Accelerated ageing in mice deficient in Zmpste24 protease is linked to p53 signalling activation

Varela, Ignacio
Cadiñanos, Juan
Pendás, Alberto M.
Gutiérrez-Fernández, Ana
Folgueras, Alicia R.
Sánchez, Luis M.
Zhou, Zhongjun
Rodríguez, Francisco J.
Stewart, Colin L.
Vega, José A
Tryggvason, Karl
Freije, José M. P.
López-Otín, Carlos

¹Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, and ²Departamento de Morfología y Biología Celular, Universidad de Oviedo, 33006 Oviedo, Spain. ³Division of Matrix Biology, Department of Biochemistry and Biophysics, Karolinska Institutet, Stockholm S-17177, Sweden. ⁴National Cancer Institute, Frederick, Maryland 21702, USA.

doi:10.1038/nature04019

†Present address: Department of Biochemistry, Facult of Medicine, University of Hong Kong, Pok Fu Lam, Hong Kong.

*These authors contributed equally to this work.

Received 19 May; accepted 20 July 2005.

Published online 3 August 2005.

Supplementary Information is linked to the online version of the paper at www.nature.com/nature.

Author Information Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests. Correspondence and requests for materials should be addressed to C.L.-O. ([email protected]).

Nature 437(7058):p 564-568, September 22, 2005.

Zmpste24 (also called FACE-1) is a metalloproteinase involved in the maturation of lamin A (Lmna), an essential component of the nuclear envelope. BothZmpste24- andLmna-deficient mice exhibit profound nuclear architecture abnormalities and multiple histopathological defects that phenocopy an accelerated ageing process. Similarly, diverse human progeroid syndromes are caused by mutations inZMPSTE24orLMNAgenes. To elucidate the molecular mechanisms underlying these devastating diseases, we have analysed the transcriptional alterations occurring in tissues fromZmpste24-deficient mice. We demonstrate thatZmpste24deficiency elicits a stress signalling pathway that is evidenced by a marked upregulation of p53 target genes, and accompanied by a senescence phenotype at the cellular level and accelerated ageing at the organismal level. These phenotypes are largely rescued inZmpste24^−/−Lmna^+/−mice and partially reversed inZmpste24^−/−p53^−/−mice. These findings provide evidence for the existence of a checkpoint response activated by the nuclear abnormalities caused by prelamin A accumulation, and support the concept that hyperactivation of the tumour suppressor p53 may cause accelerated ageing.