Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “forkhead”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 667 records · Page 37Linked to original sources
PubMed2006

Regulatory T cells in human autoimmune diseases.

In the most simplistic terms, immune tolerance can be envisioned as a balance with autoreactive cells that arise naturally in all individuals on one side and regulatory mechanisms designed to counter those autoreactive processes on the other. A tilt of the balance toward the autoreactive side, either by increasing the number or function of autoreactive cells or by diminishing regulatory mechanisms, is manifested as autoimmunity. In contrast, tilting of the balance toward increased regulation could conceivably cause immunodeficiency. Regulatory T cells (T(REG)), and particularly the naturally arising CD4(+)CD25(+) subset of T(REG) cells, provide a substantial component of the autoimmune counterbalance. The identification of forkhead box P3 (FOXP3) as a critical determinant of CD4(+)CD25(+) T(REG) development and function has provided new opportunities and generated expanded interest in studying the delicate balance between autoimmunity and regulatory mechanisms in human autoimmune diseases. Identification of both human and mouse syndromes in which FOXP3 is mutated, and consequently CD4(+)CD25(+) T(REG) cells are absent, has led to a rapid accumulation of knowledge regarding T(REG) development and function over the past 5 years. The recent development of antibody reagents to specifically identify CD4(+)CD25(+) T(REG) cells by their FOXP3 expression has provided new tools to identify these elusive cells and investigate their role in human disease. This review will focus on the current state of knowledge regarding the role of T(REG) in human autoimmune diseases and on specific human immunodeficiencies that provide interesting models of autoimmunity.

Animals↗
PubMed2006

The yeast CPC2/ASC1 gene is regulated by the transcription factors Fhl1p and Ifh1p.

CPC2/ASC1 is one of the most abundantly transcribed genes in Saccharomyces cerevisiae. It encodes a ribosome-associated Gbeta-like WD protein, which is highly conserved from yeast to man. Here, we show that CPC2 transcription depends on the carbon source and is induced during utilization of the sugar glucose. CPC2 promoter deletion and insertion analyses identified two upstream activation sequence elements for CPC2, which are required for basal expression and regulation. One of these upstream activation sequence elements has an ATGTACGGATGT motif, which has previously been described as a putative binding site for the forkhead-like transcription factor Fhl1p. Deletion of FHL1 reduces CPC2 transcription significantly in presence of glucose, but has no effect when the non-fermentable carbon source ethanol is provided. Increased amounts of the Fhl1p co-regulator Ifh1p induce CPC2 transcription even when ethanol is utilized. These data suggest that the interaction between Fhl1p and Ifh1p is critical for the regulation of CPC2 transcription during utilization of different carbon sources.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Embryonic expression of HeFoxA1 and HeFoxA2 in an indirectly developing polychaete.

Two forkhead family transcription factors, HeFoxA1 and HeFoxA2, were isolated from the serpulid annelid Hydroides elegans and their transcript distribution were characterized during embryogenesis. HeFoxA1 is first detected in second quartet blastomeres soon after their formation, and later in all vegetal half blastomeres, which comprise ectoderm, endoderm, and mesoderm precursors. HeFoxA1 expression declines first in subtrochal ectoderm and presumptive midgut precursors, as well as apparently in D quadrant blastomeres in advance of any known signaling events. Later, during gastrulation, HeFoxA1 declines in hindgut precursors, and by the end of gastrulation the expression remains active only in foregut precursors. HeFoxA1 is apparently expressed in ectomesoderm cells involved in forming the larva-specific protonephridium (the so-called head kidney). The other ortholog, HeFoxA2, is expressed in a subset of the cells in which HeFoxA1 is expressed during early stages, but later it is largely restricted to the endoderm-ectoderm boundary of the proctodaeum. In addition, HeFoxA2 has a unique expression in two hindgut cells and abutting ectoderm cells located by the imminent anal opening. The combined expression of HeFoxA1 and HeFoxA2 correlates with mesoderm and endoderm expression of their orthologs in other bilaterians.

