Kandula et al. Cardiovasc Diabetol (2016) 15:-DOI 10.1186/s12933-016-0361-1. Cardiovascular Diabetology. REVIEW Open Access. CrossMark. Forkhead box transcription factor 1: role in the pathogenesis of diabetic cardiomyopathy. Vidya Kandula1, Ramoji Kosuru1, Haobo Li1, Dan Yan1, Qiqi Zhu1,2, Qingquan Lian2, Ren-shan Ge2, Zhengyuan Xia1,2* and Michael G. Irwin1. Abstract. Diabetic cardiomyopathy (DCM) is a disorder of the heart muscle in people with diabetes that can occur independent of hypertension or vascular disease. The underlying mechanism of DCM is incompletely understood. Some transcription factors have been suggested to regulate the gene program intricate in the pathogenesis of diabetes prompted cardiac injury. Forkhead box transcription factor 1 is a pleiotropic transcription factor that plays a pivotal role in a variety of physiological processes. Altered FOXO1 expression and function have been associated with cardiovascular diseases, and the important role of FOXO1 in DCM has begun to ...
CiteWeb id: 20050000212. CiteWeb score: 2801. DOI: 10.1016/j.immuni.2005.01.016. Regulatory T cell-mediated dominant tolerance has been demonstrated to play an important role in the prevention of autoimmunity. Here, we present data arguing that the forkhead transcription factor Foxp3 acts as the regulatory T cell lineage specification factor and mediator of the genetic mechanism of dominant tolerance. We show that expression of Foxp3 is highly restricted to the subset αβ of T cells and, irrespective of CD25 expression, correlates with suppressor activity. Induction of Foxp3 expression in nonregulatory T cells does not occur during pathogen-driven immune responses, and Foxp3 deficiency does not impact the functional responses of nonregulatory T cells. Furthermore, T cell-specific ablation of Foxp3 is sufficient to induce the identical early onset lymphoproliferative syndrome observed in Foxp3-deficient mice. Analysis of Foxp3 expression during thymic development suggests that this mechanism is ...
Scurfy mice are deficient in regulatory T cells (Tregs), develop a severe, generalized autoimmune disorder that can affect almost every organ and die at an early age. Some of these manifestations resemble those found in systemic lupus erythematosus (SLE). In addition, active SLE is associated with low Treg numbers and reduced Treg function, but direct evidence for a central role of Treg malfunction in the pathophysiology of lupus-like manifestations is still missing. In the present study, we characterize the multiorgan pathology, autoantibody profile and blood count abnormalities in scurfy mice and show their close resemblances to lupus-like disease. Scurfy mice have dysfunctional Tregs due to a genetic defect in the transcription factor Forkhead box protein 3 (Foxp3). We analyzed skin, joints, lung and kidneys of scurfy mice and wild-type (WT) controls by conventional histology and immunofluorescence (IF) performed hematological workups and tested for autoantibodies by IF, immunoblotting and enzyme
Tregs play a fundamental role in immune tolerance via control of self-reactive effector T cells (Teffs). This function is dependent on maintenance of a high intracellular cAMP concentration. A number of microRNAs are implicated in the maintenance of Tregs. In this study, we demonstrate that peripheral immune tolerance is critically dependent on posttranscriptional repression of the cAMP-hydrolyzing enzyme phosphodiesterase-3b (Pde3b) by microRNA-142-5p (miR-142-5p). In this manner, miR-142-5p acts as an immunometabolic regulator of intracellular cAMP, controlling Treg suppressive function. Mir142 was associated with a super enhancer bound by the Treg lineage-determining transcription factor forkhead box P3 (FOXP3), and Treg-specific deletion of miR-142 in mice (TregΔ142) resulted in spontaneous, lethal, multisystem autoimmunity, despite preserved numbers of phenotypically normal Tregs. Pharmacological inhibition and genetic ablation of PDE3B prevented autoimmune disease and reversed the ...
This simple picture has been complicated by the discovery of two further contrasting lineages of cells. The IL-17-secreting and IL-22-secreting pro-inflammatory Th17 cell has been implicated in combating extracellular bacterial and fungal infections and has been linked to a number of mouse models of autoimmune disease.5 In contrast, the anti-inflammatory induced T regulatory (iTreg) cell, characterized by the expression of the transcription factor forkhead box P3, inhibits proliferation and cytokine production by other T cells.5 Despite their opposite roles, in mice, Th17 and iTreg cells are both induced by activation in the presence of the cytokine transforming growth factor beta (TGF-beta). The combination of TGF-beta with the STAT3-activating cytokine IL-6 produces a Th17 cell,6 whereas the combination of TGF-beta and the STAT5-activating cytokine IL-2 induces iTreg cell differentiation.7 The key regulating cytokines in humans are not fully understood, although many recent articles have ...
