The Experts below are selected from a list of 11109 Experts worldwide ranked by ideXlab platform
Domenico Accili - One of the best experts on this subject based on the ideXlab platform.
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the Forkhead Transcription Factor foxo1 regulates proliferation and transdifferentiation of hepatic stellate cells
Gastroenterology, 2007Co-Authors: Masayuki Adachi, Domenico Accili, Tadahiro Kitamura, Yosuke Osawa, Hiroshi Uchinami, David A BrennerAbstract:Background & Aims: The Forkhead box gene, group O (FoxO) family of Forkhead Transcription Factors is phopsphorylated and inactivated by the phosphatidylinositol 3-kinase (PI3K)/AKT pathway and regulates a variety of cellular functions. Hepatic stellate cells (HSCs) play a crucial role in liver fibrosis. A fibrotic stimulus causes HSCs to transdifferentiate from a quiescent phenotype to a collagen-producing myofibroblast-like phenotype and to proliferate. Methods: Mutation/deletion mutants of FoxO1 were introduced into primary rat, mouse, and immortalized human HSCs and assessed for activation, proliferation, and signal transduction. The role of FoxO1 in experimental liver fibrosis was assessed in FoxO1+/− and FoxO1+/+ mice. Results: Platelet-derived growth Factor (PDGF) or insulin phosphorylates FoxO1 and induces FoxO1 translocation from the nuclei to the cytosol via the PI3K/AKT pathway in HSCs. Constitutively active FoxO1 inhibits proliferation via cell cycle arrest at the G1 phase, whereas dominant-negative FoxO1 enhances proliferation of HSCs even in the presence of the PI3K inhibitor LY294002. In addition, the phosphorylation of FoxO1 is increased during transdifferentiation of HSCs. The transdifferentiation is also inhibited by constitutively active FoxO1 and is accelerated by dominant-negative FoxO1. FoxO1 directly induces the expression of p27kip1 and manganese superoxide dismutase (MnSOD). After bile duct ligation for 3 weeks, FoxO1+/− mice are more susceptible to liver fibrosis, consistent with our in vitro results. Conclusions: FoxO1 plays a crucial role in the transdifferentiation and proliferation of HSCs in liver fibrosis. Hyperinsulinemia inactivates FoxO1 in HSCs, resulting in HSC activation and may result in the fibrosis in nonalcoholic fatty liver disease.
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The Forkhead Transcription Factor Foxo1 Regulates Adipocyte Differentiation
Developmental cell, 2003Co-Authors: Jun Nakae, Tadahiro Kitamura, Yukari Ido Kitamura, William H. Biggs, Karen C. Arden, Domenico AcciliAbstract:An outstanding question in adipocyte biology is how hormonal cues are relayed to the nucleus to activate the Transcriptional program that promotes adipogenesis. The Forkhead Transcription Factor Foxo1 is regulated by insulin via Akt-dependent phosphorylation and nuclear exclusion. We show that Foxo1 is induced in the early stages of adipocyte differentiation but that its activation is delayed until the end of the clonal expansion phase. Constitutively active Foxo1 prevents the differentiation of preadipocytes, while dominant-negative Foxo1 restores adipocyte differentiation of fibroblasts from insulin receptor-deficient mice. Further, Foxo1 haploinsufficiency protects from diet-induced diabetes in mice. We propose that Foxo1 plays an important role in the integration of hormone-activated signaling pathways with the complex Transcriptional cascade that promotes adipocyte differentiation.
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the Forkhead Transcription Factor foxo1 links insulin signaling to pdx1 regulation of pancreatic β cell growth
Journal of Clinical Investigation, 2002Co-Authors: Tadahiro Kitamura, Jun Nakae, William H. Biggs, Karen C. Arden, Christopher V E Wright, Yukari Kitamura, Yoshiaki Kido, Morris F White, Domenico AcciliAbstract:Diabetes is caused by an absolute (type 1) or relative (type 2) deficiency of insulin-producing β cells. The mechanisms governing replication of terminally differentiated β cells and neogenesis from progenitor cells are unclear. Mice lacking insulin receptor substrate-2 (Irs2) develop β cell failure, suggesting that insulin signaling is required to maintain an adequate β cell mass. We report that haploinsufficiency for the Forkhead Transcription Factor Foxo1 reverses β cell failure in Irs2–/– mice through partial restoration of β cell proliferation and increased expression of the pancreatic Transcription Factor pancreas/duodenum homeobox gene-1 (Pdx1). Foxo1 and Pdx1 exhibit mutually exclusive patterns of nuclear localization in β cells, and constitutive nuclear expression of a mutant Foxo1 is associated with lack of Pdx1 expression. We show that Foxo1 acts as a repressor of Foxa2-dependent (Hnf-3β–dependent) expression from the Pdx1 promoter. We propose that insulin/IGFs regulate β cell proliferation by relieving Foxo1 inhibition of Pdx1 expression in a subset of cells embedded within pancreatic ducts.
