Fine-tuning p53 activity through C-terminal modification significantly contributes to HSC homeostasis and mouse radiosensitivity
Open accessAbstract
Cell cycle regulation in hematopoietic stem cells (HSCs) is tightly controlled during homeostasis and in response to extrinsic stress. p53, a well-known tumor suppressor and transducer of diverse stress signals, has been implicated in maintaining HSC quiescence and self-renewal. However, the mechanisms that control its activity in HSCs, and how p53 activity contributes to HSC cell cycle control, are poorly understood. Here, we use a genetically engineered mouse to show that p53 C-terminal modification is critical for controlling HSC abundance during homeostasis and HSC and progenitor proliferation after irradiation. Preventing p53 C-terminal modification renders mice exquisitely radiosensitive due to defects in HSC/progenitor proliferation, a critical determinant for restoring hematopoiesis after irradiation. We show that fine-tuning the expression levels of the cyclin-dependent kinase inhibitor p21, a p53 target gene, contributes significantly to p53-mediated effects on the hematopoietic system. These results have implications for understanding cell competition in response to stresses involved in stem cell transplantation, recovery from adverse hematologic effects of DNA-damaging cancer therapies, and development of radioprotection strategies.
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p53 upregulation in the haematopoietic system engenders myeloablation.
“and p53 upregulation in the haematopoietic system engenders myeloablation82,83”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [83]
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- Authors
- Wang, Y. V., Leblanc, M., Fox, N., Mao, J.-H., Tinkum, K. L., Krummel, K., Engle, D., Piwnica-Worms, D., Piwnica-Worms, H., Balmain, A., Kaushansky, K., & Wahl, G. M.
- Affiliations
- Salk Institute for Biological Studies (US)
- University of California San Diego (US)
- Lawrence Berkeley National Laboratory (US)
- Washington University in St. Louis (US)
- Howard Hughes Medical Institute (US)
- University of California, San Francisco (US)
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2011-07-01
- Volume
- 25
- Issue
- 13
- Pages
- 1426-1438
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC3134085
- OpenAlex
- W2156762829
- Cited by
- 53
- References
- 53
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 3 · 2022: 2 · 2021: 2 · 2020: 1 · 2019: 4 · 2018: 5 · 2017: 1 · 2016: 6 · 2015: 4 · 2014: 6 · 2013: 7 · 2012: 7
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Funders
- U.S. Department of Energy
- National Cancer Institute (U01CA84244, CA014195, CA61449, R01CA100845, CA 100845, R01CA061449, P50CA094056, U01CA084244, P30CA014195, CA094056)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Keywords
- p53, C-terminal modification, hematopoietic stem cells, HSC homeostasis, radiosensitivity, cell cycle regulation, p21, cyclin-dependent kinase inhibitors, HSC quiescence, self-renewal, irradiation, hematopoietic recovery, radiation protection, cell competition
- MeSH terms
- Animals, Cells, Cultured, Female, Gamma Rays, Gene Expression Regulation, Hematopoietic Stem Cells, Homeostasis, Longevity, Male, Mice, Inbred C57BL, Mutation, Radiation Tolerance, Tumor Suppressor Protein p53, Gene Dosage, Cyclin-Dependent Kinase Inhibitor p21, Mice, Proto-Oncogene Proteins c-mdm2, Gene Knock-In Techniques
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