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Different cooperating effect of p21 or p27 deficiency in combination with INK4a/ARF deletion in mice

Oncogene volume 23, pages 8231–8237 (2004)Cite this article

Abstract

The control exerted by the INK4a/ARF locus on cellular proliferation is crucial to restrict tumor development. In agreement with this, mice with defects in this locus are highly tumor prone. However, the potential contribution of other pathways in modulating tumorigenesis in the absence of INK4a/ARF is largely unexplored. In the present study, we investigated the consequences of the combined loss of either of two cyclin-dependent kinase inhibitors, p21 and p27, in cooperation with deletion of the INK4a/ARF locus. Our results show a clear differential effect in tumorigenesis depending on the CKI that is absent. The absence of p21 produced no overt alteration of the lifespan of the INK4a/ARF-null mice, although it modified their tumor spectrum, causing a significant increase in the incidence of fibrosarcomas and the appearance of a small number of rhabdomyosarcomas. In contrast, deficiency of p27 resulted in a significant increase in lethality due to accelerated tumor development, especially in the case of T-cell lymphomas. Finally, combined deficiency of INK4a/ARF and p27 resulted in a significant increase in the number of metastatic tumors. These results demonstrate genetically the oncogenic cooperation between defects on INK4a/ARF and p27, which are common alterations in human cancer.

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Acknowledgements

We thank Anxo Vidal for critical reading of the article and Pedro Aranda for excellent technical support with histopathology. Work at the laboratory of MS has been funded by the Spanish Ministry of Science and Technology (SAF2002-03402) and by the European Union (QLRT-2000-02084, QLRT-2000-00616 and INTACT).

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Authors and Affiliations

  1. Molecular Oncology Program, Spanish National Cancer Center (CNIO), Melchor Fernandez Almagro 3, Madrid, E-28029, Spain

    Juan Martín-Caballero, Manuel Collado & Manuel Serrano

  2. Animal Surgery and Medicine Department, Facultad de Veterinaria, Universidad Complutense de Madrid, Madrid, E-28040, Spain

    Juana M Flores & Pilar García-Palencia

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  1. Juan Martín-Caballero
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  2. Juana M Flores
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  3. Pilar García-Palencia
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Correspondence to Manuel Serrano.

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Martín-Caballero, J., Flores, J., García-Palencia, P. et al. Different cooperating effect of p21 or p27 deficiency in combination with INK4a/ARF deletion in mice. Oncogene 23, 8231–8237 (2004). https://doi.org/10.1038/sj.onc.1207863

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