Fine-tuning p53 activity through C-terminal modification significantly contributes to HSC homeostasis and mouse radiosensitivity.
Genes Dev
; 25(13): 1426-38, 2011 Jul 01.
Article
en En
| MEDLINE
| ID: mdl-21724834
ABSTRACT
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Tolerancia a Radiación
/
Células Madre Hematopoyéticas
/
Proteína p53 Supresora de Tumor
/
Homeostasis
Límite:
Animals
Idioma:
En
Revista:
Genes Dev
Asunto de la revista:
BIOLOGIA MOLECULAR
Año:
2011
Tipo del documento:
Article
País de afiliación:
Estados Unidos