The transcription factor Forkhead box M1 (FOXM1) is a key regulator of cell proliferation and is overexpressed in many forms of primary cancers, leading to uncontrolled cell division and genomic instability. To address the role of FOXM1 in chemoresistance, we generated a cisplatin-resistant breast cancer cell line (MCF-7-CISR), which had an elevated level of FOXM1 protein and mRNA expression relative to the parental MCF-7 cells. A close correlation was observed between FOXM1 and the expression of its proposed downstream targets that are involved in DNA repair; breast cancer-associated gene 2 (BRCA2) and X-ray cross-complementing group 1 (XRCC1) were expressed at higher levels in the resistant cell lines compared with the sensitive MCF-7 cells. Moreover, cisplatin treatment induced DNA damage repair in MCF-7-CISR and not in MCF-7 cells. Furthermore, the expression of a constitutively active FOXM1 (ΔN-FOXM1) in MCF-7 cells alone was sufficient to confer cisplatin resistance. Crucially, the ...
Metabolism is a highly integrated process that is coordinately regulated between tissues and within individual cells. FoxO proteins are major targets of insulin action and contribute to the regulation of gluconeogenesis, glycolysis, and lipogenesis in the liver. However, the mechanisms by which FoxO proteins exert these diverse effects in an integrated fashion remain poorly understood. We report that FoxO proteins also exert important effects on intrahepatic lipolysis and fatty acid oxidation via the regulation of adipose triacylglycerol lipase (ATGL), which mediates the first step in lipolysis, and its inhibitor, the G0/S1 switch 2 gene (G0S2). We also find that ATGL-dependent lipolysis plays a critical role in mediating diverse effects of FoxO proteins in the liver, including effects on gluconeogenic, glycolytic, and lipogenic gene expression and metabolism. These results indicate that intrahepatic lipolysis plays a critical role in mediating and integrating the regulation of glucose and lipid ...
Here we showed that Foxo1 is expressed in developing embryonic vasculature and complete disruption of Foxo1 resulted in embryonic lethality due to vascular defects. Thus, Foxo1 is an essential regulator in embryonic vessel formation. Formation of the embryonic vasculature has been separated into two major processes, vasculogenesis and angiogenesis (23). During the initial stages of vascular development, endothelial cell precursors form a network of homogeneous and primitive blood vessels (the primary vascular plexus) by the process of vasculogenesis. The primary vascular plexus is then remodeled through the process of angiogenesis by sprouting and pruning blood vessels and recruiting mural cells to establish the vascular structure. In Foxo1-null mutant embryos, vasculature stained by PECAM-1 can be seen at E9.5, although it is immature compared to wild-type embryos. This finding suggests that Foxo1 may not have a major role in the process of embryonic vasculogenesis. However, the failure to ...
Aromatase is an important enzyme in the local synthesis of oestrogens and its expression has been shown to be increased in breast cancer through the activation of multiple promoters. However, the mechanisms behind this are not yet fully understood. A novel candidate in this context is the transcription factor forkhead box L2 (FOXL2), which has been recognised to be co-expressed with aromatase and transcriptionally active promoter 11 in developing goat and chicken ovaries. We propose that FOXL2 could be involved in the increased expression of aromatase in breast cancer. We examined FOXL2 and its relation to aromatase in 132 postmenopausal breast cancer patients by immunohistochemistry. Using in silico analysis, we further searched for FOXL2 binding-elements in the aromatase gene promoters. The results demonstrate that FOXL2 is expressed in breast cancer and influences clinical outcome with improved recurrence-free survival in cases with nuclear expression. In a multivariate Cox model, nuclear ...
TY - JOUR. T1 - The Forkhead Box m1 transcription factor is essential for embryonic development of pulmonary vasculature. AU - Kim, Il-man. AU - Ramakrishna, Sneha. AU - Gusarova, Galina A.. AU - Yoder, Helena M.. AU - Costa, Robert H.. AU - Kalinichenko, Vladimir V.. PY - 2005/6/10. Y1 - 2005/6/10. N2 - Transgenic and gene knock-out studies demonstrated that the mouse Forkhead Box m1 (Foxm1 or Foxm1b) transcription factor (previously called HFH-11B, Trident, Win, or MPP2) is essential for hepatocyte entry into mitosis during liver development, regeneration, and liver cancer. Targeted deletion of Foxm1 gene in mice produces an embryonic lethal phenotype due to severe abnormalities in the development of liver and heart. In this study, we show for the first time that Foxm1-/- lungs exhibit severe hypertrophy of arteriolar smooth muscle cells and defects in the formation of peripheral pulmonary capillaries as evidenced by significant reduction in platelet endothelial cell adhesion molecule 1 ...