Amino Acid Sequence↗
PubMed2006

Polarised expression of FoxB and FoxQ2 genes during development of the hydrozoan Clytia hemisphaerica.

We have characterised the expression of four genes coding for Forkhead box-containing ('Fox') transcription factors identified from the hydrozoan (Leptomedusa) Clytia hemisphaerica. Phylogenetic analyses including all available non-bilaterian Fox sequences placed these genes in subfamilies B, Q2 (two genes) and O, and indicated that at least 17 Fox subfamilies were present in the common cnidarian/bilaterian ancestor, with multiple subsequent losses in cnidarian lineages. Chordate FoxB and FoxQ2A subfamily genes show polarised expression in early embryos. Correspondingly, Clytia CheFoxB expression was localised around the gastrulation site (future oral pole) at blastula and gastrula stages, with CheFoxQ2a expressed in a complementary aboral domain, maintained through larval development. Distinct later expression domains were observed for CheFoxB in the larval endoderm region, and in the statocyst, gonad and tentacle bulb of the medusa. A second Clytia FoxQ2 gene, CheFoxQ2b, not expressed in the embryo, larva or polyp, was detected uniquely in the gonads of the medusa. In contrast, CheFoxO, whose sequence indicates regulation by the PI3-Kinase/PKB signalling pathway consistent with known roles in bilaterian developmental regulation, was detected throughout the Clytia life cycle. CheFoxO expression was enhanced in regions associated with growth control including larval poles, gonad and the margin of the medusa bell. These results support the idea that an early embryonic patterning system involving FoxB and FoxQ2 family genes has been evolutionary conserved and indicate that Fox family genes have also acquired distinct roles during other phases of the hydrozoan life cycle.

Amino Acid Sequence↗
PubMed1998

Conservation of BF-1 expression in amphioxus and zebrafish suggests evolutionary ancestry of anterior cell types that contribute to the vertebrate telencephalon.

The forkhead domain containing transcription factor BF-1 has been shown to play a major role in the correct development of the cerebral hemispheres in the mouse. BF-1 orthologs have been isolated from zebrafish and the cephalocordate amphioxus. In both species, BF-1 is expressed in the anterior neural tube. In zebrafish zBF-1 expression is restricted to anterior portions of the otic vesicle and to the presumptive telencephalon. In amphioxus AmphiBF-1 is transiently seen in the frontal part of the first somite and, at 3 days of development, in a small number of cells in the cerebral vesicle (cv). The anterior expression of BF-1 in chordates and vertebrates and of slp-1/2 in Drosophila suggests that BF-1 is crucial for an evolutionarily conserved specification of anterior neuronal cell types.

Amino Acid Sequence↗
PubMed2006

Identification of single nucleotide polymorphisms in FOXJ1 and their association with allergic rhinitis.

Forkhead-box J1 (FOXJ1) is a presumed transcription factor that can suppress T cell activity, at least partially, through the repression of NFkappaB activity. Thus, dysregulation of FOXJ1 is thought to be associated with autoimmune diseases and/or other inflammatory diseases. To investigate the association between single nucleotide polymorphisms (SNPs) of human FOXJ1 and allergic rhinitis, we scanned the whole human FOXJ1 gene, including the promoter region, by direct sequencing of DNA from 32 individuals. We identified seven SNPs, three of which (g.-460C>T, g.1805G>T, and g.3375G>C) were chosen for large sample size genotyping (n=713), and to assess the genotype frequencies of these SNPs between controls and allergic rhinitis patients. We also investigated the relationships of each genotype with serum total IgE levels in allergic rhinitis patients, and compared the frequencies of haplotypes constructed by these SNPs between the two groups. Our results suggest that the SNPs g.-460C>T, g.1805G>T and g.3375G>C in the human FOXJ1 gene might be associated with susceptibility to allergic rhinitis (P=0.0184, 0.0076, and 0.0143, respectively). The main haplotype, CGG, also revealed a significant association with allergic rhinitis (P=0.000018). However, no significant association was found between serum total IgE levels and the genotypes of these polymorphisms.