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the Forkhead Transcription Factor foxo1 links insulin signaling to pdx1 regulation of pancreatic β cell growth
Journal of Clinical Investigation, 2002Co-Authors: Tadahiro Kitamura, Jun Nakae, William H. Biggs, Karen C. Arden, Christopher V E Wright, Yukari Kitamura, Yoshiaki Kido, Morris F White, Domenico AcciliAbstract:Diabetes is caused by an absolute (type 1) or relative (type 2) deficiency of insulin-producing beta cells. The mechanisms governing replication of terminally differentiated beta cells and neogenesis from progenitor cells are unclear. Mice lacking insulin receptor substrate-2 (Irs2) develop beta cell failure, suggesting that insulin signaling is required to maintain an adequate beta cell mass. We report that haploinsufficiency for the Forkhead Transcription Factor Foxo1 reverses beta cell failure in Irs2(-/-) mice through partial restoration of beta cell proliferation and increased expression of the pancreatic Transcription Factor pancreas/duodenum homeobox gene-1 (Pdx1). Foxo1 and Pdx1 exhibit mutually exclusive patterns of nuclear localization in beta cells, and constitutive nuclear expression of a mutant Foxo1 is associated with lack of Pdx1 expression. We show that Foxo1 acts as a repressor of Foxa2-dependent (Hnf-3beta-dependent) expression from the Pdx1 promoter. We propose that insulin/IGFs regulate beta cell proliferation by relieving Foxo1 inhibition of Pdx1 expression in a subset of cells embedded within pancreatic ducts.
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regulation of insulin action and pancreatic beta cell function by mutated alleles of the gene encoding Forkhead Transcription Factor foxo1
Nature Genetics, 2002Co-Authors: Jun Nakae, Tadahiro Kitamura, William H. Biggs, Karen C. Arden, Webster K Cavenee, Christopher V E Wright, Domenico AcciliAbstract:Regulation of insulin action and pancreatic β-cell function by mutated alleles of the gene encoding Forkhead Transcription Factor Foxo1
Jun Nakae - One of the best experts on this subject based on the ideXlab platform.
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Forkhead Transcription Factor foxo1 in adipose tissue regulates energy storage and expenditure
Diabetes, 2008Co-Authors: Jun Nakae, Yongheng Cao, Miyo Oki, Yasuko Orba, Hirofumi Sawa, Hiroshi Kiyonari, Kristy Iskandar, Koji Suga, Marc Lombes, Yoshitake HayashiAbstract:Objective Adipose tissue serves as an integrator of various physiological pathways, energy balance, and glucose homeostasis. Forkhead box-containing protein O subfamily (FoxO) 1 mediates insulin action at the Transcriptional level. However, physiological roles of FoxO1 in adipose tissue remain unclear. Research design and methods In the present study, we generated adipose tissue-specific FoxO1 transgenic mice (adipocyte protein 2 [aP(2)]-FLAG-Delta 256) using an aP(2) promoter/enhancer and a mutant FoxO1 (FLAG Delta 256) in which the carboxyl terminal transactivation domain was deleted. Using these mice, we analyzed the effects of the overexpression of FLAG Delta 256 on glucose metabolism and energy homeostasis. Results The aP(2)-FLAG-Delta 256 mice showed improved glucose tolerance and insulin sensitivity accompanied with smaller-sized adipocytes and increased adiponectin (adipoq) and Glut 4 (Slc2a4) and decreased tumor necrosis Factor alpha (Tnf) and chemokine (C-C motif) receptor 2 (Ccr2) gene expression levels in white adipose tissue (WAT) under a high-fat diet. Furthermore, the aP(2)-FLAG-Delta 256 mice had increased oxygen consumption accompanied with increased expression of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1 alpha protein and uncoupling protein (UCP)-1 (Ucp1), UCP-2 (Ucp2), and beta 3-AR (Adrb3) in brown adipose tissue (BAT). Overexpression of FLAG Delta 256 in T37i cells, which are derived from the hibernoma of SV40 large T antigen transgenic mice, increased expression of PGC-1 alpha protein and Ucp1. Furthermore, knockdown of endogenous FoxO1 in T37i cells increased Pgc1 alpha (Ppargc1a), Pgc1 beta (Ppargc1b), Ucp1, and Adrb3 gene expression. Conclusions These data suggest that FoxO1 modulates energy homeostasis in WAT and BAT through regulation of adipocyte size and adipose tissue-specific gene expression in response to excessive calorie intake.
