Targeting Mitotic Exit Leads to Tumor Regression InaaVivo: Modulation by Cdk1, Mastl, and the PP2A/B55 alpha ,I Phosphatase

• Published in: Cancer cell Vol. 18; no. 6; pp. 641 - 654
• Main Authors: Manchado, Eusebio, Guillamot, Maria, de Carcer, Guillermo, Eguren, Manuel, Trickey, Michelle, Garcia-Higuera, Irene, Moreno, Sergio, Yamano, Hiroyuki, Canamero, Marta, Malumbres, Marcos
• Format: Journal Article
• Language: English
• Published: 14-12-2010
• ISSN: 1535-6108
• DOI: 10.1016/j.ccr.2010.10.028

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 inaavivo 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 B55 alpha or B55I 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. Display Omitted a-[ordm Cdc20 is essential for anaphase onset in normal or tumoral cells a-[ordm Cdc20 ablation results in complete tumor regression inaavivo due to apoptotic death a-[ordm Cdc20 null cells can exit from mitosis after inhibition of Cdk1 and Mastl a-[ordm Mammalian mitotic exit depends on the activation of PP2A-B55 phosphatases