Forkhead box protein O4 is a protein that in humans is encoded by the FOXO4 gene. It is located on the long arm of the X chromosome from base pair 71,096,148 to 71,103,533. FOXO4 is a member of the forkhead family transcription factors O subclass, which is characterized by a winged helix domain used for DNA binding. There are 4 members of the FOXO family, including FOXO1, FOXO3, and FOXO6. Their activity is modified by many post translational activities, such as phosphorylation, ubiquitination, and acetylation. Depending on this modified state, FOXO4 binding affinity for DNA is altered, allowing for FOXO4 to regulate many cellular pathways including oxidative stress signaling, longevity, insulin signaling, cell cycle progression, and apoptosis. Two of the main upstream regulators of FOXO4 activity are phosphoinositide 3- kinase (PI3K) and serine/threonine kinase AKT/PKB. Both PI3K and AKT modify FOXO4 and prevent it from translocating to the nucleus, effectively preventing the transcription of ...
TY - JOUR. T1 - Activated forkhead transcription factor inhibits neointimal hyperplasia after angioplasty through induction of p27. AU - Park, Kyung Woo. AU - Kim, Dae Hee. AU - You, Hyun Jung. AU - Sir, Jung Ju. AU - Jeon, Soo In. AU - Youn, Seock Won. AU - Yang, Han Mo. AU - Skurk, Carsten. AU - Park, Young Bae. AU - Walsh, Kenneth. AU - Kim, Hyo Soo. PY - 2005/4/1. Y1 - 2005/4/1. N2 - Objective - We examined the effects of FKHRL1 (forkhead transcription factor in rhabdomyosarcoma like-1) overexpression on vascular smooth muscle cell (VSMC) proliferation, apoptosis, and cell cycle, in vitro, and the role of FKHRL1 and p27 in the pathophysiology of neointimal growth after balloon angioplasty, in vivo. Furthermore, we tested whether FKHRL1 overexpression can inhibit neointimal hyperplasia in a rat carotid artery model. Methods and Results - Adenovirus expressing the constitutively active FKHRL1 (FKHRL1-TM; triple mutant) with 3 Akt phosphorylation sites mutated was transfected to subconfluent ...
The FOXO family of forkhead transcription factors have a pivotal role in determining cell fate in response to oxidative stress. FOXO activity can either promote cell survival or induce cell death. Increased FOXO-mediated cell death has been implicated in the pathogenesis of degenerative diseases affecting musculoskeletal tissues. The aim of this study was to determine the conditions under which one member of the FOXO family, FOXO3a, promotes cell survival as opposed to cell death. Treatment of primary human tenocytes with 1 pM hydrogen peroxide for 18 h resulted in increased protein levels of FOXO3a. In peroxide-treated cells cultured in low serum media, FOXO3a inhibited cell proliferation and protected against apoptosis. However in peroxide treated cells cultured in high serum media, cell proliferation was unchanged but level of apoptosis significantly increased. Similarly, in tenocytes transduced to over-express FOXO3a, cell proliferation was inhibited and level of apoptosis unchanged in cells
To investigate the role of Foxp1 in lens development, we crossed Foxp1-flox mice5 with lens-specific Pax6-Cre transgenic mice13 and obtained Foxp1-L-CKO mice. These Foxp1-L-CKO mice were born in accordance with the Mendelian law of inheritance, and appeared healthy. At P0, expression of Foxp1 protein in the lens was almost completely abolished in Foxp1-L-CKO (Supplementary Figs. S5A, S5B). The eyes of Foxp1-L-CKO mice and littermate controls opened approximately 2 weeks after birth as expected, and appeared normal; Foxp1-L-CKO eyes did not exhibit redness or abnormal growth around the eye, neither showed signs of clouding of the cornea (Fig. 4A and data not shown). Two weeks after birth (P14), the eyes of Foxp1-L-CKO mice were smaller than those of their littermate control group (Fig. 4B). The lenses of these Foxp1-L-CKO mice were also smaller and exhibited nuclear opacity (Figs. 4C-E). Control and heterozygous (Foxp1-fl/+, Cre+) mice lens did not develop such phenotype even at 8 weeks after ...
Buy FOXO4 recombinant protein, Forkhead box protein O4 (FOXO4) Recombinant Protein-NP_001164402.1 (MBS957757) product datasheet at MyBioSource, Recombinant Proteins
This gene encodes a member of the forkhead/winged helix-box (FOX) family of transcription factors. FOX transcription factors are characterized by a distinct DNA-binding forkhead domain and play critical roles in the regulation of multiple processes including metabolism, cell proliferation and gene expression during ontogenesis. [provided by RefSeq, Nov 2012 ...
