FoxO Transcription Factors and Stem Cell Homeostasis: Insights from the Hematopoietic System
2007; Elsevier BV; Volume: 1; Issue: 2 Linguagem: Inglês
10.1016/j.stem.2007.07.017
ISSN1934-5909
AutoresZuzana Tóthová, D. Gary Gilliland,
Tópico(s)Pluripotent Stem Cells Research
ResumoThe 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. 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. Longevity in higher-level organisms is dependent on the maintenance of tissue homeostasis that is in part determined by the integrity of tissue-specific stem cells. There are several adult tissue compartments in mammalian systems that are highly reliant on stem cells for their maintenance and propagation, including skin, gastrointestinal epithelium, and blood (Blanpain et al., 2004Blanpain C. Lowry W.E. Geoghegan A. Polak L. Fuchs E. Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche.Cell. 2004; 118: 635-648Abstract Full Text Full Text PDF PubMed Scopus (1064) Google Scholar, Radtke and Clevers, 2005Radtke F. Clevers H. Self-renewal and cancer of the gut: two sides of a coin.Science. 2005; 307: 1904-1909Crossref PubMed Scopus (563) Google Scholar, Till and Mc, 1961Till J.E. McCulloch E.A. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells.Radiat. 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For example, in the gut, stem cells that reside in the base of the colonic crypts give rise to progeny that terminally differentiate into colonic epithelial cells. In the hematopoietic system, stem cells give rise to a broad spectrum of terminally differentiated effector cells that are responsible for innate and humoral immune response to infection, hemostatic homeostasis, and oxygen delivery. Hematopoietic development is regulated by a dynamic balance between HSC self-renewal and differentiation to mature effector cells. The balance between self-renewal and differentiation is of critical importance: too little self-renewal or too much differentiation may jeopardize the ability to sustain hematopoiesis throughout life, whereas excessive self-renewal and/or aberrant differentiation may result in leukemogenesis. The regulation of HSC self-renewal is not fully understood, but recent studies have underscored the importance of cell cycle, apoptosis, and oxidative stress response in HSC homeostasis. Recent data indicate that FoxO family members play a critical role in these physiologic processes in the HSC compartment and thereby regulate maintenance and integrity of HSCs. The forkhead box (Fox) family of proteins is a large family of transcription factors with diverse physiological functions. The evolutionary conservation of Fox proteins from yeast to humans, and their diverse biological functions, highlight the importance of these proteins in developmental processes. All members of the Fox family share a conserved 110 amino acid DNA-binding domain that is referred to as the "forkhead box" or "winged helix" domain. Over 100 forkhead genes have been identified to date, and in humans, this family of transcription factors has been subdivided into 19 subgroups (FOXA-FOXS) based on sequence similarity (reviewed in Wijchers et al., 2006Wijchers P.J. Burbach J.P. Smidt M.P. In control of biology: of mice, men and Foxes.Biochem. J. 2006; 397: 233-246Crossref PubMed Scopus (112) Google Scholar). The FoxO subfamily (FoxO1, FoxO3, FoxO4, and FoxO6) plays an important role as effectors of the PI3K/AKT pathway in diverse cellular processes that include induction of cell-cycle arrest, stress resistance, apoptosis, differentiation, and metabolism (reviewed in Greer and Brunet, 2005Greer E.L. Brunet A. FOXO transcription factors at the interface between longevity and tumor suppression.Oncogene. 2005; 24: 7410-7425Crossref PubMed Scopus (983) Google Scholar). FoxO1, FoxO3, and FoxO4 expression is abundant in most tissues, including those of the hematopoietic system, with highest expression of the different isoforms found in the adipose tissue, brain, and heart, respectively. In contrast, the expression of FoxO6 appears to be restricted to the developing brain and has a variant mechanism for regulation of its transcriptional activity, as described below. It is perhaps not surprising, given the diversity of functions enacted by FoxO factors, that there are multiple levels of control of FoxO function in the cellular milieu that include phosphorylation, acetylation, and ubiquitination (reviewed in van der Horst and Burgering, 2007van der Horst A. Burgering