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

Nature volume 440, pages 702–706 (2006)Cite this article

A Retraction to this article was published on 13 July 2017

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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Figure 1: Identification of a regulatory domain, RDINK4/ARF, in the INK4/ARF locus.
Figure 2: Binding of Cdc6 to RDINK4/ARF and repression of the INK4/ARF locus.
Figure 3: Oncogenic activity of Cdc6.
Figure 4: Reciprocal relationship between Cdc6 and p16INK4a protein levels in primary NSCLCs.

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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.).

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Authors and Affiliations

  1. Tumor Suppression Group,

    Susana Gonzalez, Peter Klatt & Manuel Serrano

  2. Lung Cancer Group,

    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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Correspondence to Manuel Serrano.

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Gonzalez, S., Klatt, P., Delgado, S. et al. Oncogenic activity of Cdc6 through repression of the INK4/ARF locus. Nature 440, 702–706 (2006). https://doi.org/10.1038/nature04585

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