Letter | Published:

Oncogenic activity of Cdc6 through repression of the INK4/ARF locus

Nature volume 440, pages 702706 (30 March 2006) | Download Citation

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Abstract

The INK4/ARF locus encodes three tumour suppressors (p15INK4b, ARF and p16INK4a) and is among the most frequently inactivated loci in human cancer1,2. However, little is known about the mechanisms that govern the expression of this locus. Here we have identified a putative DNA replication origin at the INK4/ARF locus that assembles a multiprotein complex containing Cdc6, Orc2 and MCMs, and that coincides with a conserved noncoding DNA element (regulatory domain RDINK4/ARF). Targeted and localized RNA-interference-induced heterochromatinization of RDINK4/ARF results in transcriptional repression of the locus, revealing that RDINK4/ARF is a relevant transcriptional regulatory element. Cdc6 is overexpressed in human cancers, where it might have roles in addition to DNA replication3,4,5. We have found that high levels of Cdc6 result in RDINK4/ARF-dependent transcriptional repression, recruitment of histone deacetylases and heterochromatinization of the INK4/ARF locus, and a concomitant decrease in the expression of the three tumour suppressors encoded by this locus. This mechanism is reminiscent of the silencing of the mating-type HM loci in yeast by replication factors6. Consistent with its ability to repress the INK4/ARF locus, Cdc6 has cellular immortalization activity and neoplastic transformation capacity in cooperation with oncogenic Ras. Furthermore, human lung carcinomas with high levels of Cdc6 are associated with low levels of p16INK4a. We conclude that aberrant expression of Cdc6 is oncogenic by directly repressing the INK4/ARF locus through the RDINK4/ARF element.

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Acknowledgements

S.G. was supported by the Human Frontiers Science Program Organization and by the FIS from the Spanish Ministry of Health. Research was supported by the CNIO and by grants from the Spanish Ministry of Education and Science (to M.S., F.A. and J.M.), the European Union project INTACT (to M.S.) and Fundacion Caja Madrid (to J.M.).

Author information

Affiliations

  1. Tumor Suppression Group,

    • Susana Gonzalez
    • , Peter Klatt
    •  & Manuel Serrano
  2. Lung Cancer Group, and

    • Esther Conde
    •  & Montserrat Sanchez-Cespedes
  3. DNA Replication Group, Spanish National Cancer Research Center (CNIO), E-28029 Madrid, Spain

    • Juan Mendez
  4. Instituto de Microbiología Bioquímica, CSIC/Universidad de Salamanca, E-37007 Salamanca, Spain

    • Sonia Delgado
    •  & Francisco Antequera
  5. Departamento de Anatomía Patológica, Hospital Universitario “12 de Octubre”, E-28041 Madrid, Spain

    • Fernando Lopez-Rios

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Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Corresponding author

Correspondence to Manuel Serrano.

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    Supplementary Notes

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https://doi.org/10.1038/nature04585

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