DNA damage in stem cells activates p21, inhibits p53, and induces symmetric self-renewing divisions.
Proc Natl Acad Sci U S A
; 110(10): 3931-6, 2013 Mar 05.
Article
em En
| MEDLINE
| ID: mdl-23417300
ABSTRACT
DNA damage leads to a halt in proliferation owing to apoptosis or senescence, which prevents transmission of DNA alterations. This cellular response depends on the tumor suppressor p53 and functions as a powerful barrier to tumor development. Adult stem cells are resistant to DNA damage-induced apoptosis or senescence, however, and how they execute this response and suppress tumorigenesis is unknown. We show that irradiation of hematopoietic and mammary stem cells up-regulates the cell cycle inhibitor p21, a known target of p53, which prevents p53 activation and inhibits p53 basal activity, impeding apoptosis and leading to cell cycle entry and symmetric self-renewing divisions. p21 also activates DNA repair, limiting DNA damage accumulation and self-renewal exhaustion. Stem cells with moderate DNA damage and diminished self-renewal persist after irradiation, however. These findings suggest that stem cells have evolved a unique, p21-dependent response to DNA damage that leads to their immediate expansion and limits their long-term survival.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Dano ao DNA
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Células-Tronco Hematopoéticas
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Divisão Celular
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Proteína Supressora de Tumor p53
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Inibidor de Quinase Dependente de Ciclina p21
Limite:
Animals
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article