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At least 685 records · Page 38Linked to original sources
PubMed2003

Control of immune homeostasis by naturally arising regulatory CD4+ T cells.

CD4(+)CD25(+) regulatory T (T(R)) cells are essential negative regulators of multiple immune functions. Their development and function are critically dependent on the forkhead transcription factor Foxp3. IL-2R-derived signals are also required for their maturation and/or proliferation. Expression of the TNF receptor family member GITR appears to define this naturally arising, thymically derived lineage more accurately than CD25. T(R) cells suppress virtually all forms of immune responsiveness investigated to date, including both adaptive and innate immunity. T(R) cells are capable of robust antigen-driven proliferation in vivo, and may participate in clonal expansion in response to infection, similar to all other adaptive immune lineages.

Animals↗
PubMed2003

Cell cycle-regulated transcription through the FHA domain of Fkh2p and the coactivator Ndd1p.

Recent studies in Saccharomyces cerevisiae by using global approaches have significantly enhanced our knowledge of the components involved in the transcriptional regulation of the cell cycle. The Mcm1p-Fkh2p complex, in combination with the coactivator Ndd1p, plays an important role in the cell cycle-dependent expression of the CLB2 gene cluster during the G2 and M phases ([4-7]; see [8-10]for reviews). Fkh2p is phosphorylated in a cell cycle-dependent manner, and peak phosphorylation occurs coincidentally with maximal expression of Mcm1p-Fkh2p-dependent gene expression. However, the mechanism by which this complex is activated in a cell cycle-dependent manner is unknown. Here, we demonstrate that the forkhead-associated (FHA) domain of Fkh2p directs cell cycle-regulated transcription and that the activity of this domain is dependent on the coactivator Ndd1p. Ndd1p was found to be phosphorylated in a cell cycle-dependent manner by Cdc28p-Clb2p, and, importantly, this phosphorylation event promotes interactions between Ndd1p and the FHA domain of Fkh2p. Furthermore, mutation of the FHA domain blocks these phosphorylation-dependent interactions and abolishes transcriptional activity. Our data therefore link the transcriptional activity of the FHA domain with cell cycle-dependent phosphorylation of the coactivator Ndd1p and reveal a mechanism that permits precise temporal activation of the Mcm1p-Fkh2p complex.

Blotting, Western↗
PubMed2004

Foxh1 is essential for development of the anterior heart field.

The anterior heart field (AHF) mediates formation of the outflow tract (OFT) and right ventricle (RV) during looping morphogenesis of the heart. Foxh1 is a forkhead DNA binding transcription factor in the TGFbeta-Smad pathway. Here we demonstrate that Foxh1-/- mutant mouse embryos form a primitive heart tube, but fail to form OFT and RV and display loss of outer curvature markers of the future working myocardium, similar to the phenotype of Mef2c-/- mutant hearts. Further, we show that Mef2c is a direct target of Foxh1, which physically and functionally interacts with Nkx2-5 to mediate strong Smad-dependent activation of a TGFbeta response element in the Mef2c gene. This element directs transgene expression to the presumptive AHF, as well as the RV and OFT, a pattern that closely parallels endogenous Mef2c expression in the heart. Thus, Foxh1 and Nkx2-5 functionally interact and are essential for development of the AHF and its derivatives, the RV and OFT, in response to TGFbeta-like signals.

Animals↗
PubMed2005

Phenotypic modulation of smooth muscle cells through interaction of Foxo4 and myocardin.

