title: Cks1 promotion of S phase entry and proliferation is independent of p27Kip1 suppression.
abstract: Cks1 is an activator of the SCF(Skp2) ubiquitin ligase complex that targets the cell cycle inhibitor p27(Kip1) for degradation. The loss of Cks1 results in p27(Kip1) accumulation and decreased proliferation and inhibits tumorigenesis. We identify here a function of Cks1 in mammalian cell cycle regulation that is independent of p27(Kip1). Specifically, Cks1(-/-); p27(Kip1-/-) mouse embryonic fibroblasts retain defects in the G(1)-S phase transition that are coupled with decreased Cdk2-associated kinase activity and defects in proliferation that are associated with Cks1 loss. Furthermore, concomitant loss of Cks1 does not rescue the tumor suppressor function of p27(Kip1) that is manifest in various organs of p27(Kip1-/-) mice. In contrast, defects in mitotic entry and premature senescence manifest in Cks1(-/-) cells are p27(Kip1) dependent. Collectively, these findings establish p27(Kip1)-independent functions of Cks1 in regulating the G(1)-S transition.
authors.affiliation: Medical Department III, Technische Universität München, Munich, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoellein
authors.forename: Steffi
authors.initials: S
authors.lastname: Graf
authors.forename: Florian
authors.initials: F
authors.lastname: Bassermann
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schoeffmann
authors.forename: Ulrich
authors.initials: U
authors.lastname: Platz
authors.forename: Gabriele
authors.initials: G
authors.lastname: Hölzlwimmer
authors.forename: Monika
authors.initials: M
authors.lastname: Kröger
authors.forename: Christian
authors.initials: C
authors.lastname: Peschel
authors.forename: Robert
authors.initials: R
authors.lastname: Oostendorp
authors.forename: Leticia
authors.initials: L
authors.lastname: Quintanilla-Fend
authors.forename: Ulrich
authors.initials: U
authors.lastname: Keller
mesh_terms: D000818:Animals; D042846:CDC2-CDC28 Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000502:physiology; D059565:G2 Phase Cell Cycle Checkpoints / Q000502:physiology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D059807:S Phase Cell Cycle Checkpoints / Q000502:physiology*; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism
chemical_list: C493961:Cdkn1b protein, mouse; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D042846:CDC2-CDC28 Kinases; C474110:Cks1 protein, mouse; D018844:Cyclin-Dependent Kinases