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Boudewijn M T Burgering - One of the best experts on this subject based on the ideXlab platform.

  • decisions on life and death foxo Forkhead Transcription Factors are in command when pkb akt is off duty
    Journal of Leukocyte Biology, 2003
    Co-Authors: Boudewijn M T Burgering, Rene H. Medema
    Abstract:

    Forkhead Transcription Factors of the FOXO family are important downstream targets of protein kinase B (PKB)/Akt, a kinase shown to play a decisive role in cell proliferation and cell survival. Direct phosphorylation by PKB/Akt inhibits Transcriptional activation by FOXO Factors, causing their displacement from the nucleus into the cytoplasm. Work from recent years has shown that this family of Transcription Factors regulates the expression of a number of genes that are crucial for the proliferative status of a cell, as well as a number of genes involved in programmed cell death. As such, these Transcription Factors appear to play an essential role in many of the effects of PKB/Akt on cell proliferation and survival. Indeed, in cells of the hematopoietic system, mere activation of a FOXO factor is sufficient to activate a variety of proapoptotic genes and to trigger apoptosis. In contrast, in most other cell types, activation of FOXO blocks cellular proliferation and drives cells into a quiescent state. In such cell types, FOXO Factors also provide the protective mechanisms that are required to adapt to the altered metabolic state of quiescent cells. Thus, as PKB/Akt signaling is switched off, FOXO Factors take over to determine the fate of a cell, long-term survival in a quiescent state, or programmed cell death. This review summarizes our current understanding of the mechanisms by which PKB/Akt and FOXO Factors regulate these decisions.

  • cell cycle inhibition by foxo Forkhead Transcription Factors involves downregulation of cyclin d
    Molecular and Cellular Biology, 2002
    Co-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. Medema
    Abstract:

    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.

  • cell cycle and death control long live Forkheads
    Trends in Biochemical Sciences, 2002
    Co-Authors: Boudewijn M T Burgering, Geert J P L Kops
    Abstract:

    The FOXO family of Forkhead Transcription Factors, FKHR (FOXO1), FKHR-L1 (FOXO3a) and AFX (FOXO4), are regulated by the phosphoinositide-3-kinase-protein-kinase-B (PI3K-PKB/c-Akt) pathway. Direct phosphorylation by PKB results in cytoplasmic retention and inactivation, inhibiting the expression of FOXO-regulated genes, which control the cell cycle, cell death, cell metabolism and oxidative stress. This pathway appears to be well conserved throughout evolution. In the nematode Caenorhabditis elegans, it affects lifespan and controls dauer formation. Recent discoveries about FOXO regulation by PI3K-PKB signalling suggest that the PI3K-PKB-FOXO pathway might participate in similar processes in higher eukaryotes.

  • the Forkhead Transcription factor foxo regulates Transcription of p27kip1 and bim in response to il 2
    Journal of Immunology, 2002
    Co-Authors: Marie Ståhl, Paul J Coffer, Pascale F Dijkers, Geert J P L Kops, Susanne M A Lens, Boudewijn M T Burgering, Rene H. Medema
    Abstract:

    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.

  • control of cell cycle exit and entry by protein kinase b regulated Forkhead Transcription Factors
    Molecular and Cellular Biology, 2002
    Co-Authors: Geert J P L Kops, Paul J Coffer, Rene H. Medema, Pascale F Dijkers, Eric Lam, Janet Glassford, Marieke A G Essers, Boudewijn M T Burgering
    Abstract:

    AFX-like Forkhead Transcription Factors, which are controlled by phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) signaling, are involved in regulating cell cycle progression and cell death. Both cell cycle arrest and induction of apoptosis are mediated in part by Transcriptional regulation of p27kip1. Here we show that the Forkheads AFX (FOXO4) and FKHR-L1 (FOXO3a) also directly control Transcription of the retinoblastoma-like p130 protein and cause upregulation of p130 protein expression. Detailed analysis of p130 regulation demonstrates that following Forkhead-induced cell cycle arrest, cells enter G0 and become quiescent. This is shown by a change in phosphorylation of p130 to G0-specific forms and increased p130/E2F-4 complex formation. Most importantly, long-term Forkhead activation causes a sustained but reversible inhibition of proliferation without a marked increase in apoptosis. As for the activity of the Forkheads, we also show that protein levels of p130 are controlled by endogenous PI3K/PKB signaling upon cell cycle reentry. Surprisingly, not only nontransformed cells, but also cancer cells such as human colon carcinoma cells, are forced into quiescence by Forkhead activation. We therefore propose that Forkhead inactivation by PKB signaling in quiescent cells is a crucial step in cell cycle reentry and contributes to the processes of transformation and regeneration.