One purported hypothesis of PAS related to a set of transcription factors called forkhead box class O (FOXOs), these are transcription factors which...
Buy FOXL2 elisa kit, Canine Forkhead box protein L2 (FOXL2) ELISA Kit-NP_075555.1 (MBS7200093) product datasheet at MyBioSource, ELISA Kits
CD4+CD25+ Tregs have been shown to be increased in the peripheral blood and in tumor-draining lymph nodes of cancer patients. Detection of Treg is hampered by the problem that these cells share a set of markers with either memory or activated T cells. Recent data in genetically modified animals elegantly showed the specific expression of the forkhead box transcription factor FoxP3 in T cells with immunosuppressive properties. These T cells are almost exclusively represented by CD4+CD25+ Treg. Thus, detection of FoxP3 might serve as a surrogate marker for the tissue infiltration grade by Treg. In this report, we used quantitative real-time reverse transcription-PCR for the quantitation of FoxP3 in 99 samples from ovarian cancer patients and in 14 control biopsies from nondiseased ovaries. FoxP3 expression was readily detectable in ovaries from healthy women as well as in ovarian cancer tissue. The expression of FoxP3 in normal ovaries and recent findings describing that day 3 thymectomized mice ...
During the past decade, the role of Treg cells in a variety of tolerance models has been explored. Many different markers, including latency-associated peptide (LAP) (78), glucocorticoid-induced TNFR (GITR) (79), CTLA-4 (66, 67), CD25 (80, 81, 82), CD45RBlow (83), and Foxp3 (84, 85, 86), have been used to describe Tregs. However, most investigators now recognize two major Treg subsets: a natural population that suppresses through cell-to-cell contact, and an induced population that secretes suppressive cytokines. The two markers that most clearly define natural Tregs are CD25 (80, 81, 82) and the forkhead transcription factor Foxp3 (84, 85, 86). Importantly, natural Tregs are anergic and can suppress T cell responses in vitro in an Ag-nonspecific manner (80, 82, 87, 88). The absence of natural Tregs (either CD25+ or Foxp3+) in both mice and humans results in severe autoimmune disease, emphasizing their vital role in the prevention of self-reactivity (84, 85, 86). Substantial evidence indicates ...
The forkhead box O (FOXO) family of transcription factors regulates the expression of genes in cellular physiological events including apoptosis, cell-cycle control, glucose metabolism, oxidative stress resistance, and longevity. A central regulatory mechanism of FOXO proteins is phosphorylation by the serine-threonine kinase Akt/protein kinase B (Akt/PKB), downstream of phosphatidylinositol 3-kinase (PI3K), in response to insulin or several growth factors. Phosphorylation at three conserved residues results in the export of FOXO proteins from the nucleus to the cytoplasm, thereby decreasing expression of FOXO target genes. In contrast, the stress-activated c-Jun N-terminal kinase (JNK) and the energy sensing AMP-activated protein kinase (AMPK), upon oxidative and nutrient stress stimuli phosphorylate and activate FoxOs. Aside from PKB, JNK and AMPK, FOXOs are regulated by multiple players through several post-translational modifications, including phosphorylation, but also acetylation, ...
CD4+CD25+ regulatory T cells are essential for the active suppression of autoimmunity. Here we report that the forkhead transcription factor Foxp3 is specifically expressed in CD4+CD25+ regulatory T cells and is required for their development. The lethal autoimmune syndrome observed in Foxp3-mutant …
The forkhead box O (FOXO) family of transcription factors regulates the expression of genes in cellular physiological events including apoptosis, cell-cycle control, glucose metabolism, oxidative stress resistance, and longevity. A central regulatory mechanism of FOXO proteins is phosphorylation by the serine-threonine kinase Akt/protein kinase B (Akt/PKB), downstream of phosphatidylinositol 3-kinase (PI3K), in response to insulin or several growth factors. Phosphorylation at three conserved residues results in the export of FOXO proteins from the nucleus to the cytoplasm, thereby decreasing expression of FOXO target genes. In contrast, the stress-activated c-Jun N-terminal kinase (JNK) and the energy sensing AMP-activated protein kinase (AMPK), upon oxidative and nutrient stress stimuli phosphorylate and activate FoxOs. Aside from PKB, JNK and AMPK, FOXOs are regulated by multiple players through several post-translational modifications, including phosphorylation, but also acetylation, ...
