Accelerated ageing in mice deficient in Zmpste24 protease is linked to p53 signalling activation.
Zmpste24 (also called FACE-1) is a metalloproteinase involved in the maturation of lamin A (Lmna), an essential component of the nuclear envelope. Both Zmpste24- and Lmna-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 in ZMPSTE24 or LMNA genes. 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 ageing.
Varela
Ignacio
I
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain.
Cadiñanos
Juan
J
Pendás
Alberto M
AM
Gutiérrez-Fernández
Ana
A
Folgueras
Alicia R
AR
Sánchez
Luis M
LM
Zhou
Zhongjun
Z
Rodríguez
Francisco J
FJ
Stewart
Colin L
CL
Vega
José A
JA
Tryggvason
Karl
K
Freije
José M P
JM
López-Otín
Carlos
C
D000375:Aging / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D017353:Gene Deletion; D006579:Heterozygote; D034904:Lamin Type A / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D008666:Metalloendopeptidases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D034904:Lamin Type A; D008565:Membrane Proteins; D016159:Tumor Suppressor Protein p53; D008666:Metalloendopeptidases; C491250:Zmpste24 protein, mouse