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

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...

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Bibliographic Details
Published in:The Journal of clinical investigation 2012-03, Vol.122 (3), p.859-872
Main Authors: Taira, Naoe, Mimoto, Rei, Kurata, Morito, Yamaguchi, Tomoko, Kitagawa, Masanobu, Miki, Yoshio, Yoshida, Kiyotsugu
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Biomedical research
Cancer
Cancer cells
Cell Cycle
Cell growth
Cell Line, Tumor
Cell Proliferation
DNA damage
Dyrk Kinases
Gene expression
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
Genetic aspects
HeLa Cells
Humans
JNK Mitogen-Activated Protein Kinases - metabolism
Kinases
Male
Mice
Mice, Inbred BALB C
Neoplasm Transplantation
Phosphorylation
Properties
Protein Serine-Threonine Kinases - metabolism
Protein Serine-Threonine Kinases - physiology
Protein-Tyrosine Kinases - metabolism
Protein-Tyrosine Kinases - physiology
Proteins
Proto-Oncogene Proteins c-myc - metabolism
Transcription factors
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Summary: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.
ISSN:0021-9738
1558-8238
DOI:10.1172/jci60818