FoxO transcription factors and stem cell homeostasis: insights from the hematopoietic system.

The forkhead O (FoxO) family of transcription factors participates in diverse physiologic processes, including induction of cell-cycle arrest, stress resistance, differentiation, apoptosis, and metabolism. Several recent studies indicate that FoxO-dependent signaling is required for long-term regenerative potential of the hematopoietic stem cell (HSC) compartment through regulation of HSC response to physiologic oxidative stress, quiescence, and survival. These observations link FoxO function in mammalian systems with the evolutionarily conserved role of FoxO in promotion of stress resistance and longevity in lower phylogenetic systems. Furthermore, these findings have implications for aging in higher organisms and in malignant stem cell biology, and suggest that FoxOs may play an important role in the maintenance and integrity of stem cell compartments in a broad spectrum of tissues.

[1]  W. Cavenee,et al.  Cloning and characterization of three human forkhead genes that comprise an FKHR-like gene subfamily. , 1998, Genomics.

[2]  Michael B. Yaffe,et al.  14-3-3 transits to the nucleus and participates in dynamic nucleocytoplasmic transport , 2002, The Journal of cell biology.

[3]  D. Gilliland,et al.  Blasts from the past: new lessons in stem cell biology from chronic myelogenous leukemia. , 2004, Cancer cell.

[4]  N. Motoyama,et al.  FOXO Forkhead Transcription Factors Induce G2-M Checkpoint in Response to Oxidative Stress* , 2002, The Journal of Biological Chemistry.

[5]  T. Hunter,et al.  SMK-1, an Essential Regulator of DAF-16-Mediated Longevity , 2006, Cell.

[6]  Geert J. P. L. Kops,et al.  Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress , 2002, Nature.

[7]  Hitomi Matsuzaki,et al.  Insulin-induced phosphorylation of FKHR (Foxo1) targets to proteasomal degradation , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[8]  H. Beug,et al.  FoxO3a regulates erythroid differentiation and induces BTG1, an activator of protein arginine methyl transferase 1 , 2004, The Journal of cell biology.

[9]  W. Biggs,et al.  Disruption of forkhead transcription factor (FOXO) family members in mice reveals their functional diversification. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[10]  S. Morrison,et al.  Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells , 2006, Nature.

[11]  Ryuji Kobayashi,et al.  IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. , 2004, Cell.

[12]  C. Kenyon,et al.  A C. elegans mutant that lives twice as long as wild type , 1993, Nature.

[13]  Hendrik C Korswagen,et al.  Functional Interaction Between ß-Catenin and FOXO in Oxidative Stress Signaling , 2005, Science.

[14]  D. Accili,et al.  Regulation of insulin-like growth factor–dependent myoblast differentiation by Foxo forkhead transcription factors , 2003, The Journal of cell biology.

[15]  J. Dick,et al.  Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell , 1997, Nature Medicine.

[16]  Jonathan D. Hron,et al.  Regulation of NF-kappaB, Th activation, and autoinflammation by the forkhead transcription factor Foxo3a. , 2004, Immunity.

[17]  B. Burgering,et al.  Stressing the role of FoxO proteins in lifespan and disease , 2007, Nature Reviews Molecular Cell Biology.

[18]  D. Tindall,et al.  Skp2 inhibits FOXO1 in tumor suppression through ubiquitin-mediated degradation. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[19]  Y Honda,et al.  The daf‐2 gene network for longevity regulates oxidative stress resistance and Mn‐superoxide dismutase gene expression in Caenorhabditis elegans , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[20]  L. P. van der Heide,et al.  FoxO6 transcriptional activity is regulated by Thr26 and Ser184, independent of nucleo-cytoplasmic shuttling. , 2005, The Biochemical journal.

[21]  D. Guertin,et al.  Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. , 2006, Developmental cell.

[22]  J. Lammers,et al.  Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1 , 2000, Current Biology.

[23]  Derick R. Peterson,et al.  The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells. , 2005, Blood.

[24]  K. Akashi,et al.  Mouse Development and Cell Proliferation in the Absence of D-Cyclins , 2004, Cell.

[25]  Hao Jiang,et al.  Triple Layer Control: Phosphorylation, Acetylation and Ubiquitination of FOXO Proteins , 2005, Cell cycle.

[26]  K. Miyamoto,et al.  Foxo3a is essential for maintenance of the hematopoietic stem cell pool , 2009 .

[27]  J. Till,et al.  A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. , 1961, Radiation research.

[28]  Michael R. Green,et al.  Identification of direct DAF-16 targets controlling longevity, metabolism and diapause by chromatin immunoprecipitation , 2006, Nature Genetics.

[29]  Cynthia Kenyon,et al.  Germ-Cell Loss Extends C. elegans Life Span through Regulation of DAF-16 by kri-1 and Lipophilic-Hormone Signaling , 2006, Cell.

