title: VRK1 regulates Cajal body dynamics and protects coilin from proteasomal degradation in cell cycle.
abstract: Cajal bodies (CBs) are nuclear organelles associated with ribonucleoprotein functions and RNA maturation. CBs are assembled on coilin, its main scaffold protein, in a cell cycle dependent manner. The Ser-Thr VRK1 (vaccinia-related kinase 1) kinase, whose activity is also cell cycle regulated, interacts with and phosphorylates coilin regulating assembly of CBs. Coilin phosphorylation is not necessary for its interaction with VRK1, but it occurs in mitosis and regulates coilin stability. Knockdown of VRK1 or VRK1 inactivation by serum deprivation causes a loss of coilin phosphorylation in Ser184 and of CBs formation, which are rescued with an active VRK1, but not by kinase-dead VRK1. The phosphorylation of coilin in Ser184 occurs during mitosis before assembly of CBs. Loss of coilin phosphorylation results in disintegration of CBs, and of coilin degradation that is prevented by proteasome inhibitors. After depletion of VRK1, coilin is ubiquitinated in nuclei, which is partly mediated by mdm2, but its proteasomal degradation occurs in cytosol and is prevented by blocking its nuclear export. We conclude that VRK1 is a novel regulator of CBs dynamics and stability in cell cycle by protecting coilin from ubiquitination and degradation in the proteasome, and propose a model of CB dynamics.
authors.affiliation: 1] Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Salamanca, Salamanca, Spain [2] Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Salamanca, Spain.
authors.forename: Lara
authors.initials: L
authors.lastname: Cantarero
authors.affiliation: Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Salamanca, Salamanca, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Sanz-García
authors.affiliation: Medical Genetics Institute, Shaare-Zedek Medical Center, Hebrew University of Jerusalem Medical School, Jerusalem, Israel.
authors.forename: Hadar
authors.initials: H
authors.lastname: Vinograd-Byk
authors.affiliation: Medical Genetics Institute, Shaare-Zedek Medical Center, Hebrew University of Jerusalem Medical School, Jerusalem, Israel.
authors.forename: Paul
authors.initials: P
authors.lastname: Renbaum
authors.affiliation: Medical Genetics Institute, Shaare-Zedek Medical Center, Hebrew University of Jerusalem Medical School, Jerusalem, Israel.
authors.forename: Ephrat
authors.initials: E
authors.lastname: Levy-Lahad
authors.affiliation: 1] Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Salamanca, Salamanca, Spain [2] Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Salamanca, Spain.
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Lazo
mesh_terms: D002453:Cell Cycle / Q000502:physiology*; D020541:Coiled Bodies / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D061986:MCF-7 Cells; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C068921:p80-coilin; D017346:Protein Serine-Threonine Kinases; C109890:VRK1 protein, human; D046988:Proteasome Endopeptidase Complex