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  • The EMBO Journal (1998) 17, 5001 - 5014
  • doi:10.1093/emboj/17.17.5001

The alternative product from the human CDKN2A locus, p14ARF, participates in a regulatory feedback loop with p53 and MDM2

Francesca J. Stott1, Stewart Bates2, Marion C. James1, Beth B. McConnell1, Maria Starborg1, Sharon Brookes1, Ignacio Palmero1,3, Kevin Ryan2, Eiji Hara1,4, Karen H. Vousden2 and Gordon Peters1

  1. Imperial Cancer Research Fund Laboratories, P.O. Box 123, 44 Lincoln's Inn Fields, London WC2A 3PX, UK
  2. NCI-Frederick Cancer Research and Development Center, Building 560, Room 22-96, West 7th Street, Frederick, MD 21702-1201, USA
  3. Centro Nacional de Biotecnologia, Campus Universidad Autonoma, Cantoblanco, 28049 Madrid, Spain
  4. Department of Preventive Medicine, 22nd Department of Surgery, Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602 Japan

Correspondence to:

Gordon Peters, E-mail: peters@icrf.icnet.uk

Received 8 May 1998; Accepted 6 July 1998; Revised 2 July 1998

The two distinct proteins encoded by the CDKN2A locus are specified by translating the common second exon in alternative reading frames. The product of the alpha transcript, p16INK4a, is a recognized tumour suppressor that induces a G1 cell cycle arrest by inhibiting the phosphorylation of the retinoblastoma protein by the cyclin-dependent kinases, CDK4 and CDK6. In contrast, the product of the human CDKN2A beta transcript, p14ARF, activates a p53 response manifest in elevated levels of MDM2 and p21CIP1 and cell cycle arrest in both G1 and G2/M. As a consequence, p14ARF-induced cell cycle arrest is p53 dependent and can be abrogated by the co-expression of human papilloma virus E6 protein. p14ARF acts by binding directly to MDM2, resulting in the stabilization of both p53 and MDM2. Conversely, p53 negatively regulates p14ARF expression and there is an inverse correlation between p14ARF expression and p53 function in human tumour cell lines. However, p14ARF expression is not involved in the response to DNA damage. These results place p14ARF in an independent pathway upstream of p53 and imply that CDKN2A encodes two proteins that are involved in tumour suppression.

  • Keywords:

    • cell cycle,
    • MDM2,
    • p53 response,
    • replicative senescence,
    • tumour suppression