Nature Communications (2013) 4:2268 doi: 10.1038/ncomms3268. PMID: 23917225


Jorge de la Rosa, José M.P. Freije, Rubén Cabanillas, Fernando G. Osorio, Mario F. Fraga, M. Soledad Fernández-García, Roland Rad, Víctor Fanjul, Alejandro P. Ugalde, Qi Liang, Haydn M. Prosser, Allan Bradley, Juan Cadiñanos y Carlos López-Otín


Defining the relationship between ageing and cancer is a crucial but challenging task. Mice deficient in Zmpste24, a metalloproteinase mutated in human progeria and involved in nuclear prelamin A maturation, recapitulate multiple features of ageing. However, their short lifespan and serious cell-intrinsic and cell-extrinsic alterations restrict the application and interpretation of carcinogenesis protocols. Here we present Zmpste24 mosaic mice that lack these limitations. Zmpste24 mosaic mice develop normally and keep similar proportions of Zmpste24-deficient (prelamin A-accumulating) and Zmpste24-proficient (mature lamin A-containing) cells throughout life, revealing that cell-extrinsic mechanisms are preeminent for progeria development. Moreover, prelamin A accumulation does not impair tumour initiation and growth, but it decreases the incidence of infiltrating oral carcinomas. Accordingly, silencing of ZMPSTE24 reduces human cancer cell invasiveness. Our results support the potential of cell-based and systemic therapies for progeria and highlight ZMPSTE24 as a new anticancer target.


La lamina A es una proteína de la envuelta nuclear producida por la maduración de su precursor, prelamina A, catalizada por la proteasa ZMPSTE24. La acumulación de precursores de la lamina A, debida a la ausencia de ZMPSTE24 o a mutaciones en el gen LMNA, desencadena enfermedades de envejecimiento acelerado, como la progeria de Hutchinson-Gilford. Estos precursores también se han relacionado con el envejecimiento normal. En este trabajo generamos ratones mosaicos de Zmpste24, y comprobamos que los principales mecanismos responsables de estas enfermedades son extrínsecos a la célula, lo cual apoya el empleo de terapias sistémicas para tratarlas. Además, demostramos que la prelamina A frena la invasión tumoral, lo cual sugiere que Zmpste24 es una posible diana antitumoral.



Los ratones deficientes en ZMPSTE24, que desarrollan envejecimiento acelerado, fueron generados en el laboratorio de Carlos López-Otín en la Universidad de Oviedo, hace más de una década, dentro del trabajo de tesis doctoral de Juan Cadiñanos. Ese fue el punto de partida de una productiva línea de investigación que ha permitido importantes avances en el conocimiento y el tratamiento de las enfermedades que cursan con envejecimiento acelerado. El presente trabajo es una colaboración entre los laboratorios de López-Otín y Juan Cadiñanos, del Instituto de Medicina Oncológica y Molecular de Asturias, y forma parte del proyecto de tesis doctoral de Jorge de la Rosa, que explora los mecanismos responsables del envejecimiento acelerado y sus conexiones con el cáncer.

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