The tumor suppressor CDKN3 controls mitosis

Grzegorz Nalepa; Jill Barnholtz-Sloan; Rikki Enzor; Dilip Dey; Ying He; Jeff R Gehlhausen; Amalia S Lehmann; Su-Jung Park; Yanzhu Yang; Xianlin Yang; Shi Chen; Xiaowei Guan; Yanwen Chen; Jamie Renbarger; Feng-Chun Yang; Luis F Parada; Wade Clapp

doi:10.1083/jcb.201205125

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The tumor suppressor CDKN3 controls mitosis

Journal article

Open access

Peer reviewed

The tumor suppressor CDKN3 controls mitosis

Grzegorz Nalepa, Jill Barnholtz-Sloan, Rikki Enzor, Dilip Dey, Ying He, Jeff R Gehlhausen, Amalia S Lehmann, Su-Jung Park, Yanzhu Yang, Xianlin Yang, …

The Journal of cell biology, Vol.201(7), pp.997-1012

2013-06-24

DOI: https://doi.org/10.1083/jcb.201205125

PMCID: PMC3691455

PMID: 23775190

Abstract

Mitosis is controlled by a network of kinases and phosphatases. We screened a library of small interfering RNAs against a genome-wide set of phosphatases to comprehensively evaluate the role of human phosphatases in mitosis. We found four candidate spindle checkpoint phosphatases, including the tumor suppressor CDKN3. We show that CDKN3 is essential for normal mitosis and G1/S transition. We demonstrate that subcellular localization of CDKN3 changes throughout the cell cycle. We show that CDKN3 dephosphorylates threonine-161 of CDC2 during mitotic exit and we visualize CDC2pThr-161 at kinetochores and centrosomes in early mitosis. We performed a phosphokinome-wide mass spectrometry screen to find effectors of the CDKN3-CDC2 signaling axis. We found that one of the identified downstream phosphotargets, CKβ phosphorylated at serine 209, localizes to mitotic centrosomes and controls the spindle checkpoint. Finally, we show that CDKN3 protein is down-regulated in brain tumors. Our findings indicate that CDKN3 controls mitosis through the CDC2 signaling axis. These results have implications for targeted anticancer therapeutics.

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Collaboration types: Domestic collaboration
Citation topics: 1 Clinical & Life Sciences; 1.25 Molecular & Cell Biology - Cancer, Autophagy & Apoptosis; 1.25.396 P16
Web Of Science research areas: Cell Biology
ESI research areas: Molecular Biology & Genetics

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Title: The tumor suppressor CDKN3 controls mitosis
Creators: Grzegorz Nalepa - Department of Pediatrics, Herman B Wells Center for Pediatric Research, Department of Microbiology and Immunology, Department of Biochemistry and Molecular Biology, and Division of Pediatric Hematology-Oncology, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN 46202, Department of Pediatrics, Herman B Wells Center for Pediatric Research, Department of Microbiology and Immunology, Department of Biochemistry and Molecular Biology, and Division of Pediatric Hematology-Oncology, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN 46202
Jill Barnholtz-Sloan - Case Western Reserve University Comprehensive Cancer Center, Cleveland, OH 44106
Rikki Enzor - Department of Pediatrics, Herman B Wells Center for Pediatric Research, Department of Microbiology and Immunology, Department of Biochemistry and Molecular Biology, and Division of Pediatric Hematology-Oncology, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN 46202
Dilip Dey - Department of Pediatrics, Herman B Wells Center for Pediatric Research, Department of Microbiology and Immunology, Department of Biochemistry and Molecular Biology, and Division of Pediatric Hematology-Oncology, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN 46202
Ying He - Department of Pediatrics, Herman B Wells Center for Pediatric Research, Department of Microbiology and Immunology, Department of Biochemistry and Molecular Biology, and Division of Pediatric Hematology-Oncology, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN 46202
Jeff R Gehlhausen - Department of Pediatrics, Herman B Wells Center for Pediatric Research, Department of Microbiology and Immunology, Department of Biochemistry and Molecular Biology, and Division of Pediatric Hematology-Oncology, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN 46202
Amalia S Lehmann - Department of Pediatrics, Herman B Wells Center for Pediatric Research, Department of Microbiology and Immunology, Department of Biochemistry and Molecular Biology, and Division of Pediatric Hematology-Oncology, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN 46202
Su-Jung Park - Department of Pediatrics, Herman B Wells Center for Pediatric Research, Department of Microbiology and Immunology, Department of Biochemistry and Molecular Biology, and Division of Pediatric Hematology-Oncology, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN 46202
Yanzhu Yang - Department of Pediatrics, Herman B Wells Center for Pediatric Research, Department of Microbiology and Immunology, Department of Biochemistry and Molecular Biology, and Division of Pediatric Hematology-Oncology, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN 46202
Xianlin Yang - Department of Pediatrics, Herman B Wells Center for Pediatric Research, Department of Microbiology and Immunology, Department of Biochemistry and Molecular Biology, and Division of Pediatric Hematology-Oncology, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN 46202
Shi Chen - Department of Pediatrics, Herman B Wells Center for Pediatric Research, Department of Microbiology and Immunology, Department of Biochemistry and Molecular Biology, and Division of Pediatric Hematology-Oncology, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN 46202
Xiaowei Guan - Case Western Reserve University Comprehensive Cancer Center, Cleveland, OH 44106
Yanwen Chen - Case Western Reserve University Comprehensive Cancer Center, Cleveland, OH 44106
Jamie Renbarger - Department of Pediatrics, Herman B Wells Center for Pediatric Research, Department of Microbiology and Immunology, Department of Biochemistry and Molecular Biology, and Division of Pediatric Hematology-Oncology, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN 46202, Department of Pediatrics, Herman B Wells Center for Pediatric Research, Department of Microbiology and Immunology, Department of Biochemistry and Molecular Biology, and Division of Pediatric Hematology-Oncology, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN 46202
Feng-Chun Yang - Department of Pediatrics, Herman B Wells Center for Pediatric Research, Department of Microbiology and Immunology, Department of Biochemistry and Molecular Biology, and Division of Pediatric Hematology-Oncology, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN 46202
Luis F Parada - Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390
Wade Clapp - Department of Pediatrics, Herman B Wells Center for Pediatric Research, Department of Microbiology and Immunology, Department of Biochemistry and Molecular Biology, and Division of Pediatric Hematology-Oncology, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN 46202, Department of Pediatrics, Herman B Wells Center for Pediatric Research, Department of Microbiology and Immunology, Department of Biochemistry and Molecular Biology, and Division of Pediatric Hematology-Oncology, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN 46202, Department of Pediatrics, Herman B Wells Center for Pediatric Research, Department of Microbiology and Immunology, Department of Biochemistry and Molecular Biology, and Division of Pediatric Hematology-Oncology, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN 46202
Publication Details: The Journal of cell biology, Vol.201(7), pp.997-1012
Language: English
Resource Type: Journal article
PMID: 23775190
PMCID: PMC3691455
Record Identifier: 991031614246302976