The Experts below are selected from a list of 26433 Experts worldwide ranked by ideXlab platform
Ronald A Depinho - One of the best experts on this subject based on the ideXlab platform.
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FOXO1 integrates direct and indirect effects of insulin on hepatic glucose production and glucose utilization
Nature Communications, 2015Co-Authors: Insug Osullivan, Ronald A Depinho, Jihye Paik, Wenwei Zhang, Chong Wee Liew, David H Wasserman, Jonathan Liu, Donna B Stolz, Ronald C Kahn, Michael W SchwartzAbstract:FoxO proteins are major targets of insulin action. To better define the role of FOXO1 in mediating insulin effects in the liver, we generated liver-specific insulin receptor knockout (LIRKO) and IR/FOXO1 double knockout (LIRFKO) mice. Here we show that LIRKO mice are severely insulin resistant based on glucose, insulin and C-peptide levels, and glucose and insulin tolerance tests, and genetic deletion of hepatic FOXO1 reverses these effects. (13)C-glucose and insulin clamp studies indicate that regulation of both hepatic glucose production (HGP) and glucose utilization is impaired in LIRKO mice, and these defects are also restored in LIRFKO mice corresponding to changes in gene expression. We conclude that (1) inhibition of FOXO1 is critical for both direct (hepatic) and indirect effects of insulin on HGP and utilization, and (2) extrahepatic effects of insulin are sufficient to maintain normal whole-body and hepatic glucose metabolism when liver FOXO1 activity is disrupted.
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Endothelial FOXO1 is an intrinsic regulator of thrombospondin 1 expression that restrains angiogenesis in ischemic muscle
Angiogenesis, 2013Co-Authors: Emilie Roudier, Ronald A Depinho, Jihye Paik, Malgorzata Milkiewicz, Olivier Birot, Dara Slopack, Andreas Montelius, Thomas Gustafsson, George P. Casale, Iraklis I. PipinosAbstract:Peripheral artery disease (PAD) is characterized by chronic muscle ischemia. Compensatory angiogenesis is minimal within ischemic muscle despite an increase in angiogenic factors. This may occur due to the prevalence of angiostatic factors. Regulatory mechanisms that could evoke an angiostatic environment during ischemia are largely unknown. Forkhead box O (FoxO) transcription factors, known to repress endothelial cell proliferation in vitro, are potential candidates. Our goal was to determine whether FoxO proteins promote an angiostatic phenotype within ischemic muscle. FOXO1 and the angiostatic matrix protein thrombospondin 1 (THBS1) were elevated in ischemic muscle from PAD patients, or from mice post-femoral artery ligation. Mice with conditional endothelial cell-directed deletion of FoxO proteins ( Mx1Cre ^+, FOXO1,3,4 ^ L/L , referred to as FoxOΔ) were used to assess the role of endothelial FoxO proteins within ischemic tissue. FoxO deletion abrogated the elevation of FOXO1 and THBS1 proteins, enhanced hindlimb blood flow recovery and improved neovascularization in murine ischemic muscle. Endothelial cell outgrowth from 3D explant cultures was more robust in muscles derived from FoxOΔ mice. FOXO1 overexpression induced THBS1 production, and a direct interaction of endogenous FOXO1 with the THBS1 promoter was detectable in primary endothelial cells. We provide evidence that FOXO1 directly regulates THBS1 within ischemic muscle. Altogether, these findings bring novel insight into the regulatory mechanisms underlying the repression of angiogenesis within peripheral ischemic tissues.
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hepatic suppression of FOXO1 and foxo3 causes hypoglycemia and hyperlipidemia in mice
Endocrinology, 2012Co-Authors: Kebin Zhang, Ronald A Depinho, Ling Li, Yajuan Qi, Travis AverittAbstract:Dysregulation of blood glucose and triglycerides are the major characteristics of type 2 diabetes mellitus. We sought to identify the mechanisms regulating blood glucose and lipid homeostasis. Cell-based studies established that the Foxo forkhead transcription factors Forkhead box O (Foxo)-1, Foxo3, and Foxo4 are inactivated by insulin via a phosphatidylinositol 3-kinase/Akt-dependent pathway, but the role of Foxo transcription factors in the liver in regulating nutrient metabolism is incompletely understood. In this study, we used the Cre/LoxP genetic approach to delete the FOXO1, Foxo3, and Foxo4 genes individually or a combination of two or all in the liver of lean or db/db mice and assessed the role of Foxo inactivation in regulating glucose and lipid homeostasis in vivo. In the lean mice or db/db mice, hepatic deletion of FOXO1, rather than Foxo3 or Foxo4, caused a modest reduction in blood glucose concentrations and barely affected lipid homeostasis. Combined deletion of FOXO1 and Foxo3 decreased bl...