Ana C. Carrera - One of the best experts on this subject based on the ideXlab platform.

  • Control of cyclin G2 mRNA expression by Forkhead Transcription Factors: novel mechanism for cell cycle control by phosphoinositide 3-kinase and Forkhead.
    Molecular and cellular biology, 2004
    Co-Authors: Lorena Martínez-gac, Miriam Marqués, Zaira García, Miguel R. Campanero, Ana C. Carrera
    Abstract:

    Cyclin G2 is an unconventional cyclin highly expressed in postmitotic cells. Unlike classical cyclins that promote cell cycle progression, cyclin G2 blocks cell cycle entry. Here we studied the mechanisms that regulate cyclin G2 mRNA expression during the cell cycle. Analysis of synchronized NIH 3T3 cell cultures showed elevated cyclin G2 mRNA expression levels at G0, with a considerable reduction as cells enter cell cycle. Downregulation of cyclin G2 mRNA levels requires activation of phosphoinositide 3-kinase, suggesting that this enzyme controls cyclin G2 mRNA expression. Because the phosphoinositide 3-kinase pathway inhibits the FoxO family of Forkhead Transcription Factors, we examined the involvement of these Factors in the regulation of cyclin G2 expression. We show that active forms of the Forkhead Transcription factor FoxO3a (FKHRL1) increase cyclin G2 mRNA levels. Cyclin G2 has Forkhead consensus motifs in its promoter, which are transactivated by constitutive active FoxO3a forms. Finally, interference with Forkhead-mediated Transcription by overexpression of an inactive form decreases cyclin G2 mRNA expression levels. These results show that FoxO genes regulate cyclin G2 expression, illustrating a new role for phosphoinositide 3-kinase and FoxO Transcription Factors in the control of cell cycle entry.

  • Forkhead Transcription Factors contribute to execution of the mitotic programme in mammals.
    Nature, 2001
    Co-Authors: Beatriz Álvarez, Boudewijn M T Burgering, Carlos Martínez-a, Ana C. Carrera
    Abstract:

    Cell cycle progression is a process that is tightly controlled by internal and external signals. Environmental cues, such as those provided by growth Factors, activate early signals that promote cell cycle entry1,2,3. Cells that have progressed past the restriction point become independent of growth Factors, and cell cycle progression is then controlled endogenously. The phosphatidylinositol 3OH kinase (PI(3)K)/protein kinase B (PKB) pathway must be activated in G1 to inactivate Forkhead Transcription Factors (FKH-TFs)4,5 and allow cell cycle entry2,3. Here we show that subsequent attenuation of the PI(3)K/PKB pathway is required to allow Transcriptional activation of FKH-TF in G2. FKH-TF activity in G2 controls mammalian cell cycle termination, as interference with FKH Transcriptional activation by disrupting PI(3)K/PKB downregulation, or by expressing a Transcriptionally inactive FKH mutant, induces cell accumulation in G2/M, defective cytokinesis, and delayed transition from M to G1 of the cell cycle. We demonstrate that FKH-TFs regulate expression of mitotic genes such as cyclin B and polo-like kinase (Plk). Our results support the important role of Forkhead in the control of mammalian cell cycle completion, and suggest that efficient execution of the mitotic programme depends on downregulation of PI(3)K/PKB and consequent induction of FKH Transcriptional activity.

Rene H. Medema - One of the best experts on this subject based on the ideXlab platform.

