Targeting Mitotic Exit Leads to Tumor Regression In Vivo: Modulation by Cdk1, Mastl, and the PP2A/B55α,δ Phosphatase

SummaryTargeting 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

Targeting mitotic exit leads to tumor regression in vivo: Modulation by Cdk1, Mastl, and the PP2A/B55α,δ phosphatase

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. © 2010 Elsevier Inc.E.M., M.G., and M.E are supported by fellowships from the Ministerio de Ciencia e Innovación (MICINN). M.T. and H.Y. are supported by Marie Curie Cancer Care and the Association for International Cancer Research (AICR). M.M. and S.M. wish to acknowledge the Fundación Cientíica de la Asociación Española contra el Cáncer for financial support. I.G.-H. and S.M. are supported by grants BFU2008-01808, Consolider CSD2007-00015, and Junta de Castilla y León Grupo de Excelencia GR 265. The Cell Division and Cancer group of the CNIO is funded by the MICINN (SAF2009-07973), Consolider-Ingenio 2010 Programme (CSD2007-00017), Comunidad de Madrid (OncoCycle Programme; S-BIO-0283-2006), Fundación Ramón Areces, AICR (08-0188), and the MitoSys project (HEALTH-F5-2010-241548; European Union Seventh Framework Program).Peer Reviewe