Cellular senescence and tumor suppressor gene p16
Open accessAbstract
Cellular senescence is an irreversible arrest of cell growth. Biochemical and morphological changes occur during cellular senescence, including the formation of a unique cellular morphology such as flattened cytoplasm. Function of mitochondria, endoplasmic reticulum and lysosomes are affected resulting in the inhibition of lysosomal and proteosomal pathways. Cellular senescence can be triggered by a number of factors including, aging, DNA damage, oncogene activation and oxidative stress. While the molecular mechanism of senescence involves p16 and p53 tumor suppressor genes and telomere shortening, this review is focused on the mechanism of p16 control. The p16‐mediated senescence acts through the retinoblastoma (Rb) pathway inhibiting the action of the cyclin dependant kinases leading to G1 cell cycle arrest. Rb is maintained in a hypophosphorylated state resulting in the inhibition of transcription factor E2F1. Regulation of p16 expression is complex and involves epigenetic control and multiple transcription factors. PRC1 (Pombe repressor complex (1) and PRC2 (Pombe repressor complex (2) proteins and histone deacetylases play an important role in the promoter hypermethylation for suppressing p16 expression. While transcription factors YY1 and Id1 suppress p16 expression, transcription factors CTCF, Sp1 and Ets family members activate p16 transcription. Senescence occurs with the inactivation of suppressor elements leading to the enhanced expression of p16.
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Both pathways exhibit substantial interconnections and crosstalk.
“Furthermore, these pathways exhibit substantial interconnections and crosstalk (Rayess et al, 2012).”
From Distinct senotypes in p16- and p21-positive cells across human and mouse aging tissues (2025) · cites this paper as Rayess et al, 2012
Hypermethylation of the p16 gene promoter, which can lead to p16 inactivation, is often detected in many types of human cancers.
“On the other hand, hypermethylation of the p16 gene promoter, which can lead to p16 inactivation, is often detected in many types of human cancers, suggesting the overcome of cellular senescence [21].”
From The role of cellular senescence and SASP in tumour microenvironment (2023) · cites this paper as [21]
After DDR activation, the p53/p21 pathway deactivates the cyclin E-CDK2 complex responsible for pRB phosphorylation, while the p16/pRB pathway inhibits pRB phosphorylation by deactivation of kinase CDK4/6.
“After DDR activation, the p53/p21 pathway deactivates the cyclin E-CDK2 complex responsible for pRB phosphorylation [242], while the p16/pRB pathway inhibits pRB phosphorylation by deactivation of kinase CDK4/6 [239].”
From Redox control of senescence and age-related disease. (2017) · cites this paper as [239]
Preventing pRB phosphorylation allows pRB to retain association with transcription factor E2F1, preventing expression of E2F1 target genes necessary for cell transition from G1 to S phase.
“Preventing pRB phosphorylation allows pRB to retain its association with the transcription factor E2F1, preventing the expression of E2F1 target genes that are necessary for the cell transition from G1 to the S phase [239].”
From Redox control of senescence and age-related disease. (2017) · cites this paper as [239]
The senescence phenotype is mediated through pathways activating p16INK4a/Rb and/or p53/p21, depending on inducer and cell type.
“These inducers ultimately mediate the cellular senescence phenotype through mechanisms that converge on pathways that activate p16INK4a/Rb and/or p53/p21, depending on the inducer and cell type [20].”
From Reducing Senescent Cell Burden in Aging and Disease (2020) · cites this paper as [20]
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- Authors
- Rayess, H., Wang, M. B., & Srivatsan, E. S.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Srivatsan, Eri S.
- Venue
- International Journal of Cancer
- Publisher
- Wiley
- Published
- 2011-12-05
- Volume
- 130
- Issue
- 8
- Pages
- 1715-1725
- ISSN
- 0020-7136 (ISSN-L)
- 1097-0215
- PMC
- PMC3288293
- OpenAlex
- W1996113298
- Cited by
- 825
- References
- 124
- Citations by year
- 2026: 62 · 2025: 79 · 2024: 92 · 2023: 96 · 2022: 78 · 2021: 69 · 2020: 47 · 2019: 48 · 2018: 41 · 2017: 48 · 2016: 39 · 2015: 41 · 2014: 43 · 2013: 31 · 2012: 11
- FWCI
- 2.91
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- public-domain
- onlinelibrary.wiley.com/termsAndConditions#vor (vor)
- Locations
- International Journal of Cancer (publishedVersion, public-domain)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5r21ca116826-02, R21 CA116826-01)
- VA Greater Los Angeles Healthcare System
- National Cancer Institute (R21 CA116826-01, R21 CA116826)
- 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
- cellular senescence, p16, tumor suppressor, retinoblastoma pathway, G1 cell cycle arrest, p53, telomere shortening, epigenetic regulation, promoter hypermethylation, histone deacetylase, transcription factors, DNA damage, oxidative stress, oncogene activation, aging
- MeSH terms
- Antineoplastic Agents, Humans, Neoplasms, Gene Expression, Tumor Suppressor Protein p53, Retinoblastoma Protein, Cellular Senescence, Cyclin-Dependent Kinase Inhibitor p16, Cell Cycle Checkpoints, Telomere Shortening
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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