Role of the alternative INK4A proteins in human keratinocyte senescence : Evidence for the specific inactivation of p16INK4A upon immortalization

The INK4A locus on human chromosome 9p21 encodes two genes that have been implicated in replicative senescence and tumor suppression, p16INK4A and p14ARF. In contrast to p16INK4A, which is up-regulated to high levels, we were unable to detect p14ARF protein in senescent human keratinocytes. Also, p5...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 1999-06, Vol.59 (11), p.2516-2521
Main Authors: MUNRO, J, STOTT, F. J, VOUSDEN, K. H, PETERS, G, PARKINSON, E. K
Format: Article
Language:English
Subjects:
3T3 Cells
Ageing, cell death
Animals
Biological and medical sciences
Carcinoma, Squamous Cell - genetics
Carcinoma, Squamous Cell - metabolism
Cell Line, Transformed
Cell physiology
Cellular Senescence - genetics
Cellular Senescence - physiology
Cyclin-Dependent Kinase Inhibitor p16 - genetics
Cyclin-Dependent Kinase Inhibitor p16 - metabolism
Cyclin-Dependent Kinase Inhibitor p21
Cyclins - metabolism
Exons - genetics
Fundamental and applied biological sciences. Psychology
Gene Deletion
Humans
Keratinocytes - physiology
Mice
Molecular and cellular biology
Proteins - genetics
Proteins - physiology
Tumor Cells, Cultured
Tumor Suppressor Protein p14ARF
Tumor Suppressor Protein p53 - metabolism
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Summary:The INK4A locus on human chromosome 9p21 encodes two genes that have been implicated in replicative senescence and tumor suppression, p16INK4A and p14ARF. In contrast to p16INK4A, which is up-regulated to high levels, we were unable to detect p14ARF protein in senescent human keratinocytes. Also, p53, an established target of p14ARF, did not increase, suggesting that p14ARF is not instrumental in human keratinocyte senescence. In neoplastic keratinocyte cultures, p16INK4A inactivation was invariably associated with the immortal phenotype, and there was evidence for the inactivation of p16INK4A, independent of p14ARF, in 6 of 10 lines that lacked large homozygous deletions. In contrast, we failed to detect exon 1beta mutations or p16INK4A-independent deletions. These results emphasize the previously proposed role for p16INK4A in human keratinocyte senescence but do not rule out a supporting role for p14ARF inactivation.
ISSN:0008-5472
1538-7445