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the lxxll motif of murine Forkhead Transcription Factor foxo1 mediates sirt1 dependent Transcriptional activity
Journal of Clinical Investigation, 2006Co-Authors: Jun Nakae, Hiroaki Daitoku, Akiyoshi Fukamizu, Wataru Ogawa, Yongheng Cao, Yoshihiko Yano, Yoshitake HayashiAbstract:The Forkhead Transcription Factor FoxO1 has been identified as a negative regulator of insulin/IGF-1 signaling. Its function is inhibited by phosphorylation and nuclear exclusion through a PI3K-dependent pathway. However, the structure/function relationship of FoxO1 has not been elucidated completely. In this study, we carried out mutation analysis of the FoxO1 coactivator–interacting LXXLL motif (amino acids 459–463). Expression of a 3A/LXXAA mutant, in which 3 Akt phosphorylation sites (T24, S253, and S316) and 2 leucine residues in the LXXLL motif (L462 and L463) were replaced by alanine, decreased both Igfbp-1 and G6Pase promoter activity and endogenous Igfbp-1 and G6Pase gene expression in simian virus 40–transformed (SV40-transformed) hepatocytes. Importantly, mutagenesis of the LXXLL motif eliminated FoxO1 interaction with the nicotinamide adenine dinucleotide–dependent (NAD-dependent) deacetylase sirtuin 1 (Sirt1), sustained the acetylated state of FoxO1, and made FoxO1 nicotinamide and resveratrol insensitive, supporting a role for this motif in Sirt1 binding. Furthermore, intravenous administration of adenovirus encoding 3A/LXXAA FoxO1 into Leprdb/db mice decreased fasting blood glucose levels and improved glucose tolerance and was accompanied by reduced G6Pase and Igfbp-1 gene expression and increased hepatic glycogen content. In conclusion, the LXXLL motif of FoxO1 may have an important role for its Transcriptional activity and Sirt1 binding and should be a target site for regulation of gene expression of FoxO1 target genes and glucose metabolism in vivo.
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The Forkhead Transcription Factor Foxo1 Regulates Adipocyte Differentiation
Developmental cell, 2003Co-Authors: Jun Nakae, Tadahiro Kitamura, Yukari Ido Kitamura, William H. Biggs, Karen C. Arden, Domenico AcciliAbstract:An outstanding question in adipocyte biology is how hormonal cues are relayed to the nucleus to activate the Transcriptional program that promotes adipogenesis. The Forkhead Transcription Factor Foxo1 is regulated by insulin via Akt-dependent phosphorylation and nuclear exclusion. We show that Foxo1 is induced in the early stages of adipocyte differentiation but that its activation is delayed until the end of the clonal expansion phase. Constitutively active Foxo1 prevents the differentiation of preadipocytes, while dominant-negative Foxo1 restores adipocyte differentiation of fibroblasts from insulin receptor-deficient mice. Further, Foxo1 haploinsufficiency protects from diet-induced diabetes in mice. We propose that Foxo1 plays an important role in the integration of hormone-activated signaling pathways with the complex Transcriptional cascade that promotes adipocyte differentiation.
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the Forkhead Transcription Factor foxo1 links insulin signaling to pdx1 regulation of pancreatic β cell growth
Journal of Clinical Investigation, 2002Co-Authors: Tadahiro Kitamura, Jun Nakae, William H. Biggs, Karen C. Arden, Christopher V E Wright, Yukari Kitamura, Yoshiaki Kido, Morris F White, Domenico AcciliAbstract:Diabetes is caused by an absolute (type 1) or relative (type 2) deficiency of insulin-producing β cells. The mechanisms governing replication of terminally differentiated β cells and neogenesis from progenitor cells are unclear. Mice lacking insulin receptor substrate-2 (Irs2) develop β cell failure, suggesting that insulin signaling is required to maintain an adequate β cell mass. We report that haploinsufficiency for the Forkhead Transcription Factor Foxo1 reverses β cell failure in Irs2–/– mice through partial restoration of β cell proliferation and increased expression of the pancreatic Transcription Factor pancreas/duodenum homeobox gene-1 (Pdx1). Foxo1 and Pdx1 exhibit mutually exclusive patterns of nuclear localization in β cells, and constitutive nuclear expression of a mutant Foxo1 is associated with lack of Pdx1 expression. We show that Foxo1 acts as a repressor of Foxa2-dependent (Hnf-3β–dependent) expression from the Pdx1 promoter. We propose that insulin/IGFs regulate β cell proliferation by relieving Foxo1 inhibition of Pdx1 expression in a subset of cells embedded within pancreatic ducts.
