Increased gene dosage of Ink4a/Arf results in cancer resistance and normal aging

  1. Ander Matheu1,
  2. Cristina Pantoja1,4,
  3. Alejo Efeyan1,
  4. Luis M. Criado2,
  5. Juan Martín-Caballero1,
  6. Juana M. Flores3,
  7. Peter Klatt1, and
  8. Manuel Serrano1,5
  1. 1Spanish National Cancer Center (CNIO), Madrid E-28029, Spain; 2Spanish National Center of Biotechnology (CNB-CSIC), Campus de Cantoblanco, Madrid E-28049, Spain; 3Complutense University of Madrid, Department of Animal Surgery and Medicine, Madrid E-28040, Spain

Abstract

Mammalian genes frequently present allelic variants that differ in their expression levels and that, in the case of tumor suppressor genes, can be of relevance for cancer susceptibility and aging. We report here the characterization of a novel mouse model with increased activity for the Ink4a and Arf tumor suppressors. We have generated a “super Ink4a/Arf” mouse strain carrying a transgenic copy of the entire Ink4a/Arf locus. Cells derived from super Ink4a/Arf mice have increased resistance to in vitro immortalization and oncogenic transformation. Importantly, super Ink4a/Arf mice manifest higher resistance to cancer compared to normal, nontransgenic, mice. Finally, super Ink4a/Arf mice have normal aging and lifespan. Together, these results indicate that modest increases in the activity of the Ink4a/Arf tumor suppressor result in a beneficial cancer-resistant phenotype without affecting normal viability or aging.

Keywords

Footnotes

  • Supplemental material is available at http://www.genesdev.org.

  • Article published online ahead of print. Article and publication date are at http://www.genesdev.org/cgi/doi/10.1101/gad.310304.

  • ↵4 Present address: The Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Ziekenhuis Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.

  • ↵5 Corresponding author. E-MAIL mserrano{at}cnio.es; FAX 34-917-328-028.

    • Accepted September 10, 2004.
    • Received May 21, 2004.
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  1. Published in Advance November 1, 2004, doi: 10.1101/gad.310304 Genes & Dev. 2004. 18: 2736-2746 Copyright © 2004, by Cold Spring Harbor Laboratory Press

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