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The CDKN2A tumour suppressor locus encodes two distinct proteins, p16(INK4a) and p14(ARF), both of which have been implicated in replicative senescence, the state of permanent growth arrest provoked in somatic cells by aberrant proliferative signals or by cumulative population doublings in culture. Here we describe primary fibroblasts from a member of a melanoma-prone family who is homozygous for an intragenic deletion in CDKN2A. Analyses of the resultant gene products imply that the cells are p16(INK4a) deficient but express physiologically relevant levels of a frameshift protein that retains the known functions of p14(ARF). Although they have a finite lifespan, the cells are resistant to arrest by oncogenic RAS. Indeed, ectopic expression of RAS and telomerase (hTERT) results in outgrowth of anchorage-independent colonies that have essentially diploid karyotypes and functional p53. We find that in human fibroblasts, ARF is not induced demonstrably by RAS, pointing to significant differences between the proliferative barriers implemented by the CDKN2A locus in different cell types or species.

Original publication

DOI

10.1093/emboj/cdf289

Type

Journal article

Journal

EMBO J

Publication Date

17/06/2002

Volume

21

Pages

2936 - 2945

Keywords

Adult, Animals, Cell Aging, Cells, Cultured, Child, Cyclin-Dependent Kinase Inhibitor p16, DNA-Binding Proteins, Fibroblasts, Gene Deletion, Humans, In Situ Hybridization, Fluorescence, Male, Recombinant Fusion Proteins, Telomerase, Tumor Suppressor Protein p14ARF, Tumor Suppressor Protein p53, Ultraviolet Rays, ras Proteins