DYRK2 priming phosphorylation of c-Jun and c-Myc modulates cell cycle progression in human cancer cells
Naoe Taira, Rei Mimoto, Morito Kurata, Tomoko Yamaguchi, Masanobu Kitagawa, Yoshio Miki, Kiyotsugu Yoshida
Naoe Taira, Rei Mimoto, Morito Kurata, Tomoko Yamaguchi, Masanobu Kitagawa, Yoshio Miki, Kiyotsugu Yoshida
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Research Article

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

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.

Authors

Naoe Taira, Rei Mimoto, Morito Kurata, Tomoko Yamaguchi, Masanobu Kitagawa, Yoshio Miki, Kiyotsugu Yoshida

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Figure 4

The G1/S transition is accelerated in DYRK2-depleted cells.

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The G1/S transition is accelerated in DYRK2-depleted cells. (A) U2OS...
(A) U2OS cells were transfected with scrambled siRNAs or DYRK2 siRNAs, followed by serum starvation and stimulation for the indicated amount of time. Lysates were subjected to immunoblot analysis with the indicated antibodies. (B) Schematic depiction of Fucci system. (C) Fucci-expressing HeLa cells were transfected with scrambled siRNA or DYRK2 siRNA. Culture medium was changed to DMEM containing 0.25% serum. After refeeding with serum, cells were subjected to time-lapse fluorescence microscopy. (D) U2OS cells were transfected with scrambled siRNA, DYRK2 siRNA, c-Jun–specific siRNA, or c-Myc–specific siRNA. After transfection, cells were subjected to the MTS assay (upper panel) or the colony formation assay (lower panel). (E) U2OS cells were cotransfected with scrambled siRNA or DYRK2 siRNA and Flag–c-Myc WT or Flag–c-Myc T58A/S62A. After transfection, cells were subjected to the MTS assay (upper panel) or the colony formation assay (lower panel). Data represent mean ± SD.