DYRK2 priming phosphorylation of c-Jun and c-Myc modulates cell cycle progression in human cancer cells

作者：Taira Naoe; Mimoto Rei; Kurata Morito; Yamaguchi Tomoko; Kitagawa Masanobu; Miki Yoshio; Yoshida Kiyotsugu^*

来源：Journal of Clinical Investigation, 2012, 122(3): 859-872.

DOI：10.1172/JCI60818

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.

• 出版日期2012-3