DYRK2 priming phosphorylation of c-Jun and c-Myc modulates cell cycle progression in human cancer cells
DYRK2 priming phosphorylation of c-Jun and c-Myc modulates cell cycle progression in human cancer cells
复制标题
DOI：
10.1172/jci60818
复制
发表时间：
2012-03-01
影响因子：
15.9
通讯作者：
Yoshida, Kiyotsugu
中科院分区：
文献类型：
--
作者：
Taira, Naoe;Mimoto, Rei;Yoshida, Kiyotsugu
细胞周期中G（1）/S转换的失调有助于肿瘤的发展。致癌转录因子c-Jun和c-Myc是这一转变过程中不可或缺的调节因子，它们的异常表达与许多恶性肿瘤有关。c-Jun/c-Myc的降解是G（1）/S转换的关键过程，G（1）/S转换在糖原合成酶激酶3 β（GSK 3 β）磷酸化后启动。然而，尚未明确鉴定出在这种GSK 3 β修饰之前负责引发磷酸化事件的一种或多种特定激酶。在这里，我们发现双特异性酪氨酸磷酸化调节激酶DYRK 2作为c-Jun和c-Myc的引发激酶发挥作用。在人类癌细胞中敲除DYRK 2缩短了G（1）期，并由于c-Jun和c-Myc逃避泛素介导的降解而加速了细胞增殖。与这些结果一致，沉默DYRK 2增加了人类癌细胞中的细胞增殖，并且这种促进作用完全被c-Jun或c-Myc的体内编码所阻碍。我们还发现在多个人类肿瘤样品中DYRK 2表达显著减弱。DYRK 2的下调与高水平的非磷酸化c-Jun和c-Myc相关，重要的是，与人类乳腺癌的侵袭性相关。这些结果表明，DYRK 2通过调节c-Jun和c-Myc来调节肿瘤进展。
Dysregulation of the G(1)/S transition in the cell cycle contributes to tumor development. The oncogenic transcription factors c-Jun and c-Myc are indispensable regulators at this transition, and their aberrant expression is associated with many malignancies. Degradation of c-Jun/c-Myc is a critical process for the G(1)/S transition, which is initiated upon phosphorylation by glycogen synthase kinase 3 beta (GSK3 beta). However, a specific kinase or kinases responsible for priming phosphorylation events that precede this GSK3 beta modification has not been definitively identified. Here, we found that the dual-specificity tyrosine phosphorylation-regulated kinase DYRK2 functions as a priming kinase of c-Jun and c-Myc. Knockdown of DYRK2 in human cancer cells shortened the G(1) phase and accelerated cell proliferation due to escape of c-Jun and c-Myc from ubiquitination-mediated degradation. In concert with these results, silencing DYRK2 increased cell proliferation in human cancer cells, and this promotion was completely impeded by codeprivation of c-Jun or c-Myc in vivo. We also found marked attenuation of DYRK2 expression in multiple human tumor samples. Downregulation of DYRK2 correlated with high levels of unphosphorylated c-Jun and c-Myc and, importantly, with invasiveness of human breast cancers. These results reveal that DYRK2 regulates tumor progression through modulation of c-Jun and c-Myc.