Adult↗
PubMed2025

Targeting FOXK2 in triple-negative breast cancer: Role of the P53/MCAS1/miR-211-5p regulatory axis.

Forkhead box K2 (FOXK2) is over-expressed in several human malignancies, yet how it is regulated triple-negative breast cancer (TNBC) remained unclear. We aimed to clarify whether FOXK2 drives TNBC progression, and elucidate the upstream molecular circuitry that controls FOXK2 abundance. FOXK2 mRNA and protein were quantified by qPCR and Western blot in 30 paired TNBC and adjacent tissues. Some assays assessed proliferation, migration and invasion after FOXK2 knockdown or overexpression. Bioinformatics predicted miR-211-5p targeting FOXK2 and lncRNA MCM3AP-AS1 (MCAS1) targeting miR-211-5p. RNA immunoprecipitation (RIP) and dual-luciferase assays validated these interactions. RNA pulldown, mass spectrometry and ChIP identified p53 binding to the MCAS1 promoter. FOXK2 was upregulated in TNBC tissues as opposed to the para-carcinoma tissues. FOXK2 silencing significantly reduced proliferation, migration and invasion, whereas overexpression accelerated these phenotypes. Mechanistically, MCAS1 acts as a sponge for miR-211-5p, ultimately protecting its target gene FOXK2 from degradation. Furthermore, employing RNA pulldown, mass spectrometry, ChIP, and luciferase reporter assays, our studies revealed a direct interaction between P53 and the promoter of MCAS1. This interaction resulted in the suppression of MCAS1 transcription. Clinical samples from TNBC patients further confirmed a correlation between FOXK2 expression and tumor size, lymphatic involvement, as well as the expression level of Ki-67. Our findings unveil a novel P53/MCAS1/miR-211-5p/FOXK2 regulatory axis that dictates TNBC aggressiveness. FOXK2 may sever as both a prognostic biomarker and a therapeutic target in TNBC.

Humans↗
PubMed1994

Regulatory gene expression boundaries demarcate sites of neuronal differentiation in the embryonic zebrafish forebrain.

During development of the zebrafish forebrain, a simple scaffold of axon pathways is pioneered by a small number of neurons. We show that boundaries of expression domains of members of the eph, forkhead, pax, and wnt gene families correlate with the positions at which these neurons differentiate and extend axons. Analysis of genetically or experimentally altered forebrains indicates that if a boundary is maintained, there is appropriate neural differentiation with respect to the boundary. Conversely, in the absence of a boundary, there is concomitant disruption of neural patterning. We also show that a strip of cells within the dorsal diencephalon shares features with ventral midline cells. This strip of cells fails to develop in mutant fish in which specification of the ventral CNS is disrupted, suggesting that its development may be regulated by the same inductive pathways that pattern the ventral midline.

Animals↗
PubMed1996

Expression of the winged helix genes fkh-4 and fkh-5 defines domains in the central nervous system.

The 'winged helix' or 'forkhead' transcription factor gene family is defined by a common 100 amino acid DNA binding domain which is a variant of the helix-turn-helix motif. Here we describe the structure and expression of the mouse fkh-4 and fkh-5 genes. The two genes encode proteins of 427 and 324 amino acids, respectively, with highly similar winged helix domains. Both genes are expressed in adjacent domains in the developing diencephalon from the headfold stage onward. Linkage analysis localised fkh-5 to chromosome 9 at 34.5 centiMorgans (cM) and fkh-4 to chromosome 19 at 10.5 cM. The potential relationship of the two genes to the mouse mutations staggerer and small thymus (for fkh-5) and muscle deficient (for fkh-4) is discussed.

Amino Acid Sequence↗
PubMed2003

Identification of potential binding sites for the FHA domain of human Chk2 by in vitro binding studies.