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the Forkhead Transcription Factor foxo1 links insulin signaling to pdx1 regulation of pancreatic β cell growth
Journal of Clinical Investigation, 2002Co-Authors: Tadahiro Kitamura, Jun Nakae, William H. Biggs, Karen C. Arden, Christopher V E Wright, Yukari Kitamura, Yoshiaki Kido, Morris F White, Domenico AcciliAbstract:Diabetes is caused by an absolute (type 1) or relative (type 2) deficiency of insulin-producing beta cells. The mechanisms governing replication of terminally differentiated beta cells and neogenesis from progenitor cells are unclear. Mice lacking insulin receptor substrate-2 (Irs2) develop beta cell failure, suggesting that insulin signaling is required to maintain an adequate beta cell mass. We report that haploinsufficiency for the Forkhead Transcription Factor Foxo1 reverses beta cell failure in Irs2(-/-) mice through partial restoration of beta cell proliferation and increased expression of the pancreatic Transcription Factor pancreas/duodenum homeobox gene-1 (Pdx1). Foxo1 and Pdx1 exhibit mutually exclusive patterns of nuclear localization in beta cells, and constitutive nuclear expression of a mutant Foxo1 is associated with lack of Pdx1 expression. We show that Foxo1 acts as a repressor of Foxa2-dependent (Hnf-3beta-dependent) expression from the Pdx1 promoter. We propose that insulin/IGFs regulate beta cell proliferation by relieving Foxo1 inhibition of Pdx1 expression in a subset of cells embedded within pancreatic ducts.
Boudewijn M. T. Burgering - One of the best experts on this subject based on the ideXlab platform.
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Regulation of sterol carrier protein gene expression by the Forkhead Transcription Factor FOXO3a
2013Co-Authors: Tobias B. Dansen, Simone Denis, Geert J. P. L. Kops, Nannette Jelluma, Johannes L. Bos, Boudewijn M. T. Burgering, Ronald J. A. W, Karel W A WirtzAbstract:Abstract The SCP gene encodes two proteins, sterol carrier protein X (SCPx) and SCP2, that are independently regulated by separate promoters. SCPx has been shown to be the thiolase involved in the breakdown of branched-chain fatty acids and in the biosynthesis of bile acids. The in vivo function of SCP2 however remains to be established. The Transcriptional regulation of SCPx and SCP2 is unclear, but their promoter regions contain several putative regulatory domains. We show here that both SCPx and SCP2 are upregulated by the daf-16-like Forkhead Transcription Factor FOXO3a (also known as FKHRL1) on the level of promoter activity. It was recently described that Forkheads regulate protection against (oxidative) stress in both Caenorhabditis elegans and mammalian cells. We looked into a role for SCP2 in the cellular defense against oxidative damage and found that a fluorescent fatty acid analog bound to SCP2 is protected against H2O2/Cu2�-induced oxidative damage. We propose a model for the way in which SCP2 could protect fatty acids from peroxidation.—Dansen, T. B., G. J. P. L
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Regulation of sterol carrier protein gene expression by the Forkhead Transcription Factor FOXO3a
Journal of Lipid Research, 2003Co-Authors: Tobias B. Dansen, Simone Denis, Geert J. P. L. Kops, Nannette Jelluma, Johannes L. Bos, Boudewijn M. T. Burgering, Karel W A WirtzAbstract:The SCP gene encodes two proteins, sterol carrier protein X (SCPx) and SCP2, that are independently regulated by separate promoters. SCPx has been shown to be the thiolase involved in the breakdown of branched-chain fattyacids and in the biosynthesis of bile acids. The in vivo function of SCP2 however remains to be established. The Transcriptional regulation of SCPx and SCP2 is unclear, but their promoter regions contain several putative regulatory domains. We show here that both SCPx and SCP2 are up-regulated by the daf-16-like Forkhead Transcription Factor FOXO3a (also known as FKHRL1) on the level of promoter activity. It was recently described that Forkheads regulate protection against (oxidative) stress in both Caenorhabditis elegans and mammalian cells. We looked into a role for SCP2 in the cellular defense against oxidative damage and found that a fluorescent fatty acid analog bound to SCP2 is protected against H 2 O 2 /Cu 2 + -induced oxidative damage. We propose a model for the way in which SCP2 could protect fatty acids from peroxidation.
