INK4a-deficient human diploid fibroblasts are resistant to RAS-induced senescence
| Autor: | Susana Llanos, Nelleke A. Gruis, Karen H. Vousden, Paula A. Clark, Stewart Bates, Gordon Peters, Margarida Ruas, Marion C. James, Janice Rowe, Radost Vatcheva, Sharon Brookes, Martine Lomax, Nico P.M. Smit, David A.D. Parry, Wilma Bergman |
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| Rok vydání: | 2002 |
| Předmět: |
Adult
Male Telomerase Ultraviolet Rays Somatic cell Recombinant Fusion Proteins Population Biology Article General Biochemistry Genetics and Molecular Biology p14arf CDKN2A Tumor Suppressor Protein p14ARF Animals Humans Telomerase reverse transcriptase Child education neoplasms Molecular Biology Cells Cultured Cellular Senescence Cyclin-Dependent Kinase Inhibitor p16 In Situ Hybridization Fluorescence education.field_of_study General Immunology and Microbiology General Neuroscience Fibroblasts DNA-Binding Proteins ras Proteins Cancer research Ectopic expression Tumor Suppressor Protein p53 Cell aging Gene Deletion |
| Zdroj: | The EMBO Journal. 21:2936-2945 |
| ISSN: | 1460-2075 |
| DOI: | 10.1093/emboj/cdf289 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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