  • decisions on life and death foxo Forkhead Transcription Factors are in command when pkb akt is off duty
    Journal of Leukocyte Biology, 2003
    Co-Authors: Boudewijn M T Burgering, Rene H. Medema
    Abstract:

    Forkhead Transcription Factors of the FOXO family are important downstream targets of protein kinase B (PKB)/Akt, a kinase shown to play a decisive role in cell proliferation and cell survival. Direct phosphorylation by PKB/Akt inhibits Transcriptional activation by FOXO Factors, causing their displacement from the nucleus into the cytoplasm. Work from recent years has shown that this family of Transcription Factors regulates the expression of a number of genes that are crucial for the proliferative status of a cell, as well as a number of genes involved in programmed cell death. As such, these Transcription Factors appear to play an essential role in many of the effects of PKB/Akt on cell proliferation and survival. Indeed, in cells of the hematopoietic system, mere activation of a FOXO factor is sufficient to activate a variety of proapoptotic genes and to trigger apoptosis. In contrast, in most other cell types, activation of FOXO blocks cellular proliferation and drives cells into a quiescent state. In such cell types, FOXO Factors also provide the protective mechanisms that are required to adapt to the altered metabolic state of quiescent cells. Thus, as PKB/Akt signaling is switched off, FOXO Factors take over to determine the fate of a cell, long-term survival in a quiescent state, or programmed cell death. This review summarizes our current understanding of the mechanisms by which PKB/Akt and FOXO Factors regulate these decisions.

  • cell cycle inhibition by foxo Forkhead Transcription Factors involves downregulation of cyclin d
    Molecular and Cellular Biology, 2002
    Co-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. Medema
    Abstract:

    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.

  • the Forkhead Transcription factor foxo regulates Transcription of p27kip1 and bim in response to il 2
    Journal of Immunology, 2002
    Co-Authors: Marie Ståhl, Paul J Coffer, Pascale F Dijkers, Geert J P L Kops, Susanne M A Lens, Boudewijn M T Burgering, Rene H. Medema
    Abstract:

    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.

  • control of cell cycle exit and entry by protein kinase b regulated Forkhead Transcription Factors
    Molecular and Cellular Biology, 2002
    Co-Authors: Geert J P L Kops, Paul J Coffer, Rene H. Medema, Pascale F Dijkers, Eric Lam, Janet Glassford, Marieke A G Essers, Boudewijn M T Burgering
    Abstract:

    AFX-like Forkhead Transcription Factors, which are controlled by phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) signaling, are involved in regulating cell cycle progression and cell death. Both cell cycle arrest and induction of apoptosis are mediated in part by Transcriptional regulation of p27kip1. Here we show that the Forkheads AFX (FOXO4) and FKHR-L1 (FOXO3a) also directly control Transcription of the retinoblastoma-like p130 protein and cause upregulation of p130 protein expression. Detailed analysis of p130 regulation demonstrates that following Forkhead-induced cell cycle arrest, cells enter G0 and become quiescent. This is shown by a change in phosphorylation of p130 to G0-specific forms and increased p130/E2F-4 complex formation. Most importantly, long-term Forkhead activation causes a sustained but reversible inhibition of proliferation without a marked increase in apoptosis. As for the activity of the Forkheads, we also show that protein levels of p130 are controlled by endogenous PI3K/PKB signaling upon cell cycle reentry. Surprisingly, not only nontransformed cells, but also cancer cells such as human colon carcinoma cells, are forced into quiescence by Forkhead activation. We therefore propose that Forkhead inactivation by PKB signaling in quiescent cells is a crucial step in cell cycle reentry and contributes to the processes of transformation and regeneration.

  • afx like Forkhead Transcription Factors mediate cell cycle regulation by ras and pkb through p27kip1
    Nature, 2000
    Co-Authors: Rene H. Medema, Geert J P L Kops, Boudewijn M T Burgering
    Abstract:

    The Forkhead Transcription Factors AFX, FKHR and FKHR-L1 are orthologues of DAF-16, a Forkhead factor that regulates longevity in Caenorhabditis elegans1,2,3. Here we show that overexpression of these Forkhead Transcription Factors causes growth suppression in a variety of cell lines, including a Ras-transformed cell line and a cell line lacking the tumour suppressor PTEN. Expression of AFX blocks cell-cycle progression at phase G1, independent of functional retinoblastoma protein (pRb) but dependent on the cell-cycle inhibitor p27kip1. Indeed, AFX Transcriptionally activates p27kip1, resulting in increased protein levels. We conclude that AFX-like proteins are involved in cell-cycle regulation and that inactivation of these proteins is an important step in oncogenic transformation.

