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Lack of p21 expression links cell cycle control and appendage regeneration in mice
Open accessAbstract
Animals capable of regenerating multiple tissue types, organs, and appendages after injury are common yet sporadic and include some sponge, hydra, planarian, and salamander (i.e., newt and axolotl) species, but notably such regenerative capacity is rare in mammals. The adult MRL mouse strain is a rare exception to the rule that mammals do not regenerate appendage tissue. Certain commonalities, such as blastema formation and basement membrane breakdown at the wound site, suggest that MRL mice may share other features with classical regenerators. As reported here, MRL fibroblast-like cells have a distinct cell-cycle (G2/M accumulation) phenotype and a heightened basal and wound site DNA damage/repair response that is also common to classical regenerators and mammalian embryonic stem cells. Additionally, a neutral and alkaline comet assay displayed a persistent level of intrinsic DNA damage in cells derived from the MRL mouse. Similar to mouse ES cells, the p53-target p21 was not expressed in MRL ear fibroblasts. Because the p53/p21 axis plays a central role in the DNA damage response and cell cycle control, we directly tested the hypothesis that p21 down-regulation could functionally induce a regenerative response in an appendage of an otherwise nonregenerating mouse strain. Using the ear hole closure phenotype, a genetically mapped and reliable quantitative indicator of regeneration in the MRL mouse, we show that the unrelated Cdkn1a tmi/Tyj /J p21 −/− mouse (unlike the B6129SF2/J WT control) closes ear holes similar to MRL mice, providing a firm link between cell cycle checkpoint control and tissue regeneration.
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“p21 deficiency supports tissue regeneration, including complete rescue of regeneration of the impaired liver”
From p21 maintains senescent cell viability under persistent DNA damage response by restraining JNK and caspase signaling (2017) · cites this paper as Bedelbaeva et al, 2010
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“when apoptosis is blocked, various apoptotic stimuli can activate autophagy and JNK to induce autophagic cell death”
From p21 maintains senescent cell viability under persistent DNA damage response by restraining JNK and caspase signaling (2017) · cites this paper as Bedelbaeva et al, 2010
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Metadata
- Authors
- Bedelbaeva, K., Snyder, A., Gourevitch, D., Clark, L., Zhang, X.-M., Leferovich, J., Cheverud, J. M., Lieberman, P., & Heber-Katz, E.
- Affiliations
- The Wistar Institute (US)
- Cellular and Molecular Oncogenesis and Gene Expression, The Wistar Institute, Philadelphia, PA 19104; and
- Washington University in St. Louis (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-03-15
- Volume
- 107
- Issue
- 13
- Pages
- 5845-5850
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2851923
- OpenAlex
- W2120729899
- Cited by
- 207
- References
- 61
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 5 · 2023: 6 · 2022: 11 · 2021: 8 · 2020: 11 · 2019: 11 · 2018: 11 · 2017: 16 · 2016: 14 · 2015: 27 · 2014: 13 · 2013: 22 · 2012: 17
- FWCI
- 7.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- F. M. Kirby Foundation
- James N. Kirby Foundation
- National Institutes of Health (CA 10815)
- National Cancer Institute ((P30 CA10815, CA-10815, P30CA010815)
- National Institute of General Medical Sciences (R01GM073226, GM073226)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Planarian Biology and Electrostimulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Health Sciences › Medicine › Surgery › Wound Healing and Treatments
- Keywords
- p21, p53, appendage regeneration, cell cycle regulation, DNA damage response, fibroblasts, blastema formation, wound healing, cell cycle checkpoints, DNA repair
- MeSH terms
- Animals, Cell Cycle, Cell Division, DNA Damage, DNA Repair, Extremities, Female, Mice, Inbred C57BL, Regeneration, Tumor Suppressor Protein p53, G2 Phase, Apoptosis, Mice, Knockout, Mice, Congenic, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p21, Rad51 Recombinase, Mice, Protein Stability, In Vitro Techniques
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