for cancer patients and these drugs arrest cells in mitosis, leading to subsequent cell death. In the present study, we define a mechanism for phospho-regulation of YES that is critical for its role in response to antitubulin agents. Specifically, we found that YES is phosphorylated at multiple sites on its N-terminal unique domain by the cell cycle kinase CDK1 during antitubulin drug-induced mitotic arrest. Phosphorylation of YES occurs during normal mitosis. Deletion of YES causes arrest in prometaphase and polyploidy in a p53-independent manner. We further show that YES regulates antitubulin chemosensitivity. Importantly, mitotic phosphorylation is essential for these effects. In support of our findings, we found that YES expression is high in recurrent ovarian cancer patients. Finally, through expression profiling, we documented that YES phosphorylation affects expression of multiple cell cycle regulators. Collectively, our results reveal a previously unrecognized mechanism for controlling the activity of YES during antitubulin chemotherapeutic treatment and suggest YES as a potential target for the treatment of antitubulin-resistant cancer.
机译：是的是SRC系列激酶（SFK）的非受体酪氨酸激酶组的成员，其涉及一种涉及血管生成的多个关键细胞过程。抗胰岛素药剂已被广泛用作癌症患者的化学治疗剂，这些药物抑制细胞有丝分裂中的细胞，导致随后的细胞死亡。在本研究中，我们定义了对磷酸的调节机制是对其响应抗原蛋白剂的作用至关重要。具体而言，我们发现是在抗原药物诱导的有丝分裂钝化中通过细胞周期激酶CDK1在其N末端独特域的多个位点上磷酸化。在正常有丝分裂期间磷酸化。缺失是以p53独立的方式导致Prometaphase和多倍体的捕获。我们进一步表明是调节抗胰岛素化学敏感性。重要的是，有丝分裂磷酸化对于这些效果至关重要。为了支持我们的研究结果，我们发现均表达在反复性卵巢癌患者中很高。最后，通过表达分析，我们记录了是磷酸化影响多个细胞周期调节器的表达。统称，我们的结果揭示了以前未被识别的用于控制抗原化学治疗治疗期间是是未被识别的机制，并表明是作为治疗抗原癌癌症的潜在目标。

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  • 来源
    《Cellular Signalling》 |2018年第2018期|共10页
  • 作者

    Wang Zhan; Chen Xingcheng; Zhong Mei-Zuo; Yang Shuping; Zhou Jiuli; Klinkebiel David L.; Karpf Adam R.; Chen Yuanhong; Dong Jixin;

  • 作者单位

    Cent S Univ Dept Oncol Xiangya Hosp Changsha 410008 Hunan Peoples R China;

    Univ Nebraska Med Ctr Eppley Inst Res Canc &

    Allied Dis Fred &

    Pamela Buffett Canc Ctr Omaha NE 68198 USA;

    Cent S Univ Dept Oncol Xiangya Hosp Changsha 410008 Hunan Peoples R China;

    Shandong Univ Dept Oncol Shandong Prov Hosp Jinan 250021 Shandong Peoples R China;

    Univ Nebraska Med Ctr Eppley Inst Res Canc &

    Allied Dis Fred &

    Pamela Buffett Canc Ctr Omaha NE 68198 USA;

    Univ Nebraska Med Ctr Dept Biochem &

    Mol Biol Fred &

    Pamela Buffett Canc Ctr Omaha NE 68198 USA;

    Univ Nebraska Med Ctr Eppley Inst Res Canc &

    Allied Dis Fred &

    Pamela Buffett Canc Ctr Omaha NE 68198 USA;

    Univ Nebraska Med Ctr Eppley Inst Res Canc &

    Allied Dis Fred &

    Pamela Buffett Canc Ctr Omaha NE 68198 USA;

    Univ Nebraska Med Ctr Eppley Inst Res Canc &

    Allied Dis Fred &

    Pamela Buffett Canc Ctr Omaha NE 68198 USA;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 细胞形态学;
  • 关键词

    YES; Mitotic phosphorylation; CDK1; Taxol sensitivity; Chemotherapy;

    机译：是的;有丝分裂磷酸化;CDK1;紫杉醇敏感;化疗;

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