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Forkhead Transcription Factor FOXO3a protects quiescent cells from oxidative stress
Nature, 2002Co-Authors: Geert J. P. L. Kops, Paul J Coffer, Rene H. Medema, Karel W A Wirtz, Tobias B. Dansen, Johannes L. Bos, Paulien E. Polderman, Ingrid Saarloos, Ting-t. Huang, Boudewijn M. T. BurgeringAbstract:Reactive oxygen species are required for cell proliferation but can also induce apoptosis1. In proliferating cells this paradox is solved by the activation of protein kinase B (PKB; also known as c-Akt), which protects cells from apoptosis2. By contrast, it is unknown how quiescent cells that lack PKB activity are protected against cell death induced by reactive oxygen species. Here we show that the PKB-regulated Forkhead Transcription Factor FOXO3a (also known as FKHR-L1) protects quiescent cells from oxidative stress by directly increasing their quantities of manganese superoxide dismutase (MnSOD) messenger RNA and protein. This increase in protection from reactive oxygen species antagonizes apoptosis caused by glucose deprivation. In quiescent cells that lack the protective mechanism of PKB-mediated signalling, an alternative mechanism is induced as a consequence of PKB inactivity. This mechanism entails the activation of Forkhead Transcription Factors, the Transcriptional activation of MnSOD and the subsequent reduction of reactive oxygen species. Increased resistance to oxidative stress is associated with longevity. The model of Forkhead involvement in regulating longevity stems from genetic analysis in Caenorhabditis elegans3,4,5,6, and we conclude that this model also extends to mammalian systems.
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Regulation of the Forkhead Transcription Factor AFX by Ral-Dependent Phosphorylation of Threonines 447 and 451
Molecular and cellular biology, 2001Co-Authors: Nancy D. De Ruiter, Boudewijn M. T. Burgering, Johannes L. BosAbstract:AFX is a Forkhead Transcription Factor that induces a G1 cell cycle arrest via upregulation of the cell cycle inhibitor p27Kip1. Previously we have shown that protein kinase B (PKB) phosphorylates AFX causing inhibition of AFX by nuclear exclusion. In addition, Ras, through the activation of the RalGEF-Ral pathway, induces phosphorylation of AFX. Here we show that the Ras-Ral pathway provokes phosphorylation of threonines 447 and 451 in the C terminus of AFX. A mutant protein in which both threonines are substituted for alanines (T447A/T451A) still responds to PKB-regulated nuclear-cytoplasmic shuttling, but Transcriptional activity and consequent G1 cell cycle arrest are greatly impaired. Furthermore, inhibition of the Ral signaling pathway abolishes both AFX-mediated Transcription and regulation of p27Kip1, while activation of Ral augments AFX activity. From these results we conclude that Ral-mediated phosphorylation of threonines 447 and 451 is required for proper activity of AFX-WT. Interestingly, the T447A/T451A mutation did not affect the induction of Transcription and G1 cell cycle arrest by the PKB-insensitive AFX-A3 mutant, suggesting that Ral-mediated phosphorylation plays a role in the regulation of AFX by PKB.
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Forkhead Transcription Factor fkhr l1 modulates cytokine dependent Transcriptional regulation of p27kip1
Molecular and Cellular Biology, 2000Co-Authors: Pascale F Dijkers, Janwillem J Lammers, Rene H. Medema, Boudewijn M. T. Burgering, Eric Lam, Cornelieke Pals, L Banerji, N S B Thomas, J A M Raaijmakers, Leo KoendermanAbstract:Interleukin-3 (IL-3), IL-5, and granulocyte-macrophage colony-stimulating Factor regulate the survival, proliferation, and differentiation of hematopoietic lineages. Phosphatidylinositol 3-kinase (PI3K) has been implicated in the regulation of these processes. Here we investigate the molecular mechanism by which PI3K regulates cytokine-mediated proliferation and survival in the murine pre-B-cell line Ba/F3. IL-3 was found to repress the expression of the cyclin-dependent kinase inhibitor p27KIP1 through activation of PI3K, and this occurs at the level of Transcription. This Transcriptional regulation occurs through modulation of the Forkhead Transcription Factor FKHR-L1, and IL-3 inhibited FKHR-L1 activity in a PI3K-dependent manner. We have generated Ba/F3 cell lines expressing a tamoxifen-inducible active FKHR-L1 mutant [FKHR-L1(A3):ER*]. Tamoxifen-mediated activation of FKHR-L1(A3):ER* resulted in a striking increase in p27KIP1 promoter activity and mRNA and protein levels as well as induction of the apoptotic program. The level of p27KIP1 appears to be critical in the regulation of cell survival since mere ectopic expression of p27KIP1 was sufficient to induce Ba/F3 apoptosis. Moreover, cell survival was increased in cytokine-starved bone marrow-derived stem cells from p27KIP1 null-mutant mice compared to that in cells from wild-type mice. Taken together, these observations indicate that inhibition of p27KIP1 Transcription through PI3K-induced FKHR-L1 phosphorylation provides a novel mechanism of regulating cytokine-mediated survival and proliferation.
Andrew D. Sharrocks - One of the best experts on this subject based on the ideXlab platform.