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hepatic suppression of FOXO1 and foxo3 causes hypoglycemia and hyperlipidemia in mice
Endocrinology, 2012Co-Authors: Kebin Zhang, Ronald A Depinho, Travis Averitt, Xiaoping Zhu, Boyi Gan, Shaodong GuoAbstract:Dysregulation of blood glucose and triglycerides are the major characteristics of type 2 diabetes mellitus. We sought to identify the mechanisms regulating blood glucose and lipid homeostasis. Cell-based studies established that the Foxo forkhead transcription factors Forkhead box O (Foxo)-1, Foxo3, and Foxo4 are inactivated by insulin via a phosphatidylinositol 3-kinase/Akt-dependent pathway, but the role of Foxo transcription factors in the liver in regulating nutrient metabolism is incompletely understood. In this study, we used the Cre/LoxP genetic approach to delete the FOXO1, Foxo3, and Foxo4 genes individually or a combination of two or all in the liver of lean or db/db mice and assessed the role of Foxo inactivation in regulating glucose and lipid homeostasis in vivo. In the lean mice or db/db mice, hepatic deletion of FOXO1, rather than Foxo3 or Foxo4, caused a modest reduction in blood glucose concentrations and barely affected lipid homeostasis. Combined deletion of FOXO1 and Foxo3 decreased blood glucose levels, elevated serum triglyceride and cholesterol concentrations, and increased hepatic lipid secretion and caused hepatosteatosis. Analysis of the liver transcripts established a prominent role of FOXO1 in regulating gene expression of gluconeogenic enzymes and Foxo3 in the expression of lipogenic enzymes. Our findings indicate that FOXO1 and Foxo3 inactivation serves as a potential mechanism by which insulin reduces hepatic glucose production and increases hepatic lipid synthesis and secretion in healthy and diabetic states.
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foxo transcription factors promote cardiomyocyte survival upon induction of oxidative stress
Journal of Biological Chemistry, 2011Co-Authors: Arunima Sengupta, Ronald A Depinho, Jihye Paik, Jeffery D Molkentin, Katherine E YutzeyAbstract:Transcriptional regulatory mechanisms of cardiac oxidative stress resistance are not well defined. FoxO transcription factors are critical mediators of oxidative stress resistance in multiple cell types, but cardioprotective functions have not been reported previously. FoxO function in oxidative stress resistance was investigated in cultured cardiomyocytes and in mice with cardiomyocyte-specific combined deficiency of FOXO1 and FoxO3 subjected to myocardial infarction (MI) or acute ischemia/reperfusion (I/R) injury. Induction of oxidative stress in cardiomyocytes promotes FOXO1 and FoxO3 nuclear localization and target gene activation. Infection of cardiomyocytes with a dominant-negative FOXO1(Δ256) adenovirus results in a significant increase in reactive oxygen species and cell death, whereas increased FOXO1 or FoxO3 expression reduces reactive oxygen species and cell death. Mice generated with combined conditional deletion of FOXO1 and FoxO3 specifically in cardiomyocytes were subjected to I/R or MI. Loss of FOXO1 and FoxO3 in cardiomyocytes results in a significant increase in infarct area with decreased expression of the antiapoptotic molecules, PTEN-induced kinase1 (PINK1) and CBP/P300-interacting transactivator (CITED2). Expressions of the antioxidants catalase and manganese superoxide dismutase-2 (SOD2) and the autophagy-related proteins LC3II and Gabarapl1 also are decreased following I/R compared with controls. Mice with cardiomyocyte-specific FoxO deficiency subjected to MI have reduced cardiac function, increased scar formation, induction of stress-responsive signaling, and increased apoptotic cell death relative to controls. These data support a critical role for FoxOs in promoting cardiomyocyte survival during conditions of oxidative stress through induction of antioxidants and cell survival pathways.
Akiyoshi Fukamizu - One of the best experts on this subject based on the ideXlab platform.
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PCAF represses transactivation function of FOXO1 in an acetyltransferase-independent manner.