Human Chk2 is a newly identified tumor suppressor protein involved in signaling pathways in response to DNA damage. The protein consists of a forkhead-associated (FHA) domain and a kinase domain. Identification of binding partners of the Chk2FHA domain is important in understanding the roles of Chk2 in signaling. We report development of an approach involving the use of combinatorial libraries, pull-down assays, surface plasmon resonance (SPR), and nuclear magnetic resonance (NMR) methods to identify possible candidates for the binding sites of Chk2FHA. The approach has been used to identify Thr329 of p53 and Thr1852 of breast cancer type 1 susceptibility protein (BRCA1) as very likely biological binding sites of Chk2FHA. The results provide useful leads for further biological analyses of cell signaling involving the FHA domain of Chk2 protein.

Binding Sites↗
PubMed2005

FoxO-dependent and -independent mechanisms mediate SirT1 effects on IGFBP-1 gene expression.

Sirtuin 1 (SirT1), an NAD-dependent deacetylase that is important for promoting longevity during caloric restriction, can deacetylate and enhance the function of forkhead box transcription factors, O subfamily (FoxO). We examined the effect of SirT1 on the regulation of insulin-like growth factor-binding protein 1 (IGFBP-1), a known target of FoxO proteins that is increased in fasting. Co-transfection with a SirT1 expression vector dose-dependently stimulated IGFBP-1 promoter activity and a heterologous reporter gene construct containing three FoxO-binding sites linked to a minimal promoter. This effect is mimicked by 20muM resveratrol, a potent SirT1 activator, and immunoprecipitation and Western blotting confirm that SirT1 and FoxO1 interact in cells. Interestingly, mutation of FoxO-binding sites in the IGFBP-1 promoter reduces, but does not completely disrupt, the stimulatory effect of SirT1 on promoter activity. We found that overexpression of SirT1 is accompanied by enhanced mitogen-activated protein kinase (MAPK) activation. Treatment of SirT1-cotransfected cells with PD98059, which inhibits MAPK activation, decreased IGFBP-1 promoter activity by approximately 50%, in a FoxO-binding site-independent manner, and disrupts the residual effect of SirT1. These results indicate that SirT1 stimulates IGFBP-1 promoter activity through FoxO-dependent and -independent mechanisms, and provides the first evidence that activation of MAPK contributes to effects of SirT1 on gene expression.

Base Sequence↗
PubMed2006

In vivo footprinting of the carbamoylphosphate synthetase I cAMP-response unit indicates important roles for FoxA and PKA in formation of the enhanceosome.

The expression of carbamoylphosphate synthetase-I (CPS), the first and rate-determining enzyme of the urea cycle, is regulated at the transcriptional level by glucocorticoids and glucagon, the latter acting via cyclic AMP (cAMP). The hormonal response is mediated by a distal enhancer located 6.3 kb upstream of the transcription-start site. Within this enhancer, a cAMP-response unit (CRU) is responsible for mediating cAMP-dependent transcriptional activity. The CPS CRU contains binding sites for cAMP-response element (CRE)-binding protein (CRE-BP), forkhead box A (FoxA), CCAAT/enhancer-binding protein (C/EBP), and an unidentified protein P1. To gain insight in the protein-DNA interactions that activate the CPS CRU in living cells, we have employed in vivo footprinting assays. Comparison of the fibroblast cell line Rat-1 and the hepatoma cell lines FTO-2B and WT-8 showed that FoxA binds the CPS CRU constitutively in CPS-expressing cells only. Comparison of FTO-2B and WT-8 hepatoma cells, which only differ in cAMP responsiveness, demonstrated that the binding of the other transcription factors is dependent on cAMP-dependent protein kinase (PKA) activity. Finally, we observed a footprint between the CRE and the P1-binding site in the in vivo footprint assay that was not detectable by in vitro footprint assays, implying a major change in CRU-associated chromatin conformation upon CRU activation. These findings indicate that activation of the CRU is initiated in a tissue-specific manner by the binding of FoxA. When cellular cAMP and glucocorticoid levels increase, CRE-BP becomes activated, allowing the binding of the remaining transcription factors and the transactivation of the CPS promoter.

