Significant Role for p16INK4a in p53-Independent Telomere-Directed Senescence
Open accessAbstract
Telomere attrition in primary human fibroblasts induces replicative senescence accompanied by activation of the p53 and p16(INK4a)/RB tumor suppressor pathways. Although the contribution of p53 and its target, p21, to telomere-driven senescence have been well established, the role of p16(INK4a) is controversial. Attempts to dissect the significance of p16(INK4a) in response to telomere shortening have been hampered by the concomitant induction of p16(INK4a) by cell culture conditions. To circumvent this problem, we studied the role of p16(INK4a) in the cellular response to acute telomere damage induced by a dominant negative allele of TRF2, TRF2(Delta B Delta M). This approach avoids the confounding aspects of culture stress because parallel cultures with and without telomere damage can be compared. Telomere damage generated with TRF2(Delta B Delta M) resulted in induction of p16(INK4a) in the majority of cells as detected by immunohistochemistry. Inhibition of p16(INK4a) with shRNA or overexpression of BMI1 had a significant effect on the telomere damage response in p53-deficient cells. While p53 deficiency alone only partially abrogated the telomere damage-induced cell cycle arrest, combined inhibition of p16(INK4a) and p53 led to nearly complete bypass of telomere-directed senescence. We conclude that p16(INK4a) contributes to the p53-independent response to telomere damage.
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p16Ink4a plays a modest role in response to DNA double-stranded breaks and telomere dysfunction in the absence of p53.
“It has been reported that p16 Ink4a plays a modest role in response to DNA doublestranded breaks and telomere dysfunction in the absence of p53 (13, 14).”
From <i>Ink4a</i> / <i>Arf</i> tumor suppressor does not modulate the degenerative conditions or tumor spectrum of the telomerase-deficient mouse (2007) · cites this paper as [14]
In MEFs, p19 Arf and p16 Ink4a contribute to the growth arrest incurred by telomere deprotection.
“In MEFs, p19 Arf and p16 Ink4a contribute to the growth arrest incurred by telomere deprotection (14, 27).”
From <i>Ink4a</i> / <i>Arf</i> tumor suppressor does not modulate the degenerative conditions or tumor spectrum of the telomerase-deficient mouse (2007) · cites this paper as [14]
Extensive telomere uncapping induces p16 in some human cells, consistent with p16 responding to a variety of stresses, including acute genotoxic stress.
“Nonetheless, extensive telomere uncapping (caused by expression of a mutant telomere binding protein) induces p16 in some human cells (Jacobs and de Lange, 2004), consistent with p16 responding to a variety of stresses, including acute genotoxic stress.”
From Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors (2005) · cites this paper as Jacobs and de Lange, 2004
p16 may act as a secondary mechanism, besides the p53-p21 pathway, mediating the senescence arrest following telomere dysfunction.
“This and other studies suggest that p16 may act as a secondary mechanism (besides the p53-p21 pathway) mediating the senescence arrest following telomere dysfunction (Beausejour et al., 2003, Jacobs and de Lange, 2004).”
From Telomeres and cell senescence—size matters not (2017) · cites this paper as Jacobs and de Lange, 2004
Deletion of TRF2 induces p16 activation.
“deletion of TRF2 was shown to induce p16 activation (Jacobs and de Lange, 2004)”
From Telomeres and cell senescence—size matters not (2017) · cites this paper as Jacobs and de Lange, 2004
Complete bypass of telomere shortening-induced senescence in human cells requires inactivation of multiple pathways, making this proliferation barrier robust.
“Because the complete bypass of telomere shortening-induced senescence in human cells requires the inactivation of multiple pathways, this mechanism of curbing the proliferation of transformed cells is likely to be robust43,45–48.”
From Telomeres in cancer: tumour suppression and genome instability (2017) · cites this paper as [43]
In this setting, p16 responds adequately to telomere damage because p53 inactivation only partially relieves the cell cycle arrest imposed by telomere signaling.
“In this setting, p16 responds adequately to telomere damage because p53 inactivation only partially relieves the cell cycle arrest imposed by telomere signaling.”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [49]
Active p16 signaling can compensate for p53 activity decline after full senescence establishment.
“It has been proposed that active p16 signaling can compensate for p53 activity decline after full senescence establishment [49,50].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [49]
When acute telomere damage is caused by inhibition of the telomere binding protein TRF2, p16 protein levels increase in senescent cells.
