Accelerated ageing in mice deficient in Zmpste24 protease is linked to p53 signalling activation (original) (raw)

• Letter
• Published: 03 August 2005
• Juan Cadiñanos1 nAff6,
• Alberto M. Pendás1,
• Ana Gutiérrez-Fernández1,
• Alicia R. Folgueras1,
• Luis M. Sánchez1,
• Zhongjun Zhou3 na1,
• Francisco J. Rodríguez1,
• Colin L. Stewart4,
• José A Vega2,
• Karl Tryggvason3,
• José M. P. Freije1 &
• …
• Carlos López-Otín1

Nature volume 437, pages 564–568 (2005)Cite this article

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Abstract

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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Acknowledgements

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.

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Author notes

1. Ignacio Varela & Juan Cadiñanos
   Present address: Department of Biochemistry, Facult of Medicine, University of Hong Kong, Pok Fu Lam, Hong Kong
2. Zhongjun Zhou: *These authors contributed equally to this work

Authors and Affiliations

1. Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología,
   Ignacio Varela, Juan Cadiñanos, Alberto M. Pendás, Ana Gutiérrez-Fernández, Alicia R. Folgueras, Luis M. Sánchez, Francisco J. Rodríguez, José M. P. Freije & Carlos López-Otín
2. Departamento de Morfología y Biología Celular, Universidad de Oviedo, 33006, Oviedo, Spain
   José A Vega
3. Division of Matrix Biology, Department of Biochemistry and Biophysics, Karolinska Institutet, S-17177, Stockholm, Sweden
   Zhongjun Zhou & Karl Tryggvason
4. National Cancer Institute, Maryland, 21702, Frederick, USA
   Colin L. Stewart

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1. Ignacio Varela
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2. Juan Cadiñanos
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3. Alberto M. Pendás
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4. Ana Gutiérrez-Fernández
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5. Alicia R. Folgueras
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6. Luis M. Sánchez
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7. Zhongjun Zhou
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9. Colin L. Stewart
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11. Karl Tryggvason
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Correspondence toCarlos López-Otín.

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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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• Received: 19 May 2005
• Accepted: 20 July 2005
• Published: 03 August 2005
• Issue Date: 22 September 2005
• DOI: https://doi.org/10.1038/nature04019

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Editorial Summary

Linking p53 and ageing

A paper published in Nature in January 2002 caught the attention of those working on both ageing and cancer researcher: mice with a hyperactive p53 tumour suppressor gene were resistant to cancer but, here was the surprise, also showed signs of premature ageing. The link between p53 signalling and ageing is further explored in a study of the molecular mechanisms behind the striking accelerated ageing observed in mutant mice deficient in a metalloprotease called Zmpste24, a condition similar to some premature ageing syndromes in humans. The protease deficiency induces a p53 signalling pathway, accompanied by increased cellular senescence and accelerated ageing at the organismal level.