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Prelamin A causes progeria through cell-extrinsic mechanisms and prevents cancer invasion

Author

Listed:
  • Jorge de la Rosa

    (Instituto de Medicina Oncológica y Molecular de Asturias (IMOMA))

  • José M.P. Freije

    (Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo)

  • Rubén Cabanillas

    (Instituto de Medicina Oncológica y Molecular de Asturias (IMOMA))

  • Fernando G. Osorio

    (Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo)

  • Mario F. Fraga

    (Unidad de Epigenética del Cáncer, IUOPA, Universidad de Oviedo)

  • M. Soledad Fernández-García

    (Unidad de Histopatología Molecular, IUOPA, Universidad de Oviedo)

  • Roland Rad

    (Klinikum Rechts der Isar; Technische Universität München
    Technische Universität München
    German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
    Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK)

  • Víctor Fanjul

    (Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo)

  • Alejandro P. Ugalde

    (Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo)

  • Qi Liang

    (Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK)

  • Haydn M. Prosser

    (Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK)

  • Allan Bradley

    (Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK)

  • Juan Cadiñanos

    (Instituto de Medicina Oncológica y Molecular de Asturias (IMOMA)
    Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK)

  • Carlos López-Otín

    (Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo)

Abstract

Defining the relationship between ageing and cancer is a crucial but challenging task. Mice deficient in Zmpste24, a metalloproteinase mutated in human progeria and involved in nuclear prelamin A maturation, recapitulate multiple features of ageing. However, their short lifespan and serious cell-intrinsic and cell-extrinsic alterations restrict the application and interpretation of carcinogenesis protocols. Here we present Zmpste24 mosaic mice that lack these limitations. Zmpste24 mosaic mice develop normally and keep similar proportions of Zmpste24-deficient (prelamin A-accumulating) and Zmpste24-proficient (mature lamin A-containing) cells throughout life, revealing that cell-extrinsic mechanisms are preeminent for progeria development. Moreover, prelamin A accumulation does not impair tumour initiation and growth, but it decreases the incidence of infiltrating oral carcinomas. Accordingly, silencing of ZMPSTE24 reduces human cancer cell invasiveness. Our results support the potential of cell-based and systemic therapies for progeria and highlight ZMPSTE24 as a new anticancer target.

Suggested Citation

  • Jorge de la Rosa & José M.P. Freije & Rubén Cabanillas & Fernando G. Osorio & Mario F. Fraga & M. Soledad Fernández-García & Roland Rad & Víctor Fanjul & Alejandro P. Ugalde & Qi Liang & Haydn M. Pros, 2013. "Prelamin A causes progeria through cell-extrinsic mechanisms and prevents cancer invasion," Nature Communications, Nature, vol. 4(1), pages 1-9, October.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3268
    DOI: 10.1038/ncomms3268
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