Zmpste24 (also called FACE-1) is a metalloproteinase involved in the maturation of lamin A (Lmna), an essential component of the nuclear envelope1,2,3. Both Zmpste24- and Lmna-deficient mice exhibit profound nuclear architecture abnormalities and multiple histopathological defects that phenocopy an accelerated ageing process1,2,4,5. Similarly, diverse human progeroid syndromes are caused by mutations in ZMPSTE24 or LMNA genes6,7,8,9,10. To elucidate the molecular mechanisms underlying these devastating diseases, we have analysed the transcriptional alterations occurring in tissues from Zmpste24-deficient mice. We demonstrate that Zmpste24 deficiency 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 in Zmpste24-/-Lmna+/- mice and partially reversed in Zmpste24-/-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 ageing11.
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We thank A. Astudillo for help with histopathological analysis; E. Fermiñán (CIC-Salamanca) for help with microarray experiments; X. S. Puente, A. Fueyo, J. Alvarez, P. Zuazua, G. Velasco, A. Bernad, S. Laín and M. Serrano for support and comments; T. Sánchez and L. Santos for help in animal care facilities; and M. Fernández, S. Alvarez and M. S. Pitiot for technical assistance. This work was supported by grants from Ministerio de Educación y Ciencia, Fundación “La Caixa”, the European Union, the Swedish Research Council, the Swedish Cancer Society and the Research Grant Council of Hong Kong. The Instituto Universitario de Oncología is supported by Obra Social Cajastur, and Red de Centros de Cancer Instituto Carlos III, Spain.
Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.
Progeria in Zmpste24-deficient mice. (PDF 86 kb)
p21 overexpression in tissues from Zmpste24-null mice. (PDF 75 kb)
p21 overexpression in Zmpste24-deficient mice increases with age and phenotype severity. (PDF 47 kb)
Heterochromatin alterations in Zmpste24-deficient mice. (PDF 92 kb)
Lack of increased apoptosis in Zmpste24-null mice . (PDF 39 kb)
Retinoblastoma protein levels (pRb) are decreased in liver from Zmpste24-deficient mice. (PDF 39 kb)
Full text to accompany the above Supplementary Figures. (DOC 30 kb)
Transcriptional alterations in tissues from Zmpste24- and Lmna- deficient mice. (PDF 49 kb)
Analysis of potential alternative splicing forms of mouse p53 mRNA in wild-type and Zmpste24-deficient mice. (PDF 24 kb)
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Varela, I., Cadiñanos, J., Pendás, A. et al. Accelerated ageing in mice deficient in Zmpste24 protease is linked to p53 signalling activation. Nature 437, 564–568 (2005). https://doi.org/10.1038/nature04019
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