Cancer Cell. 2010 Dec 14;18(6):641-54


Manchado E, Guillamot M, de Cárcer G, Eguren M, Trickey M, García-Higuera I, Moreno S, Yamano H, Cañamero M, Malumbres M.


La salida de mitosis ha sido recientemente propuesta como diana en la terapia contra el cáncer. En este estudio, mediante el uso de ratones modificados genéticamente, hemos demostrado como la eliminación condicional del cofactor Cdc20 tanto en células primarias como en fibroblastos transformados resulta en una parada permanente en mitosis que en todos los casos conduce a la muerte de la célula por apoptosis. Así, mientras el tratamiento de fibrosarcomas agresivos con las actuales drogas antimitóticas resulta en un efecto limitado, la ablación de Cdc20 favorece la completa regresión del tumor. Además, la parada permanente en mitosis provocada por la ausencia de Cdc20 nos ha permitido delinear los requerimientos esenciales de la salida de mitosis en células de mamíferos. Este análisis ha puesto de manifiesto la importancia de la de la quinasa Mastl en el mantenimiento del estado mitótico mediante la inhibición de la fosfatasa PP2A-B55α,δ.


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 progenitors/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 upon concomitant 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 reveal critical players of mitotic exit in mammals and provide new avenues for manipulating the balance between apoptotic cell death and mitotic exit in tumor cells.

Imágen artículo Febrero

Eusebio Manchado está realizando la Tesis Doctoral en el grupo de División Celular y Cáncer dirigido por el Dr. Marcos Malumbres en el Centro Nacional de Investigaciones Oncológicas (CNIO). En la actualidad el trabajo del grupo se centra fundamentalmente en el estudio de los principales reguladores mitóticos y su posible implicación en cáncer mediante el desarrollo de modelos de ratón modificados genéticamente.

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