[30]  Marco Sandri,et al.  Foxo Transcription Factors Induce the Atrophy-Related Ubiquitin Ligase Atrogin-1 and Cause Skeletal Muscle Atrophy , 2004, Cell.

[31]  Yalin H. Wei,et al.  Cloning and characterization of the t(X;II) breakpoint from a leukemic cell line identify a new member of the forkhead gene family , 1994, Genes, chromosomes & cancer.

[32]  Pamela A. Silver,et al.  A chemical genetic screen identifies inhibitors of regulated nuclear export of a Forkhead transcription factor in PTEN-deficient tumor cells. , 2003, Cancer cell.

[33]  C. Martínez-A,et al.  Forkhead transcription factors contribute to execution of the mitotic programme in mammals , 2001, Nature.

[34]  R. Bergman,et al.  Insulin action and metabolism in patients with head and neck cancer , 1991, Cancer.

[35]  T. Unterman,et al.  FoxO proteins in insulin action and metabolism , 2005, Trends in Endocrinology & Metabolism.

[36]  J. Bos,et al.  FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK , 2004, The EMBO journal.

[37]  Marten P Smidt,et al.  Spatial and temporal expression of FoxO transcription factors in the developing and adult murine brain. , 2006, Gene expression patterns : GEP.

[38]  Keisuke Ito,et al.  Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells , 2006, Nature Medicine.

[39]  P. Sternberg,et al.  DAF-16/FOXO Regulates Transcription of cki-1/Cip/Kip and Repression of lin-4 during C. elegans L1 Arrest , 2006, Current Biology.

[40]  Tak W. Mak,et al.  Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells , 2004, Nature.

[41]  A. Iwama,et al.  Cytokine signals modulated via lipid rafts mimic niche signals and induce hibernation in hematopoietic stem cells , 2006, The EMBO journal.

[42]  S. Armstrong,et al.  FoxOs Are Critical Mediators of Hematopoietic Stem Cell Resistance to Physiologic Oxidative Stress , 2007, Cell.

[43]  Judit Villén,et al.  A Conserved MST-FOXO Signaling Pathway Mediates Oxidative-Stress Responses and Extends Life Span , 2006, Cell.

[44]  S. Weiss,et al.  Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. , 1992, Science.

[45]  E. Lam,et al.  Control of Cell Cycle Exit and Entry by Protein Kinase B-Regulated Forkhead Transcription Factors , 2002, Molecular and Cellular Biology.

[46]  Hans Clevers,et al.  Self-Renewal and Cancer of the Gut: Two Sides of a Coin , 2005, Science.

[47]  R. Medema,et al.  FOXO4 Is Acetylated upon Peroxide Stress and Deacetylated by the Longevity Protein hSir2SIRT1* , 2004, Journal of Biological Chemistry.

[48]  H. Jasper,et al.  JNK Extends Life Span and Limits Growth by Antagonizing Cellular and Organism-Wide Responses to Insulin Signaling , 2005, Cell.

[49]  M. Greenberg,et al.  Akt Promotes Cell Survival by Phosphorylating and Inhibiting a Forkhead Transcription Factor , 1999, Cell.

[50]  B. Stockwell,et al.  RAS–RAF–MEK-dependent oxidative cell death involving voltage-dependent anion channels , 2007, Nature.

[51]  D. Sabatini,et al.  Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. , 2007, Blood.

[52]  D. Scadden,et al.  Hematopoietic stem cell quiescence maintained by p21cip1/waf1. , 2000, Science.

[53]  Elaine Fuchs,et al.  Self-Renewal, Multipotency, and the Existence of Two Cell Populations within an Epithelial Stem Cell Niche , 2004, Cell.

[54]  Steven P. Gygi,et al.  Stress-Dependent Regulation of FOXO Transcription Factors by the SIRT1 Deacetylase , 2004, Science.

[55]  S. Nemoto,et al.  Redox Regulation of Forkhead Proteins Through a p66shc-Dependent Signaling Pathway , 2002, Science.

[56]  S. Anderson,et al.  Integration of Smad and Forkhead Pathways in the Control of Neuroepithelial and Glioblastoma Cell Proliferation , 2004, Cell.

[57]  D. Scadden,et al.  Stem cell repopulation efficiency but not pool size is governed by p27kip1 , 2000, Nature Medicine.

[58]  Linda Partridge,et al.  Response to Comment on "Long-Lived Drosophila with Overexpressed dFOXO in Adult Fat Body" , 2005, Science.

[59]  T. Jacks,et al.  Identification of Bronchioalveolar Stem Cells in Normal Lung and Lung Cancer , 2005, Cell.

[60]  S. Nicosia,et al.  Suppression of FOXO1 activity by FHL2 through SIRT1‐mediated deacetylation , 2005, The EMBO journal.

[61]  Peng Huang,et al.  Superoxide dismutase as a target for the selective killing of cancer cells , 2000, Nature.

