title: The tumor suppressor CDKN3 controls mitosis.
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 CDC2(pThr-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.
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Nalepa
authors.forename: Jill
authors.initials: J
authors.lastname: Barnholtz-Sloan
authors.forename: Rikki
authors.initials: R
authors.lastname: Enzor
authors.forename: Dilip
authors.initials: D
authors.lastname: Dey
authors.forename: Ying
authors.initials: Y
authors.lastname: He
authors.forename: Jeff R
authors.initials: JR
authors.lastname: Gehlhausen
authors.forename: Amalia S
authors.initials: AS
authors.lastname: Lehmann
authors.forename: Su-Jung
authors.initials: SJ
authors.lastname: Park
authors.forename: Yanzhu
authors.initials: Y
authors.lastname: Yang
authors.forename: Xianlin
authors.initials: X
authors.lastname: Yang
authors.forename: Shi
authors.initials: S
authors.lastname: Chen
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Guan
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Chen
authors.forename: Jamie
authors.initials: J
authors.lastname: Renbarger
authors.forename: Feng-Chun
authors.initials: FC
authors.lastname: Yang
authors.forename: Luis F
authors.initials: LF
authors.lastname: Parada
authors.forename: Wade
authors.initials: W
authors.lastname: Clapp
mesh_terms: D016203:CDC2 Protein Kinase; D018385:Centrosome / Q000378:metabolism / Q000648:ultrastructure; D019926:Cyclin B / Q000378:metabolism; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D018844:Cyclin-Dependent Kinases; D054637:Dual-Specificity Phosphatases / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D018386:Kinetochores / Q000378:metabolism / Q000648:ultrastructure; D013058:Mass Spectrometry; D008938:Mitosis / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D034622:RNA Interference; D015398:Signal Transduction
chemical_list: D019926:Cyclin B; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; C084429:CDKN3 protein, human; D054637:Dual-Specificity Phosphatases