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A melanoma-associated germline mutation in exon 1β inactivates p14ARF

Oncogene volume 20, pages 5543–5547 (2001)Cite this article

Abstract

The INK4a/ARF locus encodes the cyclin dependent kinase inhibitor, p16INK4a and the p53 activator, p14ARF. These two proteins have an independent first exon (exon 1α and exon 1β, respectively) but share exons 2 and 3 and are translated in different reading frames. Germline mutations in this locus are associated with melanoma susceptibility in 20–40% of multiple case melanoma families. Although most of these mutations specifically inactivate p16INK4a, more than 40% of the INK4a/ARF alterations located in exon 2, affect both p16INK4a and p14ARF. We now report a 16 base pair exon 1β germline insertion specifically altering p14ARF, but not p16INK4a, in an individual with multiple primary melanomas. This mutant p14ARF, 60ins16, was restricted to the cytoplasm, did not stabilize p53 and was unable to arrest the growth of a p53 expressing melanoma cell line. This is the first example of an exon 1β mutation that inactivates p14ARF, and thus implicates a role for this tumour suppressor in melanoma predisposition.

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Acknowledgements

The identification of melanoma-associated mutations was performed within the multidisciplinary malignant melanoma group integrated by: Tessa Castel, Carles Conill, Francisco Cuellar, Loli Jimenez, Josep Malvehy, Rosa Marti, Begoña Mellado, Josep Palou, Susana Puig, Ramón Rull, Jordi Segura, Jose Soler, Mauricio Vera, Sergi Vidal, Antoni Vilalta, Ramón Vilella and Eva Yachi. We thank Dr Tom Shenk for supplying the pCMVEGFP-spectrin plasmid. This work was supported by the National Health and Medical Research Council, the NSW Cancer Council, the NSW Health Department, the Fondo de Investigaciones Sanitarias and Generalitat de Catalunya.

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  1. Helen Rizos and Susana Puig: H Rizos and S Puig contributed equally to this work

Authors and Affiliations

  1. Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead NSW 2145, Australia

    Helen Rizos, Artur P Darmanian & Richard F Kefford

  2. Hospital Clinic, IDIBAPS, Universitat de Barcelona, 08036 Barcelona, Spain

    Susana Puig, Cèlia Badenas, Josep Malvehy, Loli Jiménez & Montserrat Milà

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  1. Helen Rizos
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  2. Susana Puig
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Correspondence to Helen Rizos or Susana Puig.

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Rizos, H., Puig, S., Badenas, C. et al. A melanoma-associated germline mutation in exon 1β inactivates p14ARF. Oncogene 20, 5543–5547 (2001). https://doi.org/10.1038/sj.onc.1204728

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