[62]  Xi C. He,et al.  PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention , 2006, Nature.

[63]  宮本 佳奈.  Foxo3a is essential for maintenance of the hematopoietic stem cell pool , 2007 .

[64]  I. Weissman,et al.  The Role of Apoptosis in the Regulation of Hematopoietic Stem Cells , 2000, The Journal of experimental medicine.

[65]  H. Horvitz,et al.  C. elegans SIR-2.1 Interacts with 14-3-3 Proteins to Activate DAF-16 and Extend Life Span , 2006, Cell.

[66]  A. Carrera,et al.  Control of Cyclin G2 mRNA Expression by Forkhead Transcription Factors: Novel Mechanism for Cell Cycle Control by Phosphoinositide 3-Kinase and Forkhead , 2004, Molecular and Cellular Biology.

[67]  G. Yancopoulos,et al.  The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors. , 2004, Molecular cell.

[68]  P. Wijchers,et al.  In control of biology: of mice, men and Foxes. , 2006, The Biochemical journal.

[69]  Yonghong Xiao,et al.  FoxOs Are Lineage-Restricted Redundant Tumor Suppressors and Regulate Endothelial Cell Homeostasis , 2007, Cell.

[70]  R. Medema,et al.  AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1 , 2000, Nature.

[71]  R. Berger,et al.  AF6q21, a novel partner of the MLL gene in t(6;11)(q21;q23), defines a forkhead transcriptional factor subfamily. , 1997, Blood.

[72]  B. Emanuel,et al.  Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma , 1993, Nature Genetics.

[73]  E. Greer,et al.  FOXO transcription factors at the interface between longevity and tumor suppression , 2005, Oncogene.

[74]  S. Nishikawa,et al.  Abnormal Angiogenesis in Foxo1 (Fkhr)-deficient Mice* , 2004, Journal of Biological Chemistry.

[75]  C. Thompson,et al.  Akt Activation Promotes Degradation of Tuberin and FOXO3a via the Proteasome* , 2003, The Journal of Biological Chemistry.

[76]  Arndt Borkhardt,et al.  Cloning and characterization of AFX, the gene that fuses to MLL in acute leukemias with a t(X;11)(q13;q23) , 1997, Oncogene.

[77]  S. Nemoto,et al.  Nutrient Availability Regulates SIRT1 Through a Forkhead-Dependent Pathway , 2004, Science.

[78]  D. Accili,et al.  The forkhead transcription factor Foxo1 regulates adipocyte differentiation. , 2003, Developmental cell.

[79]  L. N. Valenti,et al.  Nuclear Trapping of the Forkhead Transcription Factor FoxO1 via Sirt-dependent Deacetylation Promotes Expression of Glucogenetic Genes* , 2005, Journal of Biological Chemistry.

[80]  J. Biegel,et al.  Fusion of PAX7 to FKHR by the variant t(1;13)(p36;q14) translocation in alveolar rhabdomyosarcoma. , 1994, Cancer research.

[81]  D. Sabatini,et al.  Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. , 2006, Molecular cell.

[82]  P. Allen,et al.  Inflammatory arthritis requires Foxo3a to prevent Fas ligand–induced neutrophil apoptosis , 2005, Nature Medicine.

[83]  Ryuji Kobayashi,et al.  IκB Kinase Promotes Tumorigenesis through Inhibition of Forkhead FOXO3a , 2004, Cell.

[84]  T. Mak,et al.  Crosstalk between p53 and FOXO Transcription Factors , 2005, Cell cycle.

[85]  J. Testa,et al.  Perturbations of the AKT signaling pathway in human cancer , 2005, Oncogene.

[86]  N. Hay,et al.  The two TORCs and Akt. , 2007, Developmental cell.

[87]  Rakesh Nagarajan,et al.  FOXO Proteins Regulate Tumor Necrosis Factor-related Apoptosis Inducing Ligand Expression , 2002, The Journal of Biological Chemistry.

[88]  W. Sellers,et al.  A novel mechanism of gene regulation and tumor suppression by the transcription factor FKHR. , 2002, Cancer cell.

[89]  I. Gout,et al.  The TSC1-2 tumor suppressor controls insulin–PI3K signaling via regulation of IRS proteins , 2004, The Journal of cell biology.

[90]  A. Fukamizu,et al.  Acetylation of Foxo1 alters its DNA-binding ability and sensitivity to phosphorylation. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[91]  F. Colland,et al.  FOXO4 transcriptional activity is regulated by monoubiquitination and USP7/HAUSP , 2006, Nature Cell Biology.

[92]  S. R. Datta,et al.  DNA Repair Pathway Stimulated by the Forkhead Transcription Factor FOXO3a Through the Gadd45 Protein , 2002, Science.

[93]  R. DePinho,et al.  Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a , 2006, Nature.