Journal of receptor and signal transduction research, 2009Co-Authors: Kenji Yoshimochi, Hiroaki Daitoku, Akiyoshi FukamizuAbstract:The FOXO transcription factors play a key role in cell cycle control, apoptosis, DNA repair, oxidative stress resistance, and longevity. In this study, we demonstrated that the acetyltransferase p300/CBP associated factor (PCAF) functions as a negative regulator of FOXO1. We showed that PCAF bound to the forkhead domain of FOXO1 and acetylated FOXO1 at the K242 and K245 residues. However, PCAF repressed FOXO1-induced transcription in an enzymatic activity-independent manner. In contrast, the transcriptional activity of FOXO1 S253A mutant, in which an Akt phosphorylation site is replaced by alanine, was not repressed by PCAF. Akt-induced phosphorylation of FOXO1 is required for its binding to PCAF, whereas the binding between FOXO1 and CBP is independent on FOXO1 S253 phosphorylation. Furthermore, overexpression of PCAF increased nuclear accumulation of FOXO1 even in the presence of serum. These results suggest that PCAF binds to phosphorylated FOXO1 by Akt and acts as a transcriptional corepressor in the ...
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Acetylation of FOXO1 alters its DNA-binding ability and sensitivity to phosphorylation
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Hitomi Matsuzaki, Hiroaki Daitoku, Mitsutoki Hatta, Hisanori Aoyama, Kenji Yoshimochi, Akiyoshi FukamizuAbstract:The FOXO family of forkhead transcription factors plays a key role in a variety of biological processes, including metabolism, cell proliferation, and oxidative stress response. We previously reported that FOXO1, a member of the FOXO family, is regulated through reversible acetylation catalyzed by histone acetyltransferase cAMP-response element-binding protein (CREB)-binding protein (CBP) and NAD-dependent histone deacetylase silent information regulator 2, and that the acetylation at Lys-242, Lys-245, and Lys-262 of FOXO1 attenuates its transcriptional activity. However, the molecular mechanism by which acetylation modulates FOXO1 activity remains unknown. Here, we show that the positive charge of these lysines in FOXO1 contributes to its DNA-binding, and acetylation at these residues by CBP attenuates its ability to bind cognate DNA sequence. Remarkably, we also show that acetylation of FOXO1 increases the levels of its phosphorylation at Ser-253 through the phosphatidylinositol 3-kinase–protein kinase B signaling pathway, and this effect was overridden on the acetylation-deficient FOXO1 mutant. Furthermore, in in vitro kinase reactions, the association of wild-type FOXO1 and its target DNA sequence inhibits the protein kinase B-dependent phosphorylation of FOXO1, whereas mutated FOXO1 proteins, which mimic constitutively acetylated states, are efficiently phosphorylated even in the presence of the DNA. These results suggest that acetylation regulates the function of FOXO1 through altering the affinity with the target DNA and the sensitivity for phosphorylation.
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silent information regulator 2 potentiates FOXO1 mediated transcription through its deacetylase activity
Proceedings of the National Academy of Sciences of the United States of America, 2004Co-Authors: Hiroaki Daitoku, Hitomi Matsuzaki, Mitsutoki Hatta, Satoko Aratani, Takayuki Ohshima, Makoto Miyagishi, Toshihiro Nakajima, Akiyoshi FukamizuAbstract:Longevity regulatory genes include the Forkhead transcription factor FOXO and the NAD-dependent histone deacetylase silent information regulator 2 (Sir2). Genetic studies demonstrate that Sir2 acts to extend lifespan in Caenorhabditis elegans upstream of DAF-16, a member of the FOXO family, in the insulin-like signaling pathway. However, the molecular mechanisms underlying the requirement of DAF-16 activity in Sir2-mediated longevity remain unknown. Here we show that reversible acetylation of FOXO1 (also known as FKHR), the mouse DAF-16 ortholog, modulates its transactivation function. cAMP-response element-binding protein (CREB)-binding protein binds and acetylates FOXO1 at the K242, K245, and K262 residues, the modification of which is involved in the attenuation of FOXO1 as a transcription factor. Conversely, Sir2 binds and deacetylates FOXO1 at residues acetylated by cAMP-response element-binding protein-binding protein. Sir2 is recruited to insulin response sequence-containing promoter and increases the expression of manganese superoxide dismutase and p27kip1 in a deacetylase-activity-dependent manner. Our findings establish FOXO1 as a direct and functional target for Sir2 in mammalian systems.
Jihye Paik - One of the best experts on this subject based on the ideXlab platform.