B.M. Stressing the role of FoxO proteins in lifespan and disease.Nat. Rev. Mol. Cell Biol. 2007; 8: 440-450Crossref PubMed Scopus (543) Google Scholar). FoxO phosphorylation can play both inhibitory and activating roles in FoxO function. AKT inactivates FoxO1, FoxO3, and FoxO4 by direct phosphorylation of three conserved serine and threonine residues (Thr32, Ser253, and Ser315 in FoxO3), creating a binding motif for the 14-3-3 chaperone proteins that interfere with the DNA binding domain of FoxOs and facilitate the translocation of FoxOs from the nucleus to the cytoplasm (Brunet et al., 1999Brunet A. Bonni A. Zigmond M.J. Lin M.Z. Juo P. Hu L.S. Anderson M.J. Arden K.C. Blenis J. Greenberg M.E. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor.Cell. 1999; 96: 857-868Abstract Full Text Full Text PDF PubMed Scopus (5158) Google Scholar, Brunet et al., 2002Brunet A. Kanai F. Stehn J. Xu J. Sarbassova D. Frangioni J.V. Dalal S.N. DeCaprio J.A. Greenberg M.E. Yaffe M.B. 14-3-3 transits to the nucleus and participates in dynamic nucleocytoplasmic transport.J. Cell Biol. 2002; 156: 817-828Crossref PubMed Scopus (419) Google Scholar). Cytoplasmic FoxOs are targeted for ubiquitination and proteosomal degradataion. The regulation of FoxO6 activity is not well understood, in that it lacks the C-terminal AKT phosphorylation site and is primarily localized in the nucleus (van der Heide et al., 2005van der Heide L.P. Jacobs F.M. Burbach J.P. Hoekman M.F. Smidt M.P. FoxO6 transcriptional activity is regulated by Thr26 and Ser184, independent of nucleo-cytoplasmic shuttling.Biochem. J. 2005; 391: 623-629Crossref PubMed Scopus (69) Google Scholar). In addition to AKT, other kinases, such as serum and glucocorticoid inducible kinase (SGK), casein kinase 1 (CK1), dual tyrosine phosphorylated regulated kinase 1 (DYRK1), and I kappa-B kinase β (IKKβ) participate in phosphorylation of specific serine residues in FoxOs and are thought to affect subcellular localization of FoxOs in a manner similar to AKT. Conversely, activation of Jun N-terminal kinase (JNK) or mammalian sterile 20-like kinase-1 (Mst1) in response to stress stimulation results in phosphorylation of FoxOs at a distinct set of threonine residues and results in nuclear import, rather than export, of FoxOs and subsequent transcriptional activation (Essers et al., 2004Essers M.A. Weijzen S. de Vries-Smits A.M. Saarloos I. de Ruiter N.D. Bos J.L. Burgering B.M. FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK.EMBO J. 2004; 23: 4802-4812Crossref PubMed Scopus (587) Google Scholar, Lehtinen et al., 2006Lehtinen M.K. Yuan Z. Boag P.R. Yang Y. Villen J. Becker E.B. DiBacco S. de la Iglesia N. Gygi S. Blackwell T.K. Bonni A. A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span.Cell. 2006; 125: 987-1001Abstract Full Text Full Text PDF PubMed Scopus (601) Google Scholar). The effects of FoxO phosphorylation by JNK thus appear to be counterregulatory to those mediated by PI3K/AKT phosphorylation. However, it should be noted that stressful stimuli override the negative regulatory effects of growth factors on FoxO activation (Brunet et al., 2004Brunet A. Sweeney L.B. Sturgill J.F. Chua K.F. Greer P.L. Lin Y. Tran H. Ross S.E. Mostoslavsky R. Cohen H.Y. et al.Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase.Science. 2004; 303: 2011-2015Crossref PubMed Scopus (2437) Google Scholar, Wang et al., 2005Wang M.C. Bohmann D. Jasper H. JNK extends life span and limits growth by antagonizing cellular and organism-wide responses to insulin signaling.Cell. 2005; 121: 115-125Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar), suggesting that among the most important functions of these highly evolutionarily conserved proteins is protection of mammalian cells from environmental stress, similar to their role in lower organisms. There is also complex modulation of FoxO activity by acetylation and deacetylation. FoxOs bind to coactivator and corepressor complexes, such as CREB-binding protein (CBP), p300/CBP-associated factor (PCAF), and SIRT1 deacetylase, and subsequent acetylation or deacetylation affects their transcriptional activity (Brunet et al., 2004Brunet A. Sweeney L.B. Sturgill J.F. Chua K.F. Greer P.L. Lin Y. Tran H. Ross S.E. Mostoslavsky R. 