“When acute telomere damage is caused by inhibition of the telomere binding protein, TRF2, p16 protein levels increase in senescent cells [49].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [49]
DDR can also signal to p16, although p16 may act as a secondary mechanism to mediate the senescence-related proliferative arrest following telomere dysfunction.
“DDR can also signal to p16, although p16 may act as a secondary mechanism to mediate the senescence-related proliferative arrest following telomere dysfunction [48,49].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [49]
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MLL Associates with Telomeres and Regulates Telomeric Repeat-Containing RNA Transcription
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“HDFs concurrently transfected with MLLand p53-targeting siRNAs showed a partial rescue of proliferation and reduced SA- -gal positivity, as did the TRF2 and p53 double knockdown (20) (Fig.”
BackgroundA Comprehensive Review on Mesenchymal Stem Cell Growth and Senescence
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“123,124 In some cells, especially those highly vulnerable to hostile culture environment, p16 Ink4a is the major mediator of senescence.”
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Senescence-Induced Oxidative Stress Causes Endothelial Dysfunction
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“Telomere attrition causes cell senescence via the p53 pathway, although p16 is also likely to be involved as senescent cells overexpress p16 (14, 15, 17).”
BackgroundCell fate determination during G1 phase progression
Blomen, V. A., & Boonstra, J. (2007) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-007-7271-z · Cited by 116 · see citing works
Engineered telomere degradation models dyskeratosis congenitaPreprint
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“Mouse telomeres recapitulate most aspects of human telomere biology, although differences in telomerase regulation, the telomere damage response pathway, and the composition of shelterin have been noted (Prowse and Greider 1995; Smogorzewska and de Lange 2002; Jacobs and de Lange 2004; Hockemeyer et al. 2006, 2007).”
BackgroundThe emerging role of senescent cells in tissue homeostasis and pathophysiology
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Premature senescence of endothelial cells: Methusaleh's dilemma
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“senescence by activating the ATM-p53-p21-pRb pathway (64), and that p16 has an important, but nonessential, role in this senescence process in the human fibroblast (20, 78).”
BackgroundBigot, A., Klein, A., Gasnier, E., Jacquemin, V., Ravassard, P., Butler-Browne, G., Mouly, V., & Furling, D. (2009) · American Journal of Pathology · doi:10.2353/ajpath.2009.080560 · Cited by 106 · see citing works
“19 Recently several reports have indicated that an increase in p16 expression in the brain, bone marrow, and pancreas progenitor cells during aging contributes to stem cell decline, senescence, and aging.”
BackgroundNagai, K., Matsushita, T., Matsuzaki, T., Takayama, K., Matsumoto, T., Kuroda, R., & Kurosaka, M. (2015) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2015.03.024 · Cited by 110 · see citing works
Role of CDKN2A/p16 expression in the prognostication of oral squamous cell carcinoma
Padhi, S. S., Roy, S., Kar, M., Saha, A., Roy, S., Adhya, A. K., Baisakh, M. R., & Banerjee, B. (2017) · Oral Oncology · doi:10.1016/j.oraloncology.2017.07.030 · Cited by 108 · see citing works
Positive feedback between p53 and TRF2 during telomere-damage signalling and cellular senescence
Fujita, K., Horikawa, I., Mondal, A. M., Jenkins, L. M. M., Appella, E., Vojtěšek, B., Bourdon, J., Lane, D. P., & Harris, C. C. (2010) · Nature Cell Biology · doi:10.1038/ncb2123 · Cited by 103 · see citing works
“6b ), the other major effector of cellular senescence in human cell”
BackgroundBmi1 regulates murine intestinal stem cell proliferation and self-renewal downstream of Notch
López‐Arribillaga, E., Rodilla, V., Pellegrinet, L., Guiu, J., Iglesias, M., Román, Á., Gutarra, S., González, S., Muñoz‐Cánoves, P., Fernández‐Salguero, P. M., et al. (2014) · Development · doi:10.1242/dev.107714 · Cited by 102 · see citing works
Ink4‐Arf locus in cancer and aging
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WRN at telomeres: implications for aging and cancer
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“However, in human ALT cells a significant fraction of WRN appears to colocalize with TRF1 and TRF2 at telomeric DNA (Johnson et al., 2001; Opresko et al., 2002; Opresko et al., 2004).”