Animals↗
PubMed2005

Absence of causative mutations and presence of autism-related allele in FOXP2 in Japanese autistic patients.

We analyzed the FOXP2 gene, which encodes a putative transcription factor containing a polyglutamine tract and a forkhead DNA-binding domain, for a possible causative mutation in autism. FOXP2 was reported to be mutated in patients with a severe speech and language disorder. FOXP2 was located on chromosome 7q31, which is one of the loci involved in autism. Autism and specific language impairment share some of their clinical phenotypes. In addition, FOXP2 was expressed abundantly in the brain. We screened all of the exons of FOXP2 for causative mutations in 53 Japanese autistic patients using denaturing high-performance liquid chromatography and direct sequencing. A delCAA in exon 5 causing one glutamine deletion in the first polyglutamine tract was detected in four patients and in 2 of 50 control individuals. The frequency of the TT allele with the G to T base change in intron 15 was significantly high in the autistic population. The other base changes included one silent base change (A569G) in exon 5 and three in introns. Our results may suggest a relationship between autism and the FOXP2 gene or a gene located nearby.

Adolescent↗
PubMed2006

Cloning and expression of PDK4, FOXO1A and DYRK1A from the hibernating greater horseshoe bat (Rhinolophus ferrumequinum).

Pyruvate dehydrogenase kinase isoenzyme 4 (PDK4) cDNA was cloned from the brain of greater horseshoe bat (Rhinolophus ferrumequinum). The deduced amino acid sequence shares strong homology with these PDK4 of other mammals. Moreover, we partially cloned homologues of dual-specificity tyrosine-phosphorylated and regulated protein kinase 1A (DYRK1A), and forkhead box protein O1A (FOXO1A) from greater horseshoe bat. Among five different tissues tested, PDK4 mRNA was highly expressed in the heart, white adipose tissue and muscle, but weakly expressed in the brain and liver, while DYRK1A and FOXO1A were expressed in all five tissues. Moreover, the transcript levels of PDK4, DYRK1A, and FOXO1A were measured in the heart, white adipose tissue and muscle of hibernating and arousal greater horseshoe bats by Northern blot and real time PCR. The results showed that transcript level of PDK4 was significantly higher in white adipose tissue. Expression level of DYRK1A was significantly higher in hibernating state in white adipose tissue, and expression level of FOXO1A was significantly higher in muscle in aroused state. These results suggest that up-regulation of the transcript levels of PDK4 during hibernation were not regulated via DYRK1A and FOXO1A in white adipose tissue and muscle, and the possible presence of another isoenzyme of PDK which is responsible for the tissue-specific regulation of Pyruvate dehydrogenase complex (PDC) activity in the bat heart during hibernation.

Animals↗
PubMed2004

Ribosome biogenesis: giant steps for a giant problem.

In this issue of Cell, the Hall group describes how the rapamycin-sensitive TOR signaling network controls ribosomal protein (RP) gene expression via the Forkhead-like transcription factor FHL1 in budding yeast (Martin et al., 2004). These findings represent a crucial advance in our understanding of the mechanism by which TOR regulates ribosome biogenesis in response to environmental cues.

Forkhead Transcription Factors↗
PubMed2006

C. elegans SIR-2.1 interacts with 14-3-3 proteins to activate DAF-16 and extend life span.

The longevity of Caenorhabditis elegans is promoted by extra copies of the sir-2.1 gene in a manner dependent on the forkhead transcription factor DAF-16. We identify two C. elegans 14-3-3 proteins as SIR-2.1 binding partners and show that 14-3-3 genes are required for the life-span extension conferred by extra copies of sir-2.1. 14-3-3 proteins are also required for SIR-2.1-induced transcriptional activation of DAF-16 and stress resistance. Following heat stress, SIR-2.1 can bind DAF-16