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the Forkhead Transcription Factor foxm1 controls cell cycle dependent gene expression through an atypical chromatin binding mechanism
Molecular and Cellular Biology, 2013Co-Authors: Xi Chen, Andrew D. Sharrocks, Gerd A Muller, Marianne Quaas, Martin Fischer, Namshik Han, Benjamin Stutchbury, Kurt EngelandAbstract:There are nearly 50 Forkhead (FOX) Transcription Factors encoded in the human genome and, due to sharing a common DNA binding domain, they are all thought to bind to similar DNA sequences. It is therefore unclear how these Transcription Factors are targeted to specific chromatin regions to elicit specific biological effects. Here, we used chromatin immunoprecipitation followed by sequencing (ChIP-seq) to investigate the genome-wide chromatin binding mechanisms used by the Forkhead Transcription Factor FOXM1. In keeping with its previous association with cell cycle control, we demonstrate that FOXM1 binds and regulates a group of genes which are mainly involved in controlling late cell cycle events in the G(2) and M phases. However, rather than being recruited through canonical RYAAAYA Forkhead binding motifs, FOXM1 binding is directed via CHR (cell cycle genes homology region) elements. FOXM1 binds these elements through protein-protein interactions with the MMB Transcriptional activator complex. Thus, we have uncovered a novel and unexpected mode of chromatin binding of a FOX Transcription Factor that allows it to specifically control cell cycle-dependent gene expression.
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The Forkhead Transcription Factor FOXK2 Promotes AP-1-Mediated Transcriptional Regulation
Molecular and cellular biology, 2011Co-Authors: Ian J. Donaldson, Jingru Liu, Andrew Hayes, Leo A. H. Zeef, Andrew D. SharrocksAbstract:The Transcriptional control circuitry in eukaryotic cells is complex and is orchestrated by combinatorially acting Transcription Factors. Forkhead Transcription Factors often function in concert with heterotypic Transcription Factors to specify distinct Transcriptional programs. Here, we demonstrate that FOXK2 participates in combinatorial Transcriptional control with the AP-1 Transcription Factor. FOXK2 binding regions are widespread throughout the genome and are often coassociated with AP-1 binding motifs. FOXK2 acts to promote AP-1-dependent gene expression changes in response to activation of the AP-1 pathway. In this context, FOXK2 is required for the efficient recruitment of AP-1 to chromatin. Thus, we have uncovered an important new molecular mechanism that controls AP-1-dependent gene expression.
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cell cycle dependent regulation of the Forkhead Transcription Factor foxk2 by cdk cyclin complexes
Journal of Biological Chemistry, 2010Co-Authors: Anett Marais, Emma S. Child, Eberhard Krause, David J. Mann, Andrew D. SharrocksAbstract:Several mammalian Forkhead Transcription Factors have been shown to impact on cell cycle regulation and are themselves linked to cell cycle control systems. Here we have investigated the little studied mammalian Forkhead Transcription Factor FOXK2 and demonstrate that it is subject to control by cell cycle-regulated protein kinases. FOXK2 exhibits a periodic rise in its phosphorylation levels during the cell cycle, with hyperphosphorylation occurring in mitotic cells. Hyperphosphorylation occurs in a cyclin-dependent kinase (CDK)·cyclin-dependent manner with CDK1·cyclin B as the major kinase complex, although CDK2 and cyclin A also appear to be important. We have mapped two CDK phosphorylation sites, serines 368 and 423, which play a role in defining FOXK2 function through regulating its stability and its activity as a Transcriptional repressor protein. These two CDK sites appear vital for FOXK2 function because expression of a mutant lacking these sites cannot be tolerated and causes apoptosis.
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Cell Cycle-dependent Regulation of the Forkhead Transcription Factor FOXK2 by CDK·Cyclin Complexes
The Journal of biological chemistry, 2010Co-Authors: Anett Marais, Emma S. Child, Eberhard Krause, David J. Mann, Andrew D. SharrocksAbstract:Several mammalian Forkhead Transcription Factors have been shown to impact on cell cycle regulation and are themselves linked to cell cycle control systems. Here we have investigated the little studied mammalian Forkhead Transcription Factor FOXK2 and demonstrate that it is subject to control by cell cycle-regulated protein kinases. FOXK2 exhibits a periodic rise in its phosphorylation levels during the cell cycle, with hyperphosphorylation occurring in mitotic cells. Hyperphosphorylation occurs in a cyclin-dependent kinase (CDK)·cyclin-dependent manner with CDK1·cyclin B as the major kinase complex, although CDK2 and cyclin A also appear to be important. We have mapped two CDK phosphorylation sites, serines 368 and 423, which play a role in defining FOXK2 function through regulating its stability and its activity as a Transcriptional repressor protein. These two CDK sites appear vital for FOXK2 function because expression of a mutant lacking these sites cannot be tolerated and causes apoptosis.