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USA. 2005; 102: 11278-11283Crossref PubMed Scopus (341) Google Scholar), whereas Sirt1-mediated deacetylation of FoxO1 appears to regulate subnuclear localization and may impact selection of transcriptional programs (Frescas et al., 2005Frescas D. Valenti L. Accili D. Nuclear trapping of the forkhead transcription factor FoxO1 via Sirt-dependent deacetylation promotes expression of glucogenetic genes.J. Biol. Chem. 2005; 280: 20589-20595Crossref PubMed Scopus (433) Google Scholar) and has been reported to globally repress FoxO1 transcriptional activity in the context of prostate cancer cells (Yang et al., 2005Yang Y. Hou H. Haller E.M. Nicosia S.V. Bai W. Suppression of FOXO1 activity by FHL2 through SIRT1-mediated deacetylation.EMBO J. 2005; 24: 1021-1032Crossref PubMed Scopus (270) Google Scholar). Ubiquitination may also result in either activation or inactivation of FoxO. Polyubiquitination targets FoxOs for proteasomal degradation and requires phosphorylation of FoxOs by AKT, SGK, or IKKβ and cytoplasmic localization (Hu et al., 2004Hu M.C. Lee D.F. Xia W. Golfman L.S. Ou-Yang F. Yang J.Y. Zou Y. Bao S. Hanada N. Saso H. et al.IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a.Cell. 2004; 117: 225-237Abstract Full Text Full Text PDF PubMed Scopus (742) Google Scholar, Huang et al., 2005Huang H. Regan K.M. Wang F. Wang D. Smith D.I. van Deursen J.M. Tindall D.J. Skp2 inhibits FOXO1 in tumor suppression through ubiquitin-mediated degradation.Proc. Natl. Acad. Sci. USA. 2005; 102: 1649-1654Crossref PubMed Scopus (404) Google Scholar, Matsuzaki et al., 2003Matsuzaki H. Daitoku H. Hatta M. Tanaka K. Fukamizu A. Insulin-induced phosphorylation of FKHR (Foxo1) targets to proteasomal degradation.Proc. Natl. Acad. Sci. USA. 2003; 100: 11285-11290Crossref PubMed Scopus (394) Google Scholar, Plas and Thompson, 2003Plas D.R. Thompson C.B. Akt activation promotes degradation of tuberin and FOXO3a via the proteasome.J. Biol. Chem. 2003; 278: 12361-12366Crossref PubMed Scopus (299) Google Scholar). Conversely, oxidative stress can induce monoubiquitination of FoxOs in the cytoplasm or nucleus and thereby mediate FoxO activation (van der Horst et al., 2006van der Horst A. de Vries-Smits A.M. Brenkman A.B. van Triest M.H. van den Broek N. Colland F. Maurice M.M. Burgering B.M. FOXO4 transcriptional activity is regulated by monoubiquitination and USP7/HAUSP.Nat. Cell Biol. 2006; 8: 1064-1073Crossref PubMed Scopus (363) Google Scholar). Thus, unique combinations of phosphorylation, acetylation, and ubiquitination of FoxOs provide mechanisms to "fine tune" FoxO function (Vogt et al., 2005Vogt P.K. Jiang H. Aoki M. Triple layer control: phosphorylation, acetylation and ubiquitination of FOXO proteins.Cell Cycle. 2005; 4: 908-913Crossref PubMed Scopus (234) Google Scholar). Taken together, these posttranslational layers of control of FoxO activity provide insight into the seeming paradox that FoxOs can regulate both a protective response to stressful stimuli as well as regulation of cell death, and mechanistic explanations for FoxOs' ability to orchestrate different transcriptional programs depending on the nature of the environmental stimulus. Whereas FoxO inactivation by PI3K/AKT pathway favors enhanced cell survival, cell proliferation, and stress sensitivity, activation of FoxOs leads to apoptosis, cell-cycle arrest, and stress resistance in most tissue contexts. In the absence of growth factors or insulin, or in the presence of stress stimuli, FoxO members reside in the nucleus and are active as transcription factors (Figure 1). Their activation engages several transcriptional programs that include proapoptotic signaling via induction of TRAIL, FasL, and Bim (Brunet et al., 1999Brunet A. Bonni A. Zigmond M.J. Lin M.Z. Juo P. Hu L.S. Anderson M.J. 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These include increased expression of p27, p130, and p21 and repression of Cyclin D expression that contributes to G1/S arrest (Kops et al., 2002bKops G.J. Medema R.H. Glassford J. Essers M.A. Dijkers P.F. Coffer P.J. Lam E.W. Burgering B.M. Control of cell cycle exit and entry by protein kinase B-regulated forkhead transcription factors.Mol. Cell. Biol. 2002; 22: 2025-2036Crossref PubMed Scopus (362) Google Scholar, Medema et al., 2000Medema R.H. Kops G.J. Bos J.L. Burgering B.M. AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1.Nature. 2000; 404: 782-787Crossref PubMed Scopus (1181) Google Scholar, Seoane et al., 2004Seoane J. Le H.V. Shen L. Anderson S.A. Massague J. 