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FOXO1 integrates direct and indirect effects of insulin on hepatic glucose production and glucose utilization
Nature Communications, 2015Co-Authors: Insug Osullivan, Ronald A Depinho, Jihye Paik, Wenwei Zhang, Chong Wee Liew, David H Wasserman, Jonathan Liu, Donna B Stolz, Ronald C Kahn, Michael W SchwartzAbstract:FoxO proteins are major targets of insulin action. To better define the role of FOXO1 in mediating insulin effects in the liver, we generated liver-specific insulin receptor knockout (LIRKO) and IR/FOXO1 double knockout (LIRFKO) mice. Here we show that LIRKO mice are severely insulin resistant based on glucose, insulin and C-peptide levels, and glucose and insulin tolerance tests, and genetic deletion of hepatic FOXO1 reverses these effects. (13)C-glucose and insulin clamp studies indicate that regulation of both hepatic glucose production (HGP) and glucose utilization is impaired in LIRKO mice, and these defects are also restored in LIRFKO mice corresponding to changes in gene expression. We conclude that (1) inhibition of FOXO1 is critical for both direct (hepatic) and indirect effects of insulin on HGP and utilization, and (2) extrahepatic effects of insulin are sufficient to maintain normal whole-body and hepatic glucose metabolism when liver FOXO1 activity is disrupted.
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Endothelial FOXO1 is an intrinsic regulator of thrombospondin 1 expression that restrains angiogenesis in ischemic muscle
Angiogenesis, 2013Co-Authors: Emilie Roudier, Ronald A Depinho, Jihye Paik, Malgorzata Milkiewicz, Olivier Birot, Dara Slopack, Andreas Montelius, Thomas Gustafsson, George P. Casale, Iraklis I. PipinosAbstract:Peripheral artery disease (PAD) is characterized by chronic muscle ischemia. Compensatory angiogenesis is minimal within ischemic muscle despite an increase in angiogenic factors. This may occur due to the prevalence of angiostatic factors. Regulatory mechanisms that could evoke an angiostatic environment during ischemia are largely unknown. Forkhead box O (FoxO) transcription factors, known to repress endothelial cell proliferation in vitro, are potential candidates. Our goal was to determine whether FoxO proteins promote an angiostatic phenotype within ischemic muscle. FOXO1 and the angiostatic matrix protein thrombospondin 1 (THBS1) were elevated in ischemic muscle from PAD patients, or from mice post-femoral artery ligation. Mice with conditional endothelial cell-directed deletion of FoxO proteins ( Mx1Cre ^+, FOXO1,3,4 ^ L/L , referred to as FoxOΔ) were used to assess the role of endothelial FoxO proteins within ischemic tissue. FoxO deletion abrogated the elevation of FOXO1 and THBS1 proteins, enhanced hindlimb blood flow recovery and improved neovascularization in murine ischemic muscle. Endothelial cell outgrowth from 3D explant cultures was more robust in muscles derived from FoxOΔ mice. FOXO1 overexpression induced THBS1 production, and a direct interaction of endogenous FOXO1 with the THBS1 promoter was detectable in primary endothelial cells. We provide evidence that FOXO1 directly regulates THBS1 within ischemic muscle. Altogether, these findings bring novel insight into the regulatory mechanisms underlying the repression of angiogenesis within peripheral ischemic tissues.
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foxo transcription factors promote cardiomyocyte survival upon induction of oxidative stress
Journal of Biological Chemistry, 2011Co-Authors: Arunima Sengupta, Ronald A Depinho, Jihye Paik, Jeffery D Molkentin, Katherine E YutzeyAbstract:Transcriptional regulatory mechanisms of cardiac oxidative stress resistance are not well defined. FoxO transcription factors are critical mediators of oxidative stress resistance in multiple cell types, but cardioprotective functions have not been reported previously. FoxO function in oxidative stress resistance was investigated in cultured cardiomyocytes and in mice with cardiomyocyte-specific combined deficiency of FOXO1 and FoxO3 subjected to myocardial infarction (MI) or acute ischemia/reperfusion (I/R) injury. Induction of oxidative stress in cardiomyocytes promotes FOXO1 and FoxO3 nuclear localization and target gene activation. Infection of cardiomyocytes with a dominant-negative FOXO1(Δ256) adenovirus results in a significant increase in reactive oxygen species and cell death, whereas increased FOXO1 or FoxO3 expression reduces reactive oxygen species and cell death. Mice generated with combined conditional deletion of FOXO1 and FoxO3 specifically in cardiomyocytes were subjected to I/R or MI. Loss of FOXO1 and FoxO3 in cardiomyocytes results in a significant increase in infarct area with decreased expression of the antiapoptotic molecules, PTEN-induced kinase1 (PINK1) and CBP/P300-interacting transactivator (CITED2). Expressions of the antioxidants catalase and manganese superoxide dismutase-2 (SOD2) and the autophagy-related proteins LC3II and Gabarapl1 also are decreased following I/R compared with controls. Mice with cardiomyocyte-specific FoxO deficiency subjected to MI have reduced cardiac function, increased scar formation, induction of stress-responsive signaling, and increased apoptotic cell death relative to controls. These data support a critical role for FoxOs in promoting cardiomyocyte survival during conditions of oxidative stress through induction of antioxidants and cell survival pathways.
