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- Title
DYRK2 priming phosphorylation of c-Jun and c-Myc modulates cell cycle progression in human cancer cells.
- Authors
Taira, Naoe; Mimoto, Rei; Kurata, Morito; Yamaguchi, Tomoko; Kitagawa, Masanobu; Miki, Yoshio; Yoshida, Kiyotsugu
- Abstract
Dysregulation of the G1/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 G1/S transition, which is initiated upon phosphorylation by glycogen synthase kinase 3 β (GSK3β). However, a specific kinase or kinases responsible for priming phosphorylation events that precede this GSK3β 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 G1 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.
- Subjects
CELL cycle; CANCER cells; PHOSPHORYLATION; TRANSCRIPTION factors; GENETIC regulation; GLYCOGEN synthase kinase-3; CANCER invasiveness
- Publication
Journal of Clinical Investigation, 2012, Vol 122, Issue 3, p859
- ISSN
0021-9738
- Publication type
Article
- DOI
10.1172/JCI60818