Park, H., Kim, C.-H., Jeong, J.-H., Park, M., & Kim, K. S. (2016) · Oncotarget · doi:10.18632/oncotarget.7457 · Cited by 92 · see citing works
“Specifically, p16 is induced by oncogenes such as Ras [19]and Raf [20], as well as by oxidative stress signals [21], and is required for telomere-independent senescence [22].”
BackgroundAGING OF THE SUBVENTRICULAR ZONE NEURAL STEM CELL NICHE.
Conover, J. C., & Shook, B. A. (2011) · Europe PMC (PubMed Central) · Cited by 92 · see citing works
Cellular Senescence in the Development and Treatment of Cancer
Saretzki, G. C. (2009) · Current Pharmaceutical Design · doi:10.2174/138161210789941874 · Cited by 88 · see citing works
miR-335 Directly Targets Rb1 (pRb/p105) in a Proximal Connection to p53-Dependent Stress Response
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Cellular Senescence in Sarcopenia: Possible Mechanisms and Therapeutic Potential
He, Y., Xie, W., Li, H., Jin, H., Zhang, Y., & Li, Y. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.793088 · Cited by 82 · see citing works
Gut microbial-derived phenylacetylglutamine accelerates host cellular senescence
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Senescence As an Anticancer Mechanism
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Pro-Proliferative Function of Mitochondrial Sirtuin Deacetylase SIRT3 in Human Melanoma
George, J., Nihal, M., Singh, C. K., Zhong, W., Liu, X., & Ahmad, N. (2015) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2015.12.026 · Cited by 77 · see citing works
Therapeutic targeting of replicative immortality
Yaswen, P., MacKenzie, K. L., Keith, W. N., Hentosh, P., Rodier, F., Zhu, J., Firestone, G. L., Matheu, A., Carnero, A., Bilsland, A. E., et al. (2015) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2015.03.007 · Cited by 74 · see citing works
“The p16/pRB umor suppressor pathway is also activated during replicative enescence in response to telomere dysfunction and DNA damge [36,37].”
Backgroundp53 Mediates Senescence-Like Arrest Induced by Chronic Replicational Stress
Marusyk, A., Wheeler, L. J., Mathews, C. K., & DeGregori, J. V. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01316-06 · Cited by 74 · see citing works
“Induction of senescence by shortened telomeres appears to occur through independent p53-p21 and p16-Rb pathways (36, 41), with the relative contributions of”
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Insulin-like growth factor-1 signaling in cardiac aging
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Książek, K., Piwocka, K., Brzezińska, A., Sikora, E., Zabel, M., Bręborowicz, A., Jörres, A., & Witowski, J. (2005) · Journal of Applied Physiology · doi:10.1152/japplphysiol.01086.2005 · Cited by 68 · see citing works
“This fact, together with a low number of PD (and hence probably only minor telomere shortening) suggests that HPMC under conditions employed here senesce predominantly as a result of “culture shock” (22, 33).”
BackgroundGeroconversion of aged muscle stem cells under regenerative pressure
Sousa-Victor, P., Perdiguero, E., & Muñoz-Cánoves, P. (2014) · Cell Cycle · doi:10.4161/15384101.2014.965072 · Cited by 68 · see citing works
“Furthermore, comparison with a comprehensive list of genes implicated in cellular senescence(57-59) showed specific up-regulation of several genes, including the master regulator of senescence Cdkn2a (p16).(15,17,49,60,61)”
Cell Senescence, Multiple Organelle Dysfunction and Atherosclerosis
Machado-Oliveira, G., Ramos, C., Marques, A. R. A., & Vieira, O. V. (2020) · Cells · doi:10.3390/cells9102146 · Cited by 66 · see citing works
“Telomere shortening activates either the p53/p21 or p16 pathways in humans, while only the p53/p21 pathway is induced in mice [34].”
BackgroundTelomeres and Cancer: Resolving the Paradox
Nassour, J., Schmidt, T. T., & Karlseder, J. (2021) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-050420-023410 · Cited by 64 · see citing works
Induced Telomere Damage to Treat Telomerase Expressing Therapy-Resistant Pediatric Brain Tumors
Sengupta, S., Sobo, M., Lee, K., Kumar, S. S., White, A. R., Mender, I., Fuller, C. E., Chow, L. M. L., Fouladi, M., Shay, J. W., et al. (2018) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-17-0792 · Cited by 61 · see citing works
“Interestingly, our data can be interpreted to suggest that 6-thio-dG–induced senescence is initiated in the G2– Mphase, whereas senescent cells are usually in the G1 phase (32).”