Introduction: The BCR-ABL1 tyrosine kinase induces malignant transformation of B cells at the pre-B cell checkpoint and induces Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). In a genome-wide search, we identified FOXM1 as a transcription factor that is specifically upregulated at the pre-B cell checkpoint. FOXM1 is a forkhead box transcription factor and a key regulator of cell growth by promoting cell cycle progression. Results: We transformed murine pre-B cells with a retroviral BCR-ABL1 expression vector and observed upregulation of Foxm1 protein levels. Consistent with this, FOXM1 protein levels in patient-derived Ph+ ALL samples are ∼10-fold higher than in healthy B cells and B cell precursors (n=5; P=0.01). In a cohort of 83 Ph+ ALL patients, the FOXM1 promoter region was significantly de-methylated compared to normal pre-B cells (n=12; P=2.4x10e-7). In order to evaluate a potential predictive value of FOXM1 expression in ALL cells, we correlated FOXM1 mRNA ...
Endothelial Foxp1 Regulates Pathological Cardiac Remodeling through TGF-β1-Endothelin-1 Signal Pathway The effects of TGF-β1 blockade on endothelial cell (EC)-forkhead box transcription factor P1 (Foxp1)-deletion mediated pro-fibrotic and pro-hypertrophic phenotypic changes were confirmed by pharmacological inhibition, and more specifically by RGD-peptide magnetic nanoparticle target delivery of TGF-β1-siRNA to ECs. [Circulation] Abstract Microphysiological Engineering of Self-Assembled and Perfusable Microvascular Beds for the Production of Vascularized Three-Dimensional Human Microtissues A system was created in a micropatterned hydrogel construct housed in an elastomeric microdevice that enabled co-culture of primary human vascular endothelial cells and fibroblasts to achieve de novo formation, anastomosis, and controlled perfusion of 3D vascular networks. [ACS Nano] Abstract Hypoxia-Enhanced Blood-Brain Barrier Chip Recapitulates Human Barrier Function and Shuttling of Drugs and ...
human lung cancers Yunneng Tang Guangwen Shu Xinwang Yuan Naihe Jing and Jianguo Song Laboratory of Molecular Cell Biology Institute of Biochemistry and Cell Biology Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Shanghai 200031 China Correspondence Jianguo Song Tel 86 21 54921167 E mail jgsong sibs ac cn The forkhead box transcription factor A2 FOXA2 is an important regulator in animal development and body homeostasis However whether FOXA2 is involved in transforming growth factor β1 TGF β1 mediated epithelial to mesenchymal transition EMT and tumor metastasis remains unknown The present study showed that in human lung cancer cell lines the abundance of FOXA2 positively correlates with epithelial phenotypes and negatively correlates with the mesenchymal phenotypes of cells and TGF β1 treatment decreased FOXA2 protein level Consistently knockdown of FOXA2 promoted EMT and invasion of lung cancer cells whereas overexpression of FOXA2 reduced the invasion and suppressed ...
Forkhead box protein C2 (FOXC2) also known as forkhead-related protein FKHL14 (FKHL14), transcription factor FKH-14, or mesenchyme fork head protein 1 (MFH1) is a protein that in humans is encoded by the FOXC2 gene. FOXC2 is a member of the fork head box (FOX) family of transcription factors. The protein is 501 amino acids in length. The gene has no introns; the single exon is approximately 1.5kb in size. FOX transcription factors are expressed during development and are associated with a number of cellular and developmental differentiation processes. FOXC2 is required during early development of the kidneys, including differentiation of podocytes and maturation of the glomerular basement membrane. It is also involved in the early development of the heart. An increased expression of FOXC2 in adipocytes can increase the amount of brown adipose tissue leading to lower weight and an increased sensitivity to insulin. Absence of FOXC2 has been shown to lead to the failure of lymphatic valves to form ...
Previous studies from our laboratory have indicated that overexpression of the epidermal growth factor receptor pathway substrate 8 (EPS8) enhances cell proliferation, migration and tumorigenicity in vivo, although the mechanisms involved remain unexplored. A microarray screen to search for potential mediators of EPS8 identified upregulation of multiple cell cycle-related targets such as the transcription factor FOXM1 and several of its reported downstream mediators, including cdc20, cyclin B1, cyclin A, aurora-B kinase and cdc25C in cells with elevated EPS8, as well as matrix metalloproteinase-9, which we reported previously to be upregulated by EPS8-dependent mechanisms. Cells engineered to overexpress FOXM1 showed increased proliferation, similar to EPS8-overexpressing cells. Conversely, targeted knockdown of FOXM1 in EPS8-overexpressing cells reduced proliferation. Cotransfection of EPS8 with a FOXM1-luciferase reporter plasmid into 293-T- or SVpgC2a-immortalized buccal keratinocytes ...
The oncogenic transcription factor FOXM1 is an attractive therapeutic target in the fight against cancer, because it is overexpressed in a majority of human tu...