Geert J P L Kops - One of the best experts on this subject based on the ideXlab platform.

  • cell cycle inhibition by foxo Forkhead Transcription Factors involves downregulation of cyclin d
    Molecular and Cellular Biology, 2002
    Co-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. Medema
    Abstract:

    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.

  • cell cycle and death control long live Forkheads
    Trends in Biochemical Sciences, 2002
    Co-Authors: Boudewijn M T Burgering, Geert J P L Kops
    Abstract:

    The FOXO family of Forkhead Transcription Factors, FKHR (FOXO1), FKHR-L1 (FOXO3a) and AFX (FOXO4), are regulated by the phosphoinositide-3-kinase-protein-kinase-B (PI3K-PKB/c-Akt) pathway. Direct phosphorylation by PKB results in cytoplasmic retention and inactivation, inhibiting the expression of FOXO-regulated genes, which control the cell cycle, cell death, cell metabolism and oxidative stress. This pathway appears to be well conserved throughout evolution. In the nematode Caenorhabditis elegans, it affects lifespan and controls dauer formation. Recent discoveries about FOXO regulation by PI3K-PKB signalling suggest that the PI3K-PKB-FOXO pathway might participate in similar processes in higher eukaryotes.

  • the Forkhead Transcription factor foxo regulates Transcription of p27kip1 and bim in response to il 2
    Journal of Immunology, 2002
    Co-Authors: Marie Ståhl, Paul J Coffer, Pascale F Dijkers, Geert J P L Kops, Susanne M A Lens, Boudewijn M T Burgering, Rene H. Medema
    Abstract:

    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.

  • control of cell cycle exit and entry by protein kinase b regulated Forkhead Transcription Factors
    Molecular and Cellular Biology, 2002
    Co-Authors: Geert J P L Kops, Paul J Coffer, Rene H. Medema, Pascale F Dijkers, Eric Lam, Janet Glassford, Marieke A G Essers, Boudewijn M T Burgering
    Abstract:

    AFX-like Forkhead Transcription Factors, which are controlled by phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) signaling, are involved in regulating cell cycle progression and cell death. Both cell cycle arrest and induction of apoptosis are mediated in part by Transcriptional regulation of p27kip1. Here we show that the Forkheads AFX (FOXO4) and FKHR-L1 (FOXO3a) also directly control Transcription of the retinoblastoma-like p130 protein and cause upregulation of p130 protein expression. Detailed analysis of p130 regulation demonstrates that following Forkhead-induced cell cycle arrest, cells enter G0 and become quiescent. This is shown by a change in phosphorylation of p130 to G0-specific forms and increased p130/E2F-4 complex formation. Most importantly, long-term Forkhead activation causes a sustained but reversible inhibition of proliferation without a marked increase in apoptosis. As for the activity of the Forkheads, we also show that protein levels of p130 are controlled by endogenous PI3K/PKB signaling upon cell cycle reentry. Surprisingly, not only nontransformed cells, but also cancer cells such as human colon carcinoma cells, are forced into quiescence by Forkhead activation. We therefore propose that Forkhead inactivation by PKB signaling in quiescent cells is a crucial step in cell cycle reentry and contributes to the processes of transformation and regeneration.