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FOXO1 is a positive regulator of bone formation by favoring protein synthesis and resistance to oxidative stress in osteoblasts
Cell Metabolism, 2010Co-Authors: Marie Therese Rached, Ronald A Depinho, Jihye Paik, Aruna Kode, Lili Xu, Yoshihiro Yoshikawa, Stavroula KousteniAbstract:Summary Osteoporosis, a disease of low bone mass, is associated with decreased osteoblast numbers and increased levels of oxidative stress within osteoblasts. Since transcription factors of the FoxO family confer stress resistance, we investigated their potential impact on skeletal integrity. Here we employ cell-specific deletion and molecular analyses to show that, among the three FoxO proteins, only FOXO1 is required for proliferation and redox balance in osteoblasts and thereby controls bone formation. FOXO1 regulation of osteoblast proliferation occurs through its interaction with ATF4, a transcription factor regulating amino acid import, as well as through its regulation of a stress-dependent pathway influencing p53 signaling. Accordingly, decreasing oxidative stress levels or increasing protein intake normalizes bone formation and bone mass in mice lacking FOXO1 specifically in osteoblasts. These results identify FOXO1 as a crucial regulator of osteoblast physiology and provide a direct mechanistic link between oxidative stress and the regulation of bone remodeling.
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forkhead transcription factors foxos promote apoptosis of insulin resistant macrophages during cholesterol induced endoplasmic reticulum stress
Diabetes, 2008Co-Authors: Takafumi Senokuchi, Chien Ping Liang, Michihiro Matsumoto, Domenico Accili, Ronald A Depinho, Jihye Paik, Ira Tabas, Alexander S. Banks, Tracie A Seimon, Alan R TallAbstract:OBJECTIVE— Endoplasmic reticulum stress increases macrophage apoptosis, contributing to the complications of atherosclerosis. Insulin-resistant macrophages are more susceptible to endoplasmic reticulum stress–associated apoptosis probably contributing to macrophage death and necrotic core formation in atherosclerotic plaques in type 2 diabetes. However, the molecular mechanisms of increased apoptosis in insulin-resistant macrophages remain unclear. RESEARCH DESIGN AND METHODS— The studies were performed in insulin-resistant macrophages isolated from insulin receptor knockout or ob/ob mice. Gain- or loss-of-function approaches were used to evaluate the roles of forkhead transcription factors (FoxOs) in endoplasmic reticulum stress–associated macrophage apoptosis. RESULTS— Insulin-resistant macrophages showed attenuated Akt activation and increased nuclear localization of FOXO1 during endoplasmic reticulum stress induced by free cholesterol loading. Overexpression of active FOXO1 or FoxO3 failed to induce apoptosis in unchallenged macrophages but exacerbated apoptosis in macrophages with an active endoplasmic reticulum stress response. Conversely, macrophages with genetic knockouts of FOXO1, -3, and -4 were resistant to apoptosis in response to endoplasmic reticulum stress. FOXO1 was shown by chromatin immunoprecipitation and promoter expression analysis to induce inhibitor of κBe gene expression and thereby to attenuate the increase of nuclear p65 and nuclear factor-κB activity during endoplasmic reticulum stress, with proapoptotic and anti-inflammatory consequences. CONCLUSIONS— Decreased Akt and increased FoxO transcription factor activity during the endoplasmic reticulum stress response leads to increased apoptosis of insulin-resistant macrophages. FoxOs may have a dual cellular function, resulting in either proapoptotic or anti-inflammatory effects in an endoplasmic reticulum stress–modulated manner. In the complex plaque milieu, the ultimate effect is likely to be an increase in macrophage apoptosis, plaque inflammation, and destabilization.
Diego H Castrillon - One of the best experts on this subject based on the ideXlab platform.