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In differentiating cells, FoxOs can either promote or inhibit differentiation, depending on the tissue context and FoxO isoform. For example, expression of FoxO1 inhibits differentiation of adipocytes and myoblasts (Hribal et al., 2003Hribal M.L. Nakae J. Kitamura T. Shutter J.R. Accili D. Regulation of insulin-like growth factor-dependent myoblast differentiation by Foxo forkhead transcription factors.J. Cell Biol. 2003; 162: 535-541Crossref PubMed Scopus (159) Google Scholar, Nakae et al., 2003Nakae J. Kitamura T. Kitamura Y. Biggs 3rd, W.H. Arden K.C. Accili D. The forkhead transcription factor Foxo1 regulates adipocyte differentiation.Dev. Cell. 2003; 4: 119-129Abstract Full Text Full Text PDF PubMed Scopus (564) Google Scholar), whereas FoxO3 potentiates differentiation of erythroid cells (Bakker et al., 2004Bakker W.J. Blazquez-Domingo M. Kolbus A. Besooyen J. Steinlein P. Beug H. Coffer P.J. Lowenberg B. von Lindern M. van Dijk T.B. FoxO3a regulates erythroid differentiation and induces BTG1, an activator of protein arginine methyl transferase 1.J. Cell Biol. 2004; 164: 175-184Crossref PubMed Scopus (136) Google Scholar). In addition, activation of FoxOs causes atrophy of fully differentiated skeletal and cardiac muscle cells by decreasing protein synthesis and cell size (Sandri et al., 2004Sandri M. Sandri C. Gilbert A. Skurk C. Calabria E. Picard A. Walsh K. Schiaffino S. Lecker S.H. Goldberg A.L. Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy.Cell. 2004; 117: 399-412Abstract Full Text Full Text PDF PubMed Scopus (2005) Google Scholar, Stitt et al., 2004Stitt T.N. Drujan D. Clarke B.A. Panaro F. Timofeyva Y. Kline W.O. Gonzalez M. Yancopoulos G.D. Glass D.J. The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors.Mol. Cell. 2004; 14: 395-403Abstract Full Text Full Text PDF PubMed Scopus (1369) Google Scholar). Loss of function of FoxOs in conditional knockout models as a consequence of excision mediated by interferon-inducible promoters also results in tumorigenesis, but in a highly tissue dependent and selective manner (Paik et al., 2007Paik J.H. Kollipara R. Chu G. Ji H. Xiao Y. Ding Z. Miao L. Tothova Z. Horner J.W. Carrasco D.R. et al.FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis.Cell. 2007; 128: 309-323Abstract Full Text Full Text PDF PubMed Scopus (803) Google Scholar). Lastly, FoxOs are important regulators of glucose metabolism by upregulating the expression of genes involved in gluconeogenesis (reviewed in Barthel et al., 2005Barthel A. Schmoll D. Unterman T.G. FoxO proteins in insulin action and metabolism.Trends Endocrinol. Metab. 2005; 16: 183-189Abstract Full Text Full Text PDF PubMed Scopus (451) Google Scholar). The basis for the highly context-dependent effects of FoxO gain or loss of function is not well understood. However, there are several potential explanations for these differences that include varying levels of expression or redundancy among different family members in different tissues or unique environmental stresses encountered by various tissue compartments. In addition, it is not clear why mammalian systems have four closely related FoxO family members, whereas Drosophila or nematodes have a single FoxO ortholog. However, it is tempting to speculate that there is a degree of functional redundancy that reflects the importance of these transcription factors in maintaining integrity of mammalian systems and that there are also distinctive and nonoverlapping functions that subserve specific physiologic needs within a specific tissue compartment. Experimental support for functional redundancy comes from loss-of-function studies in the murine system, in which there may be minimal phenotypes associated with loss of a single FoxO family member. For example, FoxO4-deficient animals are viable and do not show any overt phenotype (Hosaka et al., 2004Hosaka T. Biggs 3rd, W.H. Tieu D. Boyer A.D. Varki N.M. Cavenee W.K. Arden K.C. Disruption of forkhead transcription factor (FOXO) family members in mice reveals their functional diversification.Proc. Natl. Acad. Sci. USA. 2004; 101: 2975-2980Crossref PubMed Scopus (495) Google Scholar), and FoxO3-deficient animals are born with normal Mendelian frequencies, although females become infertile due to global primordial follicle activation with subsequent oocyte exhaustion that indicates a central role for FoxO3 in this germ cell compartment. FoxO3-deficient mice also exhibit defects in glucose uptake and autoinflammation (Castrillon et al., 2003Castrillon D.H. Miao L. Kollipara R. 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