INK4a‐deficient human diploid fibroblasts are resistant to RAS‐induced senescence
Open accessAbstract
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.
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Loss of INK4a alone appears sufficient to override senescence in some human fibroblast strains.
“However, loss of INK4a alone appears sufficient to override senescence in some human fibroblast strains (Brookes et al., 2002)”
From Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence (2003) · cites this paper as Brookes et al., 2002
The paper’s opening summary reports that p16 INK4a-deficient human fibroblasts retaining p14 ARF function resist oncogenic RAS-induced arrest. But it also says the cells have a finite lifespan, so loss of INK4a alone is not shown to override senescence generally; the supported claim is limited to RAS-induced senescence. (LLM, conf=0.87)
Experimental — accuracy not yet measuredCell culture studies indicate that p16 prevents the reversal of senescence by p53 inactivation and is required for RAS-induced senescence.
“Cell culture studies indicate that p16 prevents the reversal of senescence by p53 inactivation (Beausejour et al., 2003) and is required for RAS-induced senescence (Brookes et al., 2002; Benanti and Galloway, 2004).”
From Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors (2005) · cites this paper as Brookes et al., 2002
Some human fibroblasts express very little p16 and thus rely primarily on the p53 pathway for the senescence response; however, such cells senesce in response to overexpressed oncogenic RAS, which is thought to require p16 activity.
“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 Brookes et al., 2002
In human fibroblasts that carry p16 gene inactivating mutations, senescence is bypassed.
“In human fibroblasts that carry p16 gene inactivating mutations, senescence is bypassed [53].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [53]
Loss of functional p16 but not of p53 enables human fibroblasts to avoid Ras-induced senescence.
“Conversely, loss of functional p16 [53] but not of p53 [51,76] enables human fibroblasts to avoid Ras-induced senescence.”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [53]
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- Authors
- Brookes, S., Rowe, J., Ruas, M., Llanos, S., Clark, P. A., Lomax, M., James, M. C., Vatcheva, R., Bates, S., Vousden, K. H., Parry, D., Gruis, N., Smit, N., Bergman, W., & Peters, G.
- Affiliations
- Cancer Research UK (GB)
- Leiden University (NL)
- Corresponding author
- Peters, Gordon
- Venue
- The EMBO Journal
- Published
- 2002-06-17
- Volume
- 21
- Issue
- 12
- Pages
- 2936-2945
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC126048
- OpenAlex
- W2167097066
- Cited by
- 220
- References
- 15
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 1 · 2023: 3 · 2021: 8 · 2020: 2 · 2019: 3 · 2018: 3 · 2017: 2 · 2016: 1 · 2015: 7 · 2014: 9 · 2013: 7 · 2012: 5
- FWCI
- 16.21
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › 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
- CDKN2A, p16INK4a, p14ARF, replicative senescence, oncogenic Ras, fibroblasts, telomerase, hTERT, p53, anchorage-independent growth, karyotype
- MeSH terms
- Adult, Animals, Cells, Cultured, Child, DNA-Binding Proteins, Fibroblasts, Humans, Male, Recombinant Fusion Proteins, Ultraviolet Rays, Tumor Suppressor Protein p53, Cellular Senescence, Gene Deletion, In Situ Hybridization, Fluorescence, ras Proteins, Telomerase, Cyclin-Dependent Kinase Inhibitor p16, Tumor Suppressor Protein p14ARF
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