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FOXO1 3 and pten depletion in granulosa cells promotes ovarian granulosa cell tumor development
Molecular Endocrinology, 2015Co-Authors: Zhilin Liu, Diego H Castrillon, Yi A Ren, Stephanie A Pangas, Jaye Adams, Wei Zhou, Dagmar Wilhelm, Joanne S RichardsAbstract:The forkhead box (FOX), FOXO1 and FOXO3, transcription factors regulate multiple functions in mammalian cells. Selective inactivation of the FOXO1 and Foxo3 genes in murine ovarian granulosa cells severely impairs follicular development and apoptosis causing infertility, and as shown here, granulosa cell tumor (GCT) formation. Coordinate depletion of the tumor suppressor Pten gene in the FOXO1/3 strain enhanced the penetrance and onset of GCT formation. Immunostaining and Western blot analyses confirmed FOXO1 and phosphatase and tensin homolog (PTEN) depletion, maintenance of globin transcription factor (GATA) 4 and nuclear localization of FOXL2 and phosphorylated small mothers against decapentaplegic (SMAD) 2/3 in the tumor cells, recapitulating results we observed in human adult GCTs. Microarray and quantitative PCR analyses of mouse GCTs further confirmed expression of specific genes (Foxl2, Gata4, and Wnt4) controlling granulosa cell fate specification and proliferation, whereas others (Emx2, Nr0b1, Rspo1, and Wt1) were suppressed. Key genes (Amh, Bmp2, and Fshr) controlling follicle growth, apoptosis, and differentiation were also suppressed. Inhbb and Grem1 were selectively elevated, whereas reduction of Inha provided additional evidence that activin signaling and small mothers against decapentaplegic (SMAD) 2/3 phosphorylation impact GCT formation. Unexpectedly, markers of Sertoli/epithelial cells (SRY [sex determining region Y]-box 9/keratin 8) and alternatively activated macrophages (chitinase 3-like 3) were elevated in discrete subpopulations within the mouse GCTs, indicating that FOXO1/3/Pten depletion not only leads to GCTs but also to altered granulosa cell fate decisions and immune responses. Thus, analyses of the FOXO1/3/Pten mouse GCTs and human adult GCTs provide strong evidence that impaired functions of the FOXO1/3/PTEN pathways lead to dramatic changes in the molecular program within granulosa cells, chronic activin signaling in the presence of FOXL2 and GATA4, and tumor formation.
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FOXO1 is required in mouse spermatogonial stem cells for their maintenance and the initiation of spermatogenesis
Journal of Clinical Investigation, 2011Co-Authors: Meredith J Goertz, Zhuoru Wu, Teresa D Gallardo, Kent F Hamra, Diego H CastrillonAbstract:Spermatogonial stem cells (SSCs) capable of self-renewal and differentiation are the foundation for spermatogenesis. Although several factors important for these processes have been identified, the fundamental mechanisms regulating SSC self-renewal and differentiation remain unknown. Here, we investigated a role for the Foxo transcription factors in mouse spermatogenesis and found that FOXO1 specifically marks mouse gonocytes and a subset of spermatogonia with stem cell potential. Genetic analyses showed that FOXO1 was required for both SSC homeostasis and the initiation of spermatogenesis. Combined deficiency of FOXO1, Foxo3, and Foxo4 resulted in a severe impairment of SSC self-renewal and a complete block of differentiation, indicating that Foxo3 and Foxo4, although dispensable for male fertility, contribute to SSC function. By conditional inactivation of 3-phosphoinositide–dependent protein kinase 1 (Pdk1) and phosphatase and tensin homolog (Pten) in the male germ line, we found that PI3K signaling regulates FOXO1 stability and subcellular localization, revealing that the Foxos are pivotal effectors of PI3K-Akt signaling in SSCs. We also identified a network of Foxo gene targets — most notably Ret — that rationalized the maintenance of SSCs by the Foxos. These studies demonstrate that FOXO1 expression in the spermatogenic lineage is intimately associated with the stem cell state and revealed what we believe to be novel Foxo-dependent mechanisms underlying SSC self-renewal and differentiation, with implications for common diseases, including male infertility and testicular cancer, due to abnormalities in SSC function.
