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Taira, N, Mimoto, R, Kurata, M, Yamaguchi, T, Kitagawa, M, Miki, Y and Yoshida, K (2012) DYRK2 priming phosphorylation of c-Jun and c-Myc modulates cell cycle progression in human cancer cells. J. Clin. Invest. 122:859-72
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 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 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.
Animals; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; HeLa Cells; Humans; JNK Mitogen-Activated Protein Kinases/metabolism; Male; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Phosphorylation; Protein-Serine-Threonine Kinases/metabolism; Protein-Serine-Threonine Kinases/physiology; Protein-Tyrosine Kinases/metabolism; Protein-Tyrosine Kinases/physiology; Proto-Oncogene Proteins c-myc/metabolism
|Gene product||Qualifier||GO Term||Evidence Code||with/from||Aspect||Extension||Notes||Status|
|GO:0045786: negative regulation of cell cycle||
DYRK2 phosphorylates the ubiquination of transcription factors associated with cell cycle progression. Knockdown or knockouts of DYRK2 increase cell proliferation. See Figure 1
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