  • afx like Forkhead Transcription Factors mediate cell cycle regulation by ras and pkb through p27kip1
    Nature, 2000
    Co-Authors: Rene H. Medema, Geert J P L Kops, Boudewijn M T Burgering
    Abstract:

    The Forkhead Transcription Factors AFX, FKHR and FKHR-L1 are orthologues of DAF-16, a Forkhead factor that regulates longevity in Caenorhabditis elegans1,2,3. Here we show that overexpression of these Forkhead Transcription Factors causes growth suppression in a variety of cell lines, including a Ras-transformed cell line and a cell line lacking the tumour suppressor PTEN. Expression of AFX blocks cell-cycle progression at phase G1, independent of functional retinoblastoma protein (pRb) but dependent on the cell-cycle inhibitor p27kip1. Indeed, AFX Transcriptionally activates p27kip1, resulting in increased protein levels. We conclude that AFX-like proteins are involved in cell-cycle regulation and that inactivation of these proteins is an important step in oncogenic transformation.

Domenico Accili - One of the best experts on this subject based on the ideXlab platform.

  • Forkhead Transcription Factors foxos promote apoptosis of insulin resistant macrophages during cholesterol induced endoplasmic reticulum stress
    Diabetes, 2008
    Co-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 Tall
    Abstract:

    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.

  • nuclear trapping of the Forkhead Transcription factor foxo1 via sirt dependent deacetylation promotes expression of glucogenetic genes
    Journal of Biological Chemistry, 2005
    Co-Authors: David Frescas, Luca Valenti, Domenico Accili
    Abstract:

    Abstract Activation of NAD-dependent deacetylases, or Sirtuins, prolongs life span and mimics the effects of caloric restriction in yeast. The FoxO subfamily of Forkhead Transcription Factors has been shown to mediate some of the effects of Sirtuins. Here we have shown that Sirtuin activation or hydrogen peroxide treatment overrides the phosphorylation-dependent nuclear exclusion of FoxO1 caused by growth Factors and causes nuclear translocation of FoxO1 in hepatocytes. Kinetic measurements of nuclear fluorescence recovery after photobleaching show that FoxO1 is readily diffusible within the nucleus under normal conditions but becomes restricted within a nuclear subdomain following treatment with the prototypical Sirtuin agonist resveratrol or oxidative stress. Expression of FoxO1 target genes is accordingly increased, leading to activation of gluconeogenesis and increased glucose release from hepatocytes. Selective modulation of the FoxO/Sirtuin interaction represents a promising therapeutic modality for metabolic disorders.

  • foxos at the crossroads of cellular metabolism differentiation and transformation
    Cell, 2004
    Co-Authors: Domenico Accili, Karen C Arden
    Abstract:

    Forkhead Transcription Factors of the FoxO subfamily are emerging as a shared component among pathways regulating diverse cellular functions, such as differentiation, metabolism, proliferation, and survival. Their Transcriptional output is controlled via a two-tiered mechanism of phosphorylation and acetylation. Modest alterations of this balance can result in profound effects. The gamut of phenotypes runs from protection against diabetes and predisposition to neoplasia, conferred by FoxO loss of function, to increased cellular survival and a marked catabolic response associated with gain of function.

  • regulation of insulin like growth factor dependent myoblast differentiation by foxo Forkhead Transcription Factors
    Journal of Cell Biology, 2003
    Co-Authors: Marta Letizia Hribal, Jun Nakae, Tadahiro Kitamura, John R Shutter, Domenico Accili
    Abstract:

    Insulin-like growth Factors promote myoblast differentiation through phosphoinositol 3-kinase and Akt signaling. Akt substrates required for myogenic differentiation are unknown. Forkhead Transcription Factors of the Forkhead box gene, group O (Foxo) subfamily are phosphorylated in an insulin-responsive manner by phosphatidylinositol 3-kinase–dependent kinases. Phosphorylation leads to nuclear exclusion and inactivation. We show that a constitutively active Foxo1 mutant inhibits differentiation of C2C12 cells and prevents myotube differentiation induced by constitutively active Akt. In contrast, a Transcriptionally inactive mutant Foxo1 partially rescues inhibition of C2C12 differentiation mediated by wortmannin, but not by rapamycin, and is able to induce aggregation-independent myogenic conversion of teratocarcinoma cells. Inhibition of Foxo expression by siRNA resulted in more efficient differentiation, associated with increased myosin expression. These observations indicate that Foxo proteins are key effectors of Akt-dependent myogenesis.