Foxo3 is essential for the regulation of ataxia telangiectasia mutated and oxidative stress-mediated homeostasis of hematopoietic stem cells.
J Biol Chem
; 283(37): 25692-25705, 2008 Sep 12.
Article
en En
| MEDLINE
| ID: mdl-18424439
ABSTRACT
Unchecked accumulation of reactive oxygen species (ROS) compromises maintenance of hematopoietic stem cells. Regulation of ROS by the tumor suppressor protein ataxia telangiectasia mutated (ATM) is critical for preserving the hematopoietic stem cell pool. In this study we demonstrate that the Foxo3 member of the Forkhead Box O (FoxO) family of transcription factors is essential for normal ATM expression. In addition, we show that loss of Foxo3 leads to defects in hematopoietic stem cells, and these defects result from an overaccumulation of ROS. Foxo3 suppression of ROS in hematopoietic stem cells is mediated partly by regulation of ATM expression. We identify ROS-independent modulations of ATM and p16(INK4a) and ROS-mediated activation of p53/p21(CIP1/WAF1/Sdi1) tumor suppressor pathways as major contributors to Foxo3-null hematopoietic stem cells defects. Our studies demonstrate that Foxo3 represses ROS in part via regulation of ATM and that this repression is required for maintenance of the hematopoietic stem cell pool.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Células Madre Hematopoyéticas
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Regulación de la Expresión Génica
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Proteínas Serina-Treonina Quinasas
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Proteínas de Ciclo Celular
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Proteínas Supresoras de Tumor
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Proteínas de Unión al ADN
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Factores de Transcripción Forkhead
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
J Biol Chem
Año:
2008
Tipo del documento:
Article