title: Targeting mitotic exit leads to tumor regression in vivo: Modulation by Cdk1, Mastl, and the PP2A/B55α,δ phosphatase.
abstract: Targeting mitotic exit has been recently proposed as a relevant therapeutic approach against cancer. By using genetically engineered mice, we show that the APC/C cofactor Cdc20 is essential for anaphase onset in vivo in embryonic or adult cells, including progenitor/stem cells. Ablation of Cdc20 results in efficient regression of aggressive tumors, whereas current mitotic drugs display limited effects. Yet, Cdc20 null cells can exit from mitosis upon inactivation of Cdk1 and the kinase Mastl (Greatwall). This mitotic exit depends on the activity of PP2A phosphatase complexes containing B55α or B55δ regulatory subunits. These data illustrate the relevance of critical players of mitotic exit in mammals and their implications in the balance between cell death and mitotic exit in tumor cells.
authors.affiliation: Spanish National Cancer Research Centre, Madrid, Spain.
authors.forename: Eusebio
authors.initials: E
authors.lastname: Manchado
authors.forename: María
authors.initials: M
authors.lastname: Guillamot
authors.forename: Guillermo
authors.initials: G
authors.lastname: de Cárcer
authors.forename: Manuel
authors.initials: M
authors.lastname: Eguren
authors.forename: Michelle
authors.initials: M
authors.lastname: Trickey
authors.forename: Irene
authors.initials: I
authors.lastname: García-Higuera
authors.forename: Sergio
authors.initials: S
authors.lastname: Moreno
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamano
authors.forename: Marta
authors.initials: M
authors.lastname: Cañamero
authors.forename: Marcos
authors.initials: M
authors.lastname: Malumbres
mesh_terms: D000705:Anaphase; D000818:Animals; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors*; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D008677:Metaphase; D051379:Mice; D008810:Mice, Inbred C57BL; D008938:Mitosis; D009374:Neoplasms, Experimental / Q000473:pathology / Q000628:therapy*; D054648:Protein Phosphatase 2 / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D064199:Cdc20 Proteins; C577491:Cdc20 protein, mouse; D018797:Cell Cycle Proteins; D013629:Tamoxifen; C016601:afimoxifene; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; D054648:Protein Phosphatase 2