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Biallelic Mutations in p16INK4a Confer Resistance to Ras- and Ets-Induced Senescence in Human Diploid Fibroblasts
Open accessAbstract
The INK4a/ARF tumor suppressor locus is implicated in the senescence-like growth arrest provoked by oncogenic Ras in primary cells. INK4a and ARF are distinct proteins encoded by transcripts in which a shared exon is decoded in alternative reading frames. Here we analyze dermal fibroblasts (designated Q34) from an individual carrying independent missense mutations in each copy of the common exon. Both mutations alter the amino acid sequence of INK4a and functionally impair the protein, although they do so to different degrees. Only one of the mutations affects the sequence of ARF, causing an apparently innocuous change near its carboxy terminus. Unlike normal human fibroblasts, Q34 cells are not permanently arrested by Ras or its downstream effectors Ets1 and Ets2. Moreover, ectopic Ras enables the cells to grow as anchorage-independent colonies, and in relatively young Q34 cells anchorage independence can be achieved without addition of telomerase or perturbation of the p53 pathway. Whereas ARF plays the principal role in Ras-induced arrest of mouse fibroblasts, our data imply that INK4a assumes this role in human fibroblasts.
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“Nonetheless, some human fibroblasts express very little p16 and thus also rely primarily on the p53 pathway for the senescence response; however, such cells senesce in response to overexpressed oncogenic RAS (Beausejour et al., 2003) which is thought to require p16 activity (Brookes et al., 2002; Huot et al., 2002).”
From Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors (2005) · cites this paper as Huot et al., 2002
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Metadata
- Authors
- Huot, T. J., Rowe, J., Harland, M., Drayton, S., Brookes, S., Gooptu, C., Purkis, P., Fried, M., Bataille, V., Hara, E., Newton-Bishop, J., & Peters, G.
- Affiliations
- Cancer Research UK (GB)
- University of California, San Francisco (US)
- St Thomas' Hospital (GB)
- Cancer Research UK Manchester Institute (GB)
- Cancer Research UK Genetic Epidemiology Laboratory, St. James University Hospital, Leeds LS9 7TF
- Corresponding author
- Peters, Gordon
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2002-12-01
- Volume
- 22
- Issue
- 23
- Pages
- 8135-8143
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC134058
- OpenAlex
- W2153125876
- Cited by
- 107
- References
- 55
- Citations by year
- 2025: 1 · 2021: 4 · 2020: 1 · 2018: 2 · 2015: 1 · 2013: 4 · 2012: 2
- FWCI
- 8.79
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Molecular and Cellular Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- p16INK4a, ARF, INK4a/ARF locus, senescence, oncogenic Ras, ETS1, ETS2, dermal fibroblasts, biallelic variants, missense mutations, senescence resistance, anchorage-independent growth, telomerase, p53 pathway, tumor suppressor, alternative reading frame
- MeSH terms
- Adult, Alleles, Animals, Cell Line, Female, Fibroblasts, Gene Expression Regulation, Humans, Male, Melanoma, Mutation, Proto-Oncogene Proteins, Transcription Factors, Tumor Suppressor Protein p53, Cellular Senescence, ras Proteins, Cyclin-Dependent Kinases, Cyclin-Dependent Kinase Inhibitor p16, Dermis, Tumor Suppressor Protein p14ARF, Proto-Oncogene Proteins c-ets, Proto-Oncogene Protein c-ets-1, Cyclin-Dependent Kinase 4
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