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Functional interactions between the Forkhead Transcription Factor FOXK1 and the MADS-box protein SRF
Nucleic acids research, 2007Co-Authors: Cecilie T. Freddie, Anett Marais, Andrew D. SharrocksAbstract:The combinatorial control of gene expression by the association of members of different families of Transcription Factors is a common theme in eukaryotic Transcriptional control. The MADS-box Transcription Factors SRF and Mcm1 represent paradigms for such regulation through their interaction with numerous partner proteins. For example, in Saccharomyces cerevisiae, Mcm1 interacts with the Forkhead Transcription Factor Fkh2. Here, we identify a novel interaction between SRF and the Forkhead Transcription Factor FOXK1 in human cells. The importance of this interaction is shown for the regulation of the SRF target genes SM alpha-actin and PPGB. The binding of FOXK1 to the SM alpha-actin and PPGB promoters requires the presence of SRF on the promoter. FOXK1 acts as a Transcriptional repressor and it represses SM alpha-actin and PPGB expression. Thus FOXK1 represents an additional member of the growing repertoire of Transcription Factors that can interact with SRF and modulate the Transcriptional output from SRF-regulated promoters.
Rene H. Medema - One of the best experts on this subject based on the ideXlab platform.
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protein phosphatase 2a b55α prevents premature activation of Forkhead Transcription Factor foxm1 by antagonizing cyclin a cyclin dependent kinase mediated phosphorylation
Journal of Biological Chemistry, 2011Co-Authors: Monica Alvarezfernandez, Vincentius A Halim, Melinda Aprelia, Jamila Laoukili, Shabaz Mohammed, Rene H. MedemaAbstract:The Forkhead Transcription Factor FoxM1 controls expression of a large number of genes that are specifically expressed during the G(2) phase of the cell cycle. Throughout most of the cell cycle, FoxM1 activity is restrained by an autoinhibitory mechanism, involving a repressor domain present in the N-terminal part of the protein. Activation of FoxM1 in G(2) is achieved by Cyclin A/Cyclin-dependent kinase (Cdk)-mediated phosphorylation, which alleviates autoinhibition by the N-terminal repressor domain. Here, we show that FoxM1 interacts with B55α, a regulatory subunit of protein phosphatase 2A (PP2A). B55α binds the catalytic subunit of PP2A, and this promotes dephosphorylation and inactivation of FoxM1. Indeed, we find that overexpression of B55α results in decreased FoxM1 activity. Inversely, depletion of B55α results in premature activation of FoxM1. The activation of FoxM1 that is observed upon depletion of B55α is fully dependent on Cyclin A/Cdk-mediated phosphorylation of FoxM1. Taken together, these data demonstrate that B55α acts to antagonize Cyclin A/Cdk-dependent activation of FoxM1, to ensure that FoxM1 activity is restricted to the G(2) phase of the cell cycle.
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Forkhead Transcription Factor foxm1 regulates mitotic entry and prevents spindle defects in cerebellar granule neuron precursors
Molecular and Cellular Biology, 2007Co-Authors: Ulrich Schuller, Rene H. Medema, Qing Zhao, Susana A Godinho, Vivi M Heine, David Pellman, David H RowitchAbstract:The Forkhead Transcription Factor FoxM1 has been reported to regulate, variously, proliferation and/or spindle formation during the G2/M transition of the cell cycle. Here we define specific functions of FoxM1 during brain development by the investigation of FoxM1 loss-of-function mutations in the context of Sonic hedgehog (Shh)-induced neuroproliferation in cerebellar granule neuron precursors (CGNP). We show that FoxM1 is expressed in the cerebellar anlagen as well as in postnatal proliferating CGNP and that it is upregulated in response to activated Shh signaling. To determine the requirements for FoxM1 function, we used transgenic mice carrying conventional null alleles or conditionally targeted alleles in conjunction with specific Cre recombinase expression in CGNP or early neural precursors driven by Math1 or Nestin enhancers. Although the overall cerebellar morphology was grossly normal, we observed that the entry into mitosis was postponed both in vivo and in Shh-treated CGNP cultures. Cell cycle analysis and immunohistochemistry with antibodies against phosphorylated histone H3 indicated a significant delay in the G2/M transition. Consistent with this, FoxM1-deficient CGNP showed decreased levels of the cyclin B1 and Cdc25b proteins. Furthermore, the loss of FoxM1 resulted in spindle defects and centrosome amplification. These findings indicate that the functions of FoxM1 in Shh-induced neuroproliferation are restricted to the regulation of the G2/M transition in CGNP, most probably through Transcriptional effects on target genes such as those coding for B-type cyclins.