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FOXO1 links homing and survival of naive t cells by regulating l selectin ccr7 and interleukin 7 receptor
Nature Immunology, 2009Co-Authors: Yann M Kerdiles, Ronald A Depinho, Diego H Castrillon, Daniel R Beisner, Roberto Tinoco, Anne Dejean, Stephen M HedrickAbstract:Foxo transcription factors have a conserved role in the adaptation of cells and organisms to nutrient and growth factor availability. Here we show that FOXO1 has a crucial, nonredundant role in T cells. In naive T cells, FOXO1 controlled the expression of the adhesion molecule L-selectin, the chemokine receptor CCR7 and the transcription factor Klf2, and its deletion was sufficient to alter lymphocyte trafficking. Furthermore, FOXO1 deficiency resulted in a severe defect in interleukin 7 receptor alpha-chain (IL-7Ralpha) expression associated with its ability to bind an Il7r enhancer. Finally, growth factor withdrawal induced a FOXO1-dependent increase in Sell, Klf2 and Il7r expression. These data suggest that FOXO1 regulates the homeostasis and life span of naive T cells by sensing growth factor availability and regulating homing and survival signals.
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distinct functions for the transcription factor FOXO1 at various stages of b cell differentiation
Nature Immunology, 2008Co-Authors: Hart S Dengler, Ronald A Depinho, Diego H Castrillon, G V Baracho, Sidne A Omori, Shane Bruckner, Karen C Arden, Robert C RickertAbstract:Foxo transcription factors are linked to complex regulatory circuits governed by the availability of phosphatidylinositol-3,4,5-trisphosphate. Rickert and colleagues show that FOXO1 has nonredundant functions at many stages of B cell development.
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foxos are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress
Cell, 2007Co-Authors: Diego H Castrillon, Ramya Kollipara, Zuzana Tothova, Brian J P Huntly, Dana E Cullen, Elizabeth P Mcdowell, Suzan LazokallanianAbstract:Summary To understand the role of FoxO family members in hematopoiesis, we conditionally deleted FOXO1 , FoxO3 , and FoxO4 in the adult hematopoietic system. FoxO- deficient mice exhibited myeloid lineage expansion, lymphoid developmental abnormalities, and a marked decrease of the lineage-negative Sca-1 + , c-Kit + (LSK) compartment that contains the short- and long-term hematopoietic stem cell (HSC) populations. FoxO -deficient bone marrow had defective long-term repopulating activity that correlated with increased cell cycling and apoptosis of HSC. Notably, there was a marked context-dependent increase in reactive oxygen species (ROS) in FoxO -deficient HSC compared with wild-type HSC that correlated with changes in expression of genes that regulate ROS. Furthermore, in vivo treatment with the antioxidative agent N-acetyl-L-cysteine resulted in reversion of the FoxO -deficient HSC phenotype. Thus, FoxO proteins play essential roles in the response to physiologic oxidative stress and thereby mediate quiescence and enhanced survival in the HSC compartment, a function that is required for its long-term regenerative potential.
Rene H. Medema - One of the best experts on this subject based on the ideXlab platform.
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foxo4 is acetylated upon peroxide stress and deacetylated by the longevity protein hsir2 sirt1
Journal of Biological Chemistry, 2004Co-Authors: Armando Van Der Horst, Rene H. Medema, Leon G J Tertoolen, Lydia M M De Vriessmits, Roy A Frye, Boudewijn M T BurgeringAbstract:Abstract FOXO transcription factors have important roles in metabolism, cellular proliferation, stress tolerance, and aging. FOXOs are negatively regulated by protein kinase B/c-Akt-mediated phosphorylation. Here we show that FOXO factors are also subject to regulation by reversible acetylation. We provide evidence that the acetyltransferase CREB-binding protein (CBP) binds FOXO resulting in acetylation of FOXO. This acetylation inhibits FOXO transcriptional activity. Binding of CBP and acetylation are induced after treatment of cells with peroxide stress. Deacetylation of FOXOs involves binding of the NAD-dependent deacetylase hSir2SIRT1. Accordingly, hSir2SIRT1-mediated deacetylation precludes FOXO inhibition through acetylation and thereby prolongs FOXO-dependent transcription of stress-regulating genes. These data demonstrate that acetylation functions in a second pathway of negative control for FOXO factors and provides a novel mechanism whereby hSir2SIRT1 can promote cellular survival and increase lifespan.
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FoxO3a transcriptional regulation of Bim controls apoptosis in paclitaxel treated breast cancer cell lines.
