title: Accelerated ageing in mice deficient in Zmpste24 protease is linked to p53 signalling activation.
abstract: 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.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Varela
authors.forename: Juan
authors.initials: J
authors.lastname: Cadiñanos
authors.forename: Alberto M
authors.initials: AM
authors.lastname: Pendás
authors.forename: Ana
authors.initials: A
authors.lastname: Gutiérrez-Fernández
authors.forename: Alicia R
authors.initials: AR
authors.lastname: Folgueras
authors.forename: Luis M
authors.initials: LM
authors.lastname: Sánchez
authors.forename: Zhongjun
authors.initials: Z
authors.lastname: Zhou
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Rodríguez
authors.forename: Colin L
authors.initials: CL
authors.lastname: Stewart
authors.forename: José A
authors.initials: JA
authors.lastname: Vega
authors.forename: Karl
authors.initials: K
authors.lastname: Tryggvason
authors.forename: José M P
authors.initials: JM
authors.lastname: Freije
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Otín
mesh_terms: 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*
chemical_list: D034904:Lamin Type A; D008565:Membrane Proteins; D016159:Tumor Suppressor Protein p53; D008666:Metalloendopeptidases; C491250:Zmpste24 protein, mouse