MiR-19a-3p regulates the Forkhead box F2-mediated Wnt/β-catenin signaling pathway and affects the biological functions of colorectal cancer cells
The proximal tubule has a remarkable capacity for repair after acute injury, but the cellular lineage and molecular mechanisms underlying this repair response are incompletely understood. Here, we developed a Kim1-GFPCreERt2 knockin mouse line (Kim1-GCE) in order to perform genetic lineage tracing of dedifferentiated cells while measuring the cellular transcriptome of proximal tubule during repair. Acutely injured genetically labeled clones coexpressed KIM1, VIMENTIN, SOX9, and KI67, indicating a dedifferentiated and proliferative state. Clonal analysis revealed clonal expansion of Kim1+ cells, indicating that acutely injured, dedifferentiated proximal tubule cells, rather than fixed tubular progenitor cells, account for repair. Translational profiling during injury and repair revealed signatures of both successful and unsuccessful maladaptive repair. The transcription factor Foxm1 was induced early in injury, was required for epithelial proliferation in vitro, and was dependent on epidermal ...
Researchers have found that people with osteoarthritis seem to have a lower than normal level of FOXO proteins in their damaged joints. Increasing the protein level might help to treat the disease.
Transcription factors of the FOXO family are major targets of insulin/IGF1 receptor (InsR) signalling as well as of the upstream regulator and anti-ageing hormone Klotho. The InsRFOXO pathway contributes to the regulation of longevity and oxidative stress resistance in C. elegans and mammals. It was hypothesised that Klotho modulates this cascade, stimulating FOXO activity by interfering with InsR signalling and thereby enhancing stress resistance and lifespan. We have tested the modulation of FOXO signalling in C. elegans and mammalian cells by exposure to alkylating and redox cycling agents, by thiol depletors and other stressful stimuli known to affect cellular redox regulation. Interestingly, several of these stressful stimuli imitate insulin at the level of FOXO activity, suggesting that stressful stimuli would mimic insulin signalling, thereby antagonising Klotho-induced extension of lifespan. In fact, the expression of FOXO-regulated metabolic and antioxidant proteins was shown to be ...
A key role of Foxp3 in the development of natural T reg cells has been suggested from the molecular characterization of the scurfy mouse mutant. These mice, which suffer from a fatal lymphoproliferative disorder, harbor a mutated foxp3 gene coding for a product that lacks the forkhead domain (13). Scurfy mice receiving CD25+CD4+ T reg cells from WT mice remained virtually disease free (11). Furthermore, transduction of mutant Foxp3, lacking the forkhead domain, failed to confer suppressive activity to naive CD4+ T cells, in contrast to full-length Foxp3 (12). Thus, it is widely accepted that an intrinsic T cell failure to generate functional CD4+ T reg cells is the main cause of the fatal autoimmune disease in scurfy mice, although an additional role of the scurfy mutation in nonhematopoietic cells has been suggested (14, 15). Moreover, it remains unknown whether the mere absence of functional Foxp3+ T reg cells is sufficient to provoke the development of the scurfy phenotype or whether those ...
Background & Aims: Forkhead box protein 3 (FOXP3)+ regulatory T cell (Treg) dysfunction is associated with autoimmune diseases; however, the mechanisms responsible for inflammatory bowel disease pathophysiology are poorly understood. Here, we tested the hypothesis that a physical interaction between transcription factor FOXP3 and the epigenetic enzyme enhancer of zeste homolog 2 (EZH2) is essential for gene co-repressive function. Methods: Human FOXP3 mutations clinically relevant to intestinal inflammation were generated by site-directed mutagenesis. T lymphocytes were isolated from mice, human blood, and lamina propria of Crohns disease (CD) patients and non-CD controls. We performed proximity ligation or a co-immunoprecipitation assay in FOXP3-mutant+, interleukin 6 (IL6)-treated or CD-CD4+ T cells to assess FOXP3-EZH2 protein interaction. We studied IL2 promoter activity and chromatin state of the interferon γ locus via luciferase reporter and chromatin-immunoprecipitation assays, ...
Background & Aims: Forkhead box protein 3 (FOXP3)+ regulatory T cell (Treg) dysfunction is associated with autoimmune diseases; however, the mechanisms responsible for inflammatory bowel disease pathophysiology are poorly understood. Here, we tested the hypothesis that a physical interaction between transcription factor FOXP3 and the epigenetic enzyme enhancer of zeste homolog 2 (EZH2) is essential for gene co-repressive function. Methods: Human FOXP3 mutations clinically relevant to intestinal inflammation were generated by site-directed mutagenesis. T lymphocytes were isolated from mice, human blood, and lamina propria of Crohns disease (CD) patients and non-CD controls. We performed proximity ligation or a co-immunoprecipitation assay in FOXP3-mutant+, interleukin 6 (IL6)-treated or CD-CD4+ T cells to assess FOXP3-EZH2 protein interaction. We studied IL2 promoter activity and chromatin state of the interferon γ locus via luciferase reporter and chromatin-immunoprecipitation assays, ...
