Journal
GENES & DEVELOPMENT
Volume 25, Issue 13, Pages 1426-1438Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.2024411
Keywords
p53; C-terminal modification; HSC; radiosensitivity; cell cycle; apoptosis
Categories
Funding
- NCI [CA100845, CA61449, CA094056, U01 CA84244]
- Cancer Center Core Grant for Core Facility support [5 P30 CA014195]
- DOE
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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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