Cancer Research, 2004Co-Authors: Andrew Sunters, Catherine A Saunders, Silvia Fernández De Mattos, Georgia Zoumpoulidou, Jan J. Brosens, Marie Ståhl, Paul J Coffer, Rene H. Medema, R. Charles CoombesAbstract:Proc Amer Assoc Cancer Res, Volume 45, 2004 2420 Paclitaxel is used to treat breast cancers, but the mechanisms by which it induces apoptosis are poorly understood. Consequently, we have studied the role of the FoxO subfamily of forkhead transcription factors in determining cellular response to paclitaxel. Western blotting revealed that in a panel of breast cancer cell lines expression of FOXO1a and FoxO3a correlated with the expression of the pro-apoptotic FoxO target Bim, which was associated with paclitaxel-induced apoptosis. In MCF-7 cells, which were paclitaxel sensitive, the already high basal levels of FoxO3a and Bim protein increased dramatically after drug treatment, as did Bim mRNA, which correlated with apoptosis induction. This was not observed in MDA-231 cells which expressed low levels of FoxOs and Bim. Gene reporter experiments demonstrated that in MCF-7 cells maximal induction of Bim promoter was dependent on a FoxO binding site, suggesting that FoxO3a is responsible for the transcriptional upregulation of Bim . Gene silencing experiments showed that siRNA specific for FoxO3a reduced the levels of FoxO3a and Bim protein as well as inhibited apoptosis in paclitaxel-treated MCF-7 cells. Furthermore, siRNA specific for Bim reduced the levels of Bim protein and inhibited apoptosis in paclitaxel-treated MCF-7 cells. This is the first demonstration that upregulation of FoxO3a by paclitaxel can result in increased levels of Bim mRNA and protein which can be a direct cause of apoptosis in breast cancer , and therefore FoxOs and Bim can be useful prognostic markers or suitable targets for therapeutic intervention.
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cell cycle inhibition by foxo forkhead transcription factors involves downregulation of cyclin d
Molecular and Cellular Biology, 2002Co-Authors: Marc Schmidt, Geert J P L Kops, Boudewijn M T Burgering, Sylvia Fernandez De Mattos, Armando Van Der Horst, Rob Klompmaker, Eric Lam, Rene H. MedemaAbstract:The FoxO forkhead transcription factors FoxO4 (AFX), FoxO3a (FKHR.L1), and FOXO1a (FKHR) represent important physiological targets of phosphatidylinositol-3 kinase (PI3K)/protein kinase B (PKB) signaling. Overexpression or conditional activation of FoxO factors is able to antagonize many responses to constitutive PI3K/PKB activation including its effect on cellular proliferation. It was previously shown that the FoxO-induced cell cycle arrest is partially mediated by enhanced transcription and protein expression of the cyclin-dependent kinase inhibitor p27kip1 (R. H. Medema, G. J. Kops, J. L. Bos, and B. M. Burgering, Nature 404:782-787, 2000). Here we have identified a p27kip1-independent mechanism that plays an important role in the antiproliferative effect of FoxO factors. Forced expression or conditional activation of FoxO factors leads to reduced protein expression of the D-type cyclins D1 and D2 and is associated with an impaired capacity of CDK4 to phosphorylate and inactivate the S-phase repressor pRb. Downregulation of D-type cyclins involves a transcriptional repression mechanism and does not require p27kip1 function. Ectopic expression of cyclin D1 can partially overcome FoxO factor-induced cell cycle arrest, demonstrating that downregulation of D-type cyclins represents a physiologically relevant mechanism of FoxO-induced cell cycle inhibition.
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the forkhead transcription factor foxo regulates transcription of p27kip1 and bim in response to il 2
Journal of Immunology, 2002Co-Authors: Marie Ståhl, Paul J Coffer, Pascale F Dijkers, Geert J P L Kops, Susanne M A Lens, Boudewijn M T Burgering, Rene H. MedemaAbstract:The cytokine IL-2 plays a very important role in the proliferation and survival of activated T cells. These effects of IL-2 are dependent on signaling through the phosphatidylinositol 3-kinase (PI3K) pathway. We and others have shown that PI3K, through activation of protein kinase B/Akt, inhibits transcriptional activation by a number of forkhead transcription factors (FOXO1, FoxO3, and FoxO4). In this study we have investigated the role of these forkhead transcription factors in the IL-2-induced T cell proliferation and survival. We show that IL-2 regulates phosphorylation of FoxO3 in a PI3K-dependent fashion. Phosphorylation and inactivation of FoxO3 appears to play an important role in IL-2-mediated T cell survival, because mere activation of FoxO3 is sufficient to trigger apoptosis in T cells. Indeed, active FoxO3 can induce expression of IL-2-regulated genes, such as the cdk inhibitor p27Kip1 and the proapoptotic Bcl-2 family member Bim. Furthermore, we show that IL-2 triggers a rapid, PI3K-dependent, phosphorylation of FOXO1a in primary T cells. Thus, we propose that inactivation of FoxO transcription factors by IL-2 plays a critical role in T cell proliferation and survival.