PubMed journal article SIRT1 is critical regulator of FOXO-mediated transcription in response to oxidative stres were found in PRIME PubMed. Download Prime PubMed App to iPhone or iPad.
FOXA3 encodes a member of the forkhead class of DNA-binding proteins. These hepatocyte nuclear factors are transcriptional activators for liver-specific transcripts such as albumin and transthyretin, and they also interact with chromatin. Similar family members in mice have roles in the regulation of metabolism and in the differentiation of the pancreas and liver. The crystal structure of a similar protein in rat has been resolved. Mincheva et al. (1997) used fluorescence in situ hybridization to map the HNF3G gene to human chromosome 19q13.2-q13.4. By analysis of RFLPs in interspecific backcross mice, Avraham et al. (1992) mapped the mouse Hnf3-gamma gene to the proximal region of chromosome 7.
Clone REA788 recognizes the forkhead/winged-helix transcriptional regulator FoxP3, also known as forkhead box P3, scurfin, or JM2. FoxP3 is expressed pre-dominantly in regulatory T cells (Tregs) and is a major marker and functional regulator of Treg cell development and function. Mutations in the FoxP3 gene are linked to the autoimmune manifestations observed in the Scurfy mouse and humans with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Studies in mice have shown that FoxP3-deficient animals lack Treg cells, whereas overexpression of the FoxP3 protein leads to profound immune suppression. Additional information: Clone REA788 displays negligible binding to Fc receptors. - Nederland
PURPOSE: Mutations in murine and human versions of an ancestrally related gene usually result in similar phenotypes. However, interspecies differences exist, and in the case of two forkhead transcription factor genes (FOXC1 and FOXC2), these differences include corneal or anterior segment phenotypes, respectively. This study was undertaken to determine whether such discrepancies provide an opportunity for identifying novel human-murine ocular phenotypes. METHODS: Four pedigrees with early-onset glaucoma phenotypes secondary to segmental chromosomal duplications or deletions encompassing FOXC1 and 18 individuals from 9 FOXC2 mutation pedigrees underwent detailed ocular phenotyping. Subsequently, mice with mutations in Foxc1 or a related forkhead gene, Foxe3, were assessed for features of the human phenotypes. RESULTS: A significant increase in central corneal thickness was present in affected individuals from the segmental duplication pedigrees compared with their unaffected relatives (mean
The discovery of CD25 as a marker of Tregs raised a concern that Tregs may not represent a distinct T-cell lineage, but a particular state of activation, because CD25 is upregulated by all activated T cells. Other highly expressed markers on CD25+ Tregs, including CTLA-4 and GITR, are also upregulated upon activation of T cells. However, adoptive transfer of CD4+CD25+ T cells into lymphopenic mice showed that they proliferate in an MHC-dependent manner and, despite a decline in CD25 expression, their suppressive capacity increases (7). This finding and others spurred an intense exploration of potential genetic mechanisms underlying the differentiation and function of Tregs and a search for a more specific marker of these cells.. These efforts resulted in identification of Foxp3, an X chromosome-encoded member of the forkhead transcription factor family, as a specific marker of Tregs (8-10). Foxp3 was identified as the gene whose loss-of-function mutation is responsible for a disease in mutant ...
Similar to what has been shown for the Na+-coupled glucose transporter 1 (SGLT1) (31), SGK1 stimulates the facilitated glucose transporter GLUT1 by enhancing transporter abundance in the plasma membrane. The effect requires the catalytical activity of the kinase. SGK1 shuttles between cytoplasm and nucleus in a stimulus-dependent manner (38). The serum-induced nuclear import of SGK1 suggests that SGK1 acts at a transcriptional level. In fact, SGK1 has been shown to modulate the forkhead transcription factor FKHRL1 (39). Thus, SGK1 might regulate glucose transport in part by increasing GLUT1 transcript levels. However, the stimulation of glucose transport in Xenopus oocytes point to posttranscriptional regulation of GLUT1, as GLUT1 mRNA has been injected thus circumventing transcription. In addition, Western blotting of whole-cell lysates exclude GLUT1 regulation at a translational level.. SGK1 is not effective through phosphorylation of GLUT1, since the Ser-to-Ala mutation in the SGK consensus ...
Accumulated evidence indicates that, by the phosphorylation of its physiological substrates, Akt promotes cell survival, proliferation and angiogenesis. While a number of Akt targets have been identified, the mechanism by which Akt regulates cell survival and growth and induces malignant transformation still remains elusive. During the last 5 years, I have shown that AKT1 cross-talks with Src/Stat3 pathway. AKT1 is a direct target gene of Stat3. Protein/mRNA levels and promoter activity of AKT1 are significantly induced by constitutively active Src and Stat3. Knockdown of Stat3 or dominant-negative Stat3 reduced AKT1 expression induced by constitutively active Src. Blockage of AKT1 expression largely reduced Stat3 function in cell survival and angiogenesis. Furthermore, I have shown that proapoptotic protein 24p3 is a major target of Akt to mediate IL3 signaling in hematopoietic cells. Forkhead transcription factor FOXO3a directly binds to and activates 24p3 promoter leading to expression of 24p3 in
Costimulatory signals by CD28 are critical for thymic regulatory T-cell (Treg) development. To determine the functional relevance of CD28 for peripheral Treg post thymic selection, we crossed the widely used Forkhead box protein 3 (Foxp3)-CreYFP mice to mice bearing a conditional Cd28 allele. Treg-specific CD28 deficiency provoked a severe autoimmune syndrome as a result of a strong disadvantage in competitive fitness and proliferation of CD28-deficient Tregs. By contrast, Treg survival and lineage integrity were not affected by the lack of CD28. This data demonstrate that, even after the initial induction requirement, Treg maintain a higher dependency on CD28 signalling than conventional T cells for homeostasis. In addition, we found the Foxp3-CreYFP allele to be a hypomorph, with reduced Foxp3 protein levels. Furthermore, we report here the stochastic activity of the Foxp3-CreYFP allele in non-Tregs, sufficient to recombine some conditional alleles (including Cd28) but not others (including ...
Transcriptional factor regulating the expression of cell cycle genes essential for DNA replication and mitosis. Plays a role in the control of cell proliferation. Plays also a role in DNA breaks repair participating in the DNA damage checkpoint response.
p>The checksum is a form of redundancy check that is calculated from the sequence. It is useful for tracking sequence updates.,/p> ,p>It should be noted that while, in theory, two different sequences could have the same checksum value, the likelihood that this would happen is extremely low.,/p> ,p>However UniProtKB may contain entries with identical sequences in case of multiple genes (paralogs).,/p> ,p>The checksum is computed as the sequence 64-bit Cyclic Redundancy Check value (CRC64) using the generator polynomial: x,sup>64,/sup> + x,sup>4,/sup> + x,sup>3,/sup> + x + 1. The algorithm is described in the ISO 3309 standard. ,/p> ,p class="publication">Press W.H., Flannery B.P., Teukolsky S.A. and Vetterling W.T.,br /> ,strong>Cyclic redundancy and other checksums,/strong>,br /> ,a href="http://www.nrbook.com/b/bookcpdf.php">Numerical recipes in C 2nd ed., pp896-902, Cambridge University Press (1993),/a>),/p> Checksum:i ...
InterPro provides functional analysis of proteins by classifying them into families and predicting domains and important sites. We combine protein signatures from a number of member databases into a single searchable resource, capitalising on their individual strengths to produce a powerful integrated database and diagnostic tool.
Build: Wed Jun 21 18:33:50 EDT 2017 (commit: 4a3b2dc). National Center for Advancing Translational Sciences (NCATS), 6701 Democracy Boulevard, Bethesda MD 20892-4874 • 301-435-0888. ...
The observation of three distinct patterns (nuclear, cytoplasmic, and both) of localization of FKHR1 suggested the possibility that its intracellular localization might be regulated by extracellular growth signals or cell cycle progression. This hypothesis was tested by determining the localization of FKHR1-HA in serum-starved cells. CV1 cells transiently transfected with FKHR1-HA subsequently were maintained in serum-free medium for 24 hr before fixation. Under conditions of serum starvation FKHR1-HA was restricted to the nucleus in greater than 90% of the cells (Fig. 1 B and I). Moreover, treatment of serum-starved cells expressing FKHR1-HA with either 50 nM insulin-like growth factor I (Fig. 1O) or 10% serum (data not shown) for periods of time as short as 15-30 min was sufficient to cause export of FKHR1-HA from the nucleus in 70% of cells.. The growth factor stimulation of FKHR1-HA nuclear export could reflect either a passive process, such as inhibition of DNA binding leading to a ...
Gentaur molecular products has all kinds of products like :search , Prosci \ Checkpoint suppressor 1 is a member of the forkhead_winged helix transcription factor family. Checkpoints are eukaryotic DNA damage-inducible cell cycle arrests at G1 and G2. Checkpoint suppressor 1 s \ 27-724 for more molecular products just contact us