title: Casein kinase 1δ-dependent Wee1 protein degradation.
abstract: Eukaryotic mitotic entry is controlled by Cdk1, which is activated by the Cdc25 phosphatase and inhibited by Wee1 tyrosine kinase, a target of the ubiquitin proteasome pathway. Here we use a reporter of Wee1 degradation, K328M-Wee1-luciferase, to screen a kinase-directed chemical library. Hit profiling identified CK1δ-dependent Wee1 degradation. Small-molecule CK1δ inhibitors specifically disrupted Wee1 destruction and arrested HeLa cell proliferation. Pharmacological inhibition, siRNA knockdown, or conditional deletion of CK1δ also reduced Wee1 turnover. Thus, these studies define a previously unappreciated role for CK1δ in controlling the cell cycle.
authors.affiliation: From the Center for Therapeutic Innovation, Department of Psychiatry and Behavioral Sciences and.
authors.forename: Clara
authors.initials: C
authors.lastname: Penas
authors.affiliation: From the Center for Therapeutic Innovation, Department of Psychiatry and Behavioral Sciences and.
authors.forename: Vimal
authors.initials: V
authors.lastname: Ramachandran
authors.affiliation: the Department of Cancer Biology.
authors.forename: Scott
authors.initials: S
authors.lastname: Simanski
authors.affiliation: the Department of Biological Sciences, College of Medicine, Florida State University, Tallahassee, Florida 32306, and.
authors.forename: Choogon
authors.initials: C
authors.lastname: Lee
authors.affiliation: Lead Identification Division, Translational Research Institute, and.
authors.forename: Franck
authors.initials: F
authors.lastname: Madoux
authors.affiliation: Department of Chemistry, Scripps Florida, Jupiter, Florida 33458.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Rahaim
authors.affiliation: the Department of Neurology, Children's Hospital, Boston, Boston, Massachusetts 02115.
authors.forename: Ruchi
authors.initials: R
authors.lastname: Chauhan
authors.affiliation: the Department of Neurology, Children's Hospital, Boston, Boston, Massachusetts 02115.
authors.forename: Omar
authors.initials: O
authors.lastname: Barnaby
authors.affiliation: Department of Pharmacology, University of Miami, Miami, Florida 33136.
authors.forename: Stephan
authors.initials: S
authors.lastname: Schurer
authors.affiliation: Lead Identification Division, Translational Research Institute, and.
authors.forename: Peter
authors.initials: P
authors.lastname: Hodder
authors.affiliation: the Department of Neurology, Children's Hospital, Boston, Boston, Massachusetts 02115.
authors.forename: Judith
authors.initials: J
authors.lastname: Steen
authors.affiliation: Department of Chemistry, Scripps Florida, Jupiter, Florida 33458.
authors.forename: William R
authors.initials: WR
authors.lastname: Roush
authors.affiliation: From the Center for Therapeutic Innovation, Department of Psychiatry and Behavioral Sciences and nayad@med.miami.edu.
authors.forename: Nagi G
authors.initials: NG
authors.lastname: Ayad
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D048148:Casein Kinase Idelta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D055550:Protein Stability / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects; D054852:Small Molecule Libraries / Q000494:pharmacology
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; D048148:Casein Kinase Idelta
keywords: Cell Cycle; Chemical Biology; E3 Ubiquitin Ligase; Kinase; Mitosis; Signal Transduction