title: Foxo3 is essential for the regulation of ataxia telangiectasia mutated and oxidative stress-mediated homeostasis of hematopoietic stem cells.
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.
authors.affiliation: Department of Gene and Cell Medicine, New York, New York 10029.
authors.forename: Safak
authors.initials: S
authors.lastname: Yalcin
authors.affiliation: Department of Gene and Cell Medicine, New York, New York 10029.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Gene and Cell Medicine, New York, New York 10029.
authors.forename: Julia P
authors.initials: JP
authors.lastname: Luciano
authors.affiliation: Department of Gene and Cell Medicine, New York, New York 10029.
authors.forename: Sathish Kumar
authors.initials: SK
authors.lastname: Mungamuri
authors.affiliation: Department of Gene and Cell Medicine, New York, New York 10029.
authors.forename: Dragan
authors.initials: D
authors.lastname: Marinkovic
authors.affiliation: Department of Developmental and Regenerative Biology, New York, New York 10029.
authors.forename: Cécile
authors.initials: C
authors.lastname: Vercherat
authors.affiliation: Department of Gene and Cell Medicine, New York, New York 10029.
authors.forename: Abby
authors.initials: A
authors.lastname: Sarkar
authors.affiliation: Department of Gene and Cell Medicine, New York, New York 10029.
authors.forename: Marcos
authors.initials: M
authors.lastname: Grisotto
authors.affiliation: Department of Developmental and Regenerative Biology, New York, New York 10029; Black Family Stem Cell Institute, New York, New York 10029.
authors.forename: Reshma
authors.initials: R
authors.lastname: Taneja
authors.affiliation: Department of Gene and Cell Medicine, New York, New York 10029; Department of Developmental and Regenerative Biology, New York, New York 10029; Black Family Stem Cell Institute, New York, New York 10029; Department of Medicine Division of Hematology, Oncology, Mount Sinai School of Medicine, New York, New York 10029. Electronic address: Saghi.Ghaffari@mssm.edu.
authors.forename: Saghi
authors.initials: S
authors.lastname: Ghaffari
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism / Q000502:physiology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism / Q000502:physiology*; D005786:Gene Expression Regulation; D005838:Genotype; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006579:Heterozygote; D051379:Mice; D008954:Models, Biological; D018384:Oxidative Stress; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism / Q000502:physiology*
chemical_list: D000975:Antioxidants; C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases