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INK4a‐deficient human diploid fibroblasts are resistant to RAS‐induced senescence
Author(s) -
Brookes Sharon,
Rowe Janice,
Ruas Margarida,
Llanos Susana,
Clark Paula A.,
Lomax Martine,
James Marion C.,
Vatcheva Radost,
Bates Stewart,
Vousden Karen H.,
Parry David,
Gruis Nelleke,
Smit Nico,
Bergman Wilma,
Peters Gordon
Publication year - 2002
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/cdf289
Subject(s) - biology , cdkn2a , ectopic expression , telomerase , senescence , somatic cell , genetics , locus (genetics) , ploidy , frameshift mutation , gene , population , cancer research , microbiology and biotechnology , phenotype , demography , sociology
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.