Tumor Suppression in the Absence of p53-Mediated Cell-Cycle Arrest, Apoptosis, and Senescence
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Cell-cycle arrest, apoptosis, and senescence are widely accepted as the major mechanisms by which p53 inhibits tumor formation. Nevertheless, it remains unclear whether they are the rate-limiting steps in tumor suppression. Here, we have generated mice bearing lysine to arginine mutations at one (p53(K117R)) or three (p53(3KR); K117R+K161R+K162R) of p53 acetylation sites. Although p53(K117R/K117R) cells are competent for p53-mediated cell-cycle arrest and senescence, but not apoptosis, all three of these processes are ablated in p53(3KR/3KR) cells. Surprisingly, unlike p53 null mice, which rapidly succumb to spontaneous thymic lymphomas, early-onset tumor formation does not occur in either p53(K117R/K117R) or p53(3KR/3KR) animals. Notably, p53(3KR) retains the ability to regulate energy metabolism and reactive oxygen species production. These findings underscore the crucial role of acetylation in differentially modulating p53 responses and suggest that unconventional activities of p53, such as metabolic regulation and antioxidant function, are critical for suppression of early-onset spontaneous tumorigenesis.
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Waves of cellular senescence followed by RCD contribute to developmental embryogenesis (dispensable) and to adult tissue repair/regeneration, immunity, stem cell preservation, and oncosuppression.
“Waves of cellular senescence (followed by RCD) appear to contribute to developmental embryogenesis (although in a dispensable manner) [6, 946, 947] as well as to multiple pathophysiological processes in the adult, including tissue repair and regeneration, immunity, preservation of the stem cell compartment, and oncosuppression [948–957].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [953]
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Regulation of Metabolic Activity by p53
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Self-citationMultifaceted role for p53 in pancreatic cancer suppression
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The Impact of Sunlight on Skin Aging
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- Authors
- Li, T., Kon, N., Jiang, L., Tan, M., Ludwig, T., Zhao, Y., Baer, R., & Gu, W.
- Affiliations
- Columbia University (US)
- University of Chicago (US)
- Corresponding author
- Gu, Wei
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2012-06
- Volume
- 149
- Issue
- 6
- Pages
- 1269-1283
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3688046
- OpenAlex
- W2104014368
- Cited by
- 912
- References
- 56
- Citations by year
- 2026: 21 · 2025: 42 · 2024: 49 · 2023: 65 · 2022: 86 · 2021: 62 · 2020: 56 · 2019: 82 · 2018: 79 · 2017: 64 · 2016: 84 · 2015: 52 · 2014: 69 · 2013: 75 · 2012: 26
- FWCI
- 35.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Leukemia and Lymphoma Society
- National Institutes of Health (2r01ca085533-16)
- National Cancer Institute (R01-CA085533, P01CA97403, P01CA097403, P01CA080058, R01CA098821)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- p53, tumor suppression, p53 acetylation, cell cycle arrest, apoptosis, cellular senescence, thymic lymphoma, spontaneous tumor development, energy metabolism, reactive oxygen species, antioxidant function, p53-null mice
- MeSH terms
- Amino Acid Sequence, Animals, Fibroblasts, Humans, Lymphoma, Molecular Sequence Data, Mutation, Neoplasms, Thymus Neoplasms, Tumor Suppressor Protein p53, Sequence Alignment, Cellular Senescence, Apoptosis, Mice, Gene Knock-In Techniques, Cell Cycle Checkpoints
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