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“It is also worth emphasizing that p53 inactivation alone is not sufficient to fully abrogate telomere-directed cellular senescence, but the combined inactivation of p53 and p16 does do so [59,60].”
Give me a break: How telomeres suppress the DNA damage response
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Telomeres, cellular senescence, and aging: past and future
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“Activation of p16 in response to telomere damage has also been observed upon TRF2 deletion (Jacobs and de Lange 2004).”
Telomere function and regulation from mouse models to human ageing and disease
Jones-Weinert, C. W., Mainz, L., & Karlseder, J. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00800-5 · Cited by 57 · see citing works
“TIF-induced 18,20,52 and genome-wide DNA damage-induced 193 senescence in human cells is likely to depend on both p53–p21 and p16 INK4a pathways.”
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Genomic Changes in Normal Breast Tissue in Women at Normal Risk or at High Risk for Breast Cancer
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IGF-I enhances cellular senescence via the reactive oxygen species–p53 pathway
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p16INK4a protects against dysfunctional telomere–induced ATR-dependent DNA damage responses
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“In human cells, critically shortened telomeres have been associated with the induction of the cyclin-dependent kinase inhibitor p16INK4a, resulting in the disruption of cyclin-dependent kinase (CDK) 4/6 binding to D-type cyclins, Rb hypophosphorylation, and the activation of Rb checkpoint functions to elicit cellular…”
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“Evidence has also been found supporting a role for another CDKi and associated protein, the protein 16 inhibitor of kinase 4a (p16 INK4A )-RB pathway, in mediating telomere-associated cellular senescence (26).”
Stepwise Neoplastic Transformation of a Telomerase Immortalized Fibroblast Cell Line
Zongaro, S., de Stanchina, E., Colombo, T., D’Incalci, M., Giulotto, E., & Mondello, C. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-1140 · Cited by 45 · see citing works
“This gene is up-regulated in replicative arrested cells; the signals triggering p16INK4A expression during senescence are presently unknown, and the possible role of telomere dysfunction in its induction is controversial (18, 19 ).”
BackgroundDeregulated transcription factors in the emerging cancer hallmarks
Hasan, A., Khan, N. A., Shahab Uddin, M. S., Khan, A. Q., & Steinhoff, M. S. (2023) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2023.12.001 · Cited by 43 · see citing works
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“or by activation of tumour suppressor genes ( Jacobs & de Lange, 2004, Tyner et al., 2002).”
DNA double strand break responses and chromatin alterations within the aging cell
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Protection against chromosome degradation at the telomeres
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“December 15, 2007 senescence of human cells (44, 45 ).”
BackgroundNoncoding RNAs Controlling Telomere Homeostasis in Senescence and Aging
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“Both p21 and p16 enable the function of the retinoblastoma protein (RB) and reinforce the cell cycle arrest [11, 12].”
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Telomere dysfunction and stem cell ageing
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Structural variant evolution after telomere crisis
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Telomere uncapping during in vitro T‐lymphocyte senescence
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- Authors
- Jacobs, J. J. L., & de Lange, T.
- Affiliations
- Rockefeller University (US)
- Venue
- Current Biology
- Publisher
- Elsevier BV
- Published
- 2004-12
- Volume
- 14
- Issue
- 24
- Pages
- 2302-2308
- ISSN
- 0960-9822 (ISSN-L)
- OpenAlex
- W2081944825
- Cited by
- 237
- References
- 46
- Citations by year
- 2026: 8 · 2025: 6 · 2024: 7 · 2023: 9 · 2022: 12 · 2021: 11 · 2020: 9 · 2019: 5 · 2018: 14 · 2017: 9 · 2016: 10 · 2015: 14 · 2014: 7 · 2013: 9 · 2012: 16
- FWCI
- 8.43
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 3150 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Current Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG16642)
- 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
- p16INK4a, p53-independent senescence, telomere damage, replicative senescence, telomere shortening, p53 deficiency, BMI1, cell cycle arrest, p21, tumor suppressor pathways, shRNA knockdown
- MeSH terms
- Bromodeoxyuridine, Cells, Cultured, DNA Damage, Fibroblasts, Fluorescent Antibody Technique, Humans, Immunohistochemistry, Tumor Suppressor Protein p53, Telomere, Cellular Senescence, Cyclin-Dependent Kinase Inhibitor p16, Telomeric Repeat Binding Protein 2
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