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Forkhead Transcription Factor FOXO3a protects quiescent cells from oxidative stress
Nature, 2002Co-Authors: Geert J. P. L. Kops, Paul J Coffer, Rene H. Medema, Karel W A Wirtz, Tobias B. Dansen, Johannes L. Bos, Paulien E. Polderman, Ingrid Saarloos, Ting-t. Huang, Boudewijn M. T. BurgeringAbstract:Reactive oxygen species are required for cell proliferation but can also induce apoptosis1. In proliferating cells this paradox is solved by the activation of protein kinase B (PKB; also known as c-Akt), which protects cells from apoptosis2. By contrast, it is unknown how quiescent cells that lack PKB activity are protected against cell death induced by reactive oxygen species. Here we show that the PKB-regulated Forkhead Transcription Factor FOXO3a (also known as FKHR-L1) protects quiescent cells from oxidative stress by directly increasing their quantities of manganese superoxide dismutase (MnSOD) messenger RNA and protein. This increase in protection from reactive oxygen species antagonizes apoptosis caused by glucose deprivation. In quiescent cells that lack the protective mechanism of PKB-mediated signalling, an alternative mechanism is induced as a consequence of PKB inactivity. This mechanism entails the activation of Forkhead Transcription Factors, the Transcriptional activation of MnSOD and the subsequent reduction of reactive oxygen species. Increased resistance to oxidative stress is associated with longevity. The model of Forkhead involvement in regulating longevity stems from genetic analysis in Caenorhabditis elegans3,4,5,6, and we conclude that this model also extends to mammalian systems.
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Forkhead Transcription Factor fkhr l1 modulates cytokine dependent Transcriptional regulation of p27kip1
Molecular and Cellular Biology, 2000Co-Authors: Pascale F Dijkers, Janwillem J Lammers, Rene H. Medema, Boudewijn M. T. Burgering, Eric Lam, Cornelieke Pals, L Banerji, N S B Thomas, J A M Raaijmakers, Leo KoendermanAbstract:Interleukin-3 (IL-3), IL-5, and granulocyte-macrophage colony-stimulating Factor regulate the survival, proliferation, and differentiation of hematopoietic lineages. Phosphatidylinositol 3-kinase (PI3K) has been implicated in the regulation of these processes. Here we investigate the molecular mechanism by which PI3K regulates cytokine-mediated proliferation and survival in the murine pre-B-cell line Ba/F3. IL-3 was found to repress the expression of the cyclin-dependent kinase inhibitor p27KIP1 through activation of PI3K, and this occurs at the level of Transcription. This Transcriptional regulation occurs through modulation of the Forkhead Transcription Factor FKHR-L1, and IL-3 inhibited FKHR-L1 activity in a PI3K-dependent manner. We have generated Ba/F3 cell lines expressing a tamoxifen-inducible active FKHR-L1 mutant [FKHR-L1(A3):ER*]. Tamoxifen-mediated activation of FKHR-L1(A3):ER* resulted in a striking increase in p27KIP1 promoter activity and mRNA and protein levels as well as induction of the apoptotic program. The level of p27KIP1 appears to be critical in the regulation of cell survival since mere ectopic expression of p27KIP1 was sufficient to induce Ba/F3 apoptosis. Moreover, cell survival was increased in cytokine-starved bone marrow-derived stem cells from p27KIP1 null-mutant mice compared to that in cells from wild-type mice. Taken together, these observations indicate that inhibition of p27KIP1 Transcription through PI3K-induced FKHR-L1 phosphorylation provides a novel mechanism of regulating cytokine-mediated survival and proliferation.
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expression of the pro apoptotic bcl 2 family member bim is regulated by the Forkhead Transcription Factor fkhr l1
Current Biology, 2000Co-Authors: Pascale F Dijkers, Leo Koenderman, Janwillem J Lammers, Rene H. Medema, Paul J CofferAbstract:Cell death is regulated mainly through an evolutionarily conserved form of cell suicide termed apoptosis [1]. Deregulation of apoptosis has been associated with cancer, autoimmune diseases and degenerative disorders. Many cells, particularly those of the hematopoietic system, have a default program of cell death and survival that is dependent on the constant supply of survival signals. The Bcl-2 family, which has both pro- and anti-apoptotic members, plays a critical role in regulating cell survival [2]. One family member, the Bcl-2 interacting mediator of cell death (Bim), contains only a protein-interaction motif known as the BH3 domain, allowing it to bind pro-survival Bcl-2 molecules, neutralizing their function [3]. Disruption of the bim gene results in resistance to apoptosis following cytokine withdrawal in leukocytes, indicating that regulation of the pro-apoptotic activity of Bim is critical for maintenance of the default apoptotic program [4]. Here, we report that withdrawal of cytokine results in upregulation of Bim expression concomitant with induction of the apoptotic program in lymphocytes. Activation of the Forkhead Transcription Factor FKHR-L1, previously implicated in regulation of apoptosis in T lymphocytes [5], was sufficient to induce Bim expression. We propose a mechanism by which cytokines promote lymphocyte survival by inhibition of FKHR-L1, preventing Bim expression.