INK4a-deficient human diploid fibroblasts are resistant to RAS-induced senescence

AUTOR(ES)

Brookes, Sharon

FONTE

Oxford University Press

RESUMO

The CDKN2A tumour suppressor locus encodes two distinct proteins, p16INK4a and p14ARF, 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 p16INK4a deficient but express physiologically relevant levels of a frameshift protein that retains the known functions of p14ARF. 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.

Documentos Relacionados

• Normal Human Fibroblasts Are Resistant to RAS-Induced Senescence
• Biallelic Mutations in p16INK4a Confer Resistance to Ras- and Ets-Induced Senescence in Human Diploid Fibroblasts
• Abolition of Cyclin-Dependent Kinase Inhibitor p16Ink4a and p21Cip1/Waf1 Functions Permits Ras-Induced Anchorage-Independent Growth in Telomerase-Immortalized Human Fibroblasts
• Suppression of Ras-Induced Apoptosis by the Rac GTPase
• Role of phosphatidylinositide metabolism in ras-induced Xenopus oocyte maturation.