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Foxo3 Is Essential for the Regulation of Ataxia Telangiectasia Mutated and Oxidative Stress-mediated Homeostasis of Hematopoietic Stem Cells

2008; Elsevier BV; Volume: 283; Issue: 37 Linguagem: Inglês

10.1074/jbc.m800517200

1083-351X

Safak Yalcin, Xin Zhang, Julia P. Luciano, Sathish Kumar Mungamuri, Dragan Marinković, Cécile Vercherat, Abby Sarkar, Marcos Grisotto, Reshma Taneja, Saghi Ghaffari,

Effects of Radiation Exposure

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.