Smooth muscle cells (SMCs) modulate their phenotype between proliferative and differentiated states in response to physiological and pathological cues. Insulin-like growth factor-I stimulates differentiation of SMCs by activating phosphoinositide-3-kinase (PI3K)-Akt signaling. Foxo forkhead transcription factors act as downstream targets of Akt and are inactivated through phosphorylation by Akt. We show that Foxo4 represses SMC differentiation by interacting with and inhibiting the activity of myocardin, a transcriptional coactivator of smooth muscle genes. PI3K/Akt signaling promotes SMC differentiation, at least in part, by stimulating nuclear export of Foxo4, thereby releasing myocardin from its inhibitory influence. Accordingly, reduction of Foxo4 expression in SMCs by siRNA enhances myocardin activity and SMC differentiation. We conclude that signal-dependent interaction of Foxo4 with myocardin couples extracellular signals with the transcriptional program for SMC differentiation.

Active Transport, Cell Nucleus↗
PubMed2006

Targets of DAF-16 involved in Caenorhabditis elegans adult longevity and dauer formation.

The Forkhead Box O transcription factor DAF-16 regulates genes affecting dauer larva formation and adult life span. Expression profiling and genome-wide searches for DAF-16 binding sites in gene regulatory regions have identified thousands of potential DAF-16 targets. Some of these genes have been shown to alter longevity when their expression is attenuated by RNAi treatment. DAF-16 also associates with other transcription factors, allowing combinatorial modulation of gene expression. Although extensive descriptions of the gene network regulated by DAF-16 have been attempted, there remain many gaps in the understanding of how DAF-16 regulates dauer formation and longevity.

Aging↗
PubMed2006

Reduced PDE4 expression and activity contributes to enhanced catecholamine-induced cAMP accumulation in adipocytes from FOXC2 transgenic mice.

Overexpression of forkhead transcription factor FOXC2 in white adipose tissue (WAT) leads to a lean phenotype resistant to diet-induced obesity. This is due, in part, to enhanced catecholamine-induced cAMP-PKA signaling in FOXC2 transgenic mice. Here we show that rolipram treatment of adipocytes from FOXC2 transgenic mice did not increase isoproterenol-induced cAMP accumulation to the same extent as in wild type cells. Accordingly, phosphodiesterase-4 (PDE4) activity was reduced by 75% and PDE4A5 protein expression reduced by 30-50% in FOXC2 transgenic WAT compared to wild type. Thus, reduced PDE4 activity in adipocytes from FOXC2 transgenic mice contributes to amplified beta-AR induced cAMP responses observed in these cells.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2006

PI3-kinase/Akt-dependent antiapoptotic signaling by the PDGF alpha receptor is negatively regulated by Src family kinases.

Regulation of growth factor dependent cell survival is crucial for development and disease progression. Here, we report a novel function of Src kinases as a negative regulator of platelet-derived growth factor (PDGF) dependent cell survival. We characterized a series of PDGF alpha receptor (PDGFRA) mutants, which lack the binding sites for Src, phosphatidylinositol 3'-kinase (PI3K), SHP-2 or phospholipase C-gamma. We found that PDGFRA-dependent cell survival was mainly mediated through activation of PI3K, and was negatively regulated by Src. Characterization of the downstream signaling events revealed that PI3K activates the protein kinase Akt, which in turn phosphorylates and thus inactivates proapoptotic Forkhead transcription factors. Src phosphorylates the ubiquitin-ligase c-Cbl, which is required for degradation of the activated receptor. Consequently, overexpression of c-Cbl prevented PDGFRA-mediated cell survival, whereas it did not affect this response, when Src was unable to associate with the receptor. This novel function of Src in antiapoptotic signaling introduces Src kinases as an interesting therapeutic target in apoptosis related diseases.

Apoptosis↗
PubMed2005

Expression of FOXP3 mRNA is not confined to CD4+CD25+ T regulatory cells in humans.

Expression of the transcription factor Foxp3 (forkhead box P3) has been implicated as a key element for CD25(+) T regulatory cell function in mice. However, literature over similar involvement of FOXP3 expression in human T regulatory cells is limited. We found that, unlike murine cells, FOXP3 mRNA expression could be induced in human CD25(-) and CD8(+) peripheral blood mononuclear cells, which were both negative for FOXP3 mRNA expression after isolation. Expression of FOXP3 mRNA began as soon as 24-40 hours after stimulation, demonstrating a correlation between activation and FOXP3 mRNA expression in human cells. In order to determine whether FOXP3 expression is confined to CD4(+)CD25(+) T cells with a regulatory phenotype, we analyzed several well-defined T-cell clones and lines with various specificities. Surprisingly, expression of FOXP3 mRNA was detected in all clones and limited to the CD25(hi) populations. Nonetheless, the CD25(hi) fraction did not display regulatory properties because both the CD25(hi) and CD25(low) populations exhibited a similar proliferative- and interferon-gamma-secreting potential after antigenic stimulation. These results indicate that FOXP3 expression in humans, unlike mice, may not be specific for cells with a regulatory phenotype and may be only a consequence of activation status.

Animals↗
PubMed2004

Overlap between molecular markers expressed by naturally occurring CD4+CD25+ regulatory T cells and antigen specific CD4+CD25+ and CD8+CD28- T suppressor cells.

Alloantigen specific CD8+CD28- T suppressor (TS) cells differ from naturally occurring CD4+CD25+ T-regulatory (natural TR) cells not only by their phenotype but also by their mechanism of action. Natural TR have been extensively studied, leading to the identification of characteristic "molecular markers" such as Forkhead box P3 (FOXP3), glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). We have investigated the expression of these genes in alloantigen specific TS and CD4+CD25+ T regulatory (TR) cells and found that they are expressed at levels similar to those observed in natural TR. Furthermore, similar to natural CD4+CD25+ TR, antigen-specific CD8+CD28-CD62L+ TS cells have more suppressive capacity than CD8+CD28-CD62L- TS cells. In spite of these similarities, natural TR are not antigen-specific and inhibit other T cells by T cell-to-T cell interaction, whereas TS are antigen-specific and exert their inhibitory function by interacting with antigen-presenting cells and render them tolerogenic to other T cells. The molecular characterization of TS cells may contribute to a better understanding of mechanisms involved in inhibition of immune responses in autoimmunity, transplantation, and chronic viral infection.

Biomarkers↗
PubMed2006

Regulation of class-switch recombination and plasma cell differentiation by phosphatidylinositol 3-kinase signaling.

Class-switch recombination (CSR) is essential for humoral immunity. However, the regulation of CSR is not completely understood. Here we demonstrate that phosphatidylinositol 3-kinase (PI3K) actively suppressed the onset and frequency of CSR in primary B cells. Consistently, mice lacking the lipid phosphatase, PTEN, in B cells exhibited a hyper-IgM condition due to impaired CSR, which could be restored in vitro by specific inhibition of PI3Kdelta. Inhibition of CSR by PI3K was partially dependent on the transcription factor, BLIMP1, linking plasma cell commitment and cessation of CSR. PI3K-dependent activation of the serine-threonine kinase, Akt, suppressed CSR, in part, through the inactivation of the Forkhead Box family (Foxo) of transcription factors. Reduced PI3K signaling enhanced the expression of AID (activation-induced cytidine deaminase) and accelerated CSR. However, ectopic expression of AID could not fully overcome inhibition of CSR by PI3K, suggesting that PI3K regulates both the expression and function of AID.

Animals↗
PubMed2006

CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome, and defective IL-10 expression from CD4 lymphocytes.

BACKGROUND: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) results in systemic autoimmunity from birth and can be caused by mutations in the transcription factor forkhead box P3 (FOXP3). OBJECTIVE: To determine if Foxp3 is required for the generation of IL-10-expressing T regulatory cells. METHODS: CD4 lymphocytes were isolated from patients with IPEX-like syndromes and activated with antibodies to CD3 and CD46 to generate IL-10-expressing T regulatory cells. RESULTS: We describe a patient with clinical manifestations of IPEX that had a normal Foxp3 gene, but who had CD25 deficiency due to autosomal recessive mutations in this gene. This patient exhibited defective IL-10 expression from CD4 lymphocytes, whereas a Foxp3-deficient patient expressed normal levels of IL-10. CONCLUSION: These data show that CD25 deficiency results in an IPEX-like syndrome and suggests that although Foxp3 is not required for normal IL-10 expression by human CD4 lymphocytes, CD25 expression is important. CLINICAL IMPLICATIONS: Any patient with features of IPEX but with a normal Foxp3 gene should be screened for mutations in the IL-2 receptor subunit CD25.

Alleles↗
PubMed2004

Structure of human Ki67 FHA domain and its binding to a phosphoprotein fragment from hNIFK reveal unique recognition sites and new views to the structural basis of FHA domain functions.

Recent studies by use of short phosphopeptides showed that forkhead-associated (FHA) domains recognize pTXX(D/I/L) motifs. Solution structures and crystal structures of several different FHA domains and their complexes with short phosphopeptides have been reported by several groups. We now report the solution structure of the FHA domain of human Ki67, a large nuclear protein associated with the cell-cycle. Using fragments of its binding partner hNIFK, we show that Ki67-hNIFK binding involves ca 44 residues without a pTXX(D/I/L) motif. The pThr site of hNIFK recognized by Ki67 FHA is pThr234-Pro235, a motif also recognized by the proline isomerase Pin1. Heteronuclear single quantum coherence (HSQC) NMR was then used to map out the binding surface, and structural analyses were used to identify key binding residues of Ki67 FHA. The results represent the first structural characterization of the complex of an FHA domain with a biologically relevant target protein fragment. Detailed analyses of the results led us to propose that three major factors control the interaction of FHA with its target protein: the pT residue, +1 to +3 residues, and an extended binding surface, and that variation in the three factors is the likely cause of the great diversity in the function and specificity of FHA domains from different sources.

Binding Sites↗
PubMed2005

Overlapping and distinct functions for a Caenorhabditis elegans SIR2 and DAF-16/FOXO.

The conserved SIR2 protein regulates life span in both yeast and worms: in both organisms overexpression of SIR2 can extend life span and in Caenorhabditis elegans this life span extension is dependent on the forkhead transcription factor, DAF-16. Here, we have done extensive genetic analysis with sir-2.1(ok434), a null mutant of C. elegans sir-2.1, the closest homolog to yeast Sir2p and human SIRT1 to further elucidate its function in life span regulation. sir-2.1(ok434) mutants show a slight decrease in life span as well as sensitivity to various stresses. Our genetic analysis suggests that sir-2.1 is required for life span extension by caloric restriction, independent of the insulin/IGF-1 signaling pathway. Importantly, analysis with unc-13 mutants indicates that sir-2.1 and daf-16 have overlapping and distinct roles in life span regulation. Our expression analysis shows that sir-2.1 has overlapping and distinct expression pattern compared with daf-16, consistent with the results from our genetic data. Our data defines a central role for C. elegans SIR2 in regulation of life span by caloric restriction and demonstrates that sir-2.1 and daf-16 have both overlapping and distinct functions in regulation of C. elegans life span.

Aging↗
PubMed2006

C. elegans 14-3-3 proteins regulate life span and interact with SIR-2.1 and DAF-16/FOXO.

14-3-3 proteins are evolutionarily conserved and ubiquitous proteins that function in a wide variety of biological processes. Here we define a new role for C. elegans 14-3-3 proteins in life span regulation. We identify two C. elegans 14-3-3 proteins as interacting proteins of a major life span regulator, the C. elegans SIR2 ortholog, SIR-2.1. Similar to sir-2.1, we find that overexpression of either 14-3-3 protein (PAR-5 or FTT-2) extends life span and that this is dependent on DAF-16, a forkhead transcription factor (FOXO), another important life span regulator in the insulin/IGF-1 signaling pathway. Furthermore, we show that both 14-3-3 proteins are co-expressed with DAF-16 and SIR-2.1 in the tissues critical for life span regulation. Finally, we show that DAF-16/FOXO also physically interacts with the 14-3-3 proteins. These results suggest that C. elegans 14-3-3 proteins can regulate longevity by cooperating with both SIR-2.1 and DAF-16/FOXO.

14-3-3 Proteins↗
PubMed2006

Expression and shifting subcellular localization of the transcription factor, Foxd3, in embryonic and adult pancreas.

Multipotent progenitor cells self renew throughout an animal's lifetime and can differentiate to give rise to different cell types. Before we can fully understand the developmental potential of progenitor cells and control their differentiation both in vivo and in vitro as stem cells, identification and characterization of the genes that control stem cell fate must first be obtained. Foxd3, a member of the forkhead family of transcriptional regulators, is required for the maintenance of embryonic stem cells and trophoblast stem cells of the early mouse embryo. We describe here the expression of this protein in the developing pancreas. Foxd3 is expressed in most beta cells and infrequently in alpha and PP cells but is not expressed in somatostatin cells. The subcellular localization of Foxd3 varies with fat content in the diet; with a high fat diet the protein is found primarily in the cytoplasm while a low fat diet results in nuclear localization. Foxd3 is differentially localized in a rat model of diabetes: it is nuclear in ZDF rats but cytoplasmic in their lean counterparts. Foxd3 is nuclear in Lep(Ob/Ob) mice.

Animals↗
PubMed2005

No association of FOXP2 and PTPRZ1 on 7q31 with autism from the Japanese population.

Autism is a child-onset pervasive developmental disorder, with a significant role of genetic factors in its development. Genome-wide linkage studies have suggested a 7q region as a susceptibility locus for autism. We investigated several single nucleotide polymorphisms (SNPs) of Forkhead Box P2 (FOXP2) and Protein-Tyrosine Phosphatase, Receptor-type, Zeta-1 (PTPRZ1) at the 7q region in Japanese patients with autism and healthy controls. No significant difference was observed, after correction for the multiple testing, in allele, genotype or haplotype frequencies of the SNPs of FOXP2 or PTPRZ1 between patients and controls. No evidence was thus obtained for a major role of FOXP2 or PTPRZ1 in the development of autism.

Adolescent↗
PubMed2005

Molecular lymphangiogenesis: new players.

The function of the lymphatic vascular system as a conduit for immune cells and excess tissue fluid has been known for over a century, but the molecular players involved in lymphangiogenesis--the formation of lymphatic vessels--have remained unknown until recently. Signals mediated by vascular endothelial growth factor-C, the homeodomain transcription factor PROX1 and the forkhead transcription factor FOXC2 have been implicated in the growth, morphogenesis and hierarchic organization of the lymphatic vascular network. Recent results have also shown the importance of the angiopoietin-Tie and ephrin-Eph signaling systems in lymphangiogenesis, suggesting that these pathways regulate the lymphatic vascular system in a manner similar to, yet distinct from, their regulation of angiogenesis. This review provides an overview of the molecular players involved in lymphangiogenesis, with special emphasis on recently discovered molecular mechanisms.

Animals↗
PubMed2006

Integrin signals, transcription factors, and monocyte differentiation.

The precise signals responsible for differentiation of circulating monocytes into tissue macrophages are incompletely defined. "Outside-in" integrin signaling has been implicated in modulating gene expression that affects cellular differentiation. This review highlights the role of transcription factors in monocyte differentiation and describes how integrin engagement orchestrates monocyte differentiation signals by regulating the expression of the forkhead transcription factor Foxp1, which functions as a transcriptional repressor of the macrophage colony-stimulating factor receptor c-fms. This represents a new pathway for integrin-dependent modulation of gene expression and control of cellular differentiation.

Cell Differentiation↗