title: Caspases uncouple p27(Kip1) from cell cycle regulated degradation and abolish its ability to stimulate cell migration and invasion.
abstract: In addition to their role in programmed cell death, caspases exert non-lethal functions in diverse developmental processes including cell differentiation or tissue remodeling. Terminal cell cycle exit and differentiation can be promoted by increased level of the CDK inhibitor p27(Kip1). Activated caspases cause proteolytic processing of p27, and we identified a novel caspase cleavage site in human p27 that removes a C-terminal fragment of 22 amino acids from the CDK inhibitor, including a phosphodegron. Thereby, caspases protect the inhibitor from SCF-Skp2-mediated degradation in S, G2 and M phases of the cell cycle. As a consequence, p27 becomes stabilized and remains an efficient nuclear inhibitor of cell cycle progression. Besides controlling cyclin/CDK kinase activity, p27 also regulates cytoskeletal dynamics, cell motility and cell invasion. Following processing by caspases, p27 fails to bind to RhoA and to inhibit its activation, and thereby abolishes the ability of p27 to stimulate cell migration and invasion. We propose that the stabilization of the CDK inhibitor and elimination of RhoA-induced cytoskeletal remodeling upon caspase processing could contribute to cell cycle exit and cytoskeletal remodeling during non-lethal caspase controlled differentiation processes.
authors.affiliation: Division of Medical Biochemistry; Biocenter; Innsbruck Medical University; Innsbruck, Austria.
authors.forename: S R
authors.initials: SR
authors.lastname: Podmirseg
authors.affiliation: Division of Medical Biochemistry; Biocenter; Innsbruck Medical University; Innsbruck, Austria.
authors.forename: H
authors.initials: H
authors.lastname: Jäkel
authors.affiliation: Division of Medical Biochemistry; Biocenter; Innsbruck Medical University; Innsbruck, Austria.
authors.forename: G D
authors.initials: GD
authors.lastname: Ranches
authors.affiliation: Division of Medical Biochemistry; Biocenter; Innsbruck Medical University; Innsbruck, Austria.
authors.forename: M K
authors.initials: MK
authors.lastname: Kullmann
authors.affiliation: Laboratoire Interdisciplinaire des Environnements Continentaux (LIEC), UMR 7360, Université de Lorraine, Metz, France.|CNRS, LIEC, UMR 7360, Metz, France.
authors.forename: B
authors.initials: B
authors.lastname: Sohm
authors.affiliation: Division of Developmental Immunology; Biocenter; Innsbruck Medical University; Innsbruck, Austria.|Tyrolean Cancer Research Institute, Innsbruck, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Villunger
authors.affiliation: Division of Clinical Biochemistry; Biocenter; Innsbruck Medical University; Innsbruck, Austria.
authors.forename: H
authors.initials: H
authors.lastname: Lindner
authors.affiliation: Division of Medical Biochemistry; Biocenter; Innsbruck Medical University; Innsbruck, Austria.
authors.forename: L
authors.initials: L
authors.lastname: Hengst
mesh_terms: D020169:Caspases / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics* / Q000378:metabolism; D003599:Cytoskeleton / Q000235:genetics; D006801:Humans; D009361:Neoplasm Invasiveness / Q000235:genetics; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D011485:Protein Binding; D059748:Proteolysis; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics*
chemical_list: D044786:S-Phase Kinase-Associated Proteins; C066737:RHOA protein, human; D050760:Cyclin-Dependent Kinase Inhibitor p27; D044843:SKP Cullin F-Box Protein Ligases; D020169:Caspases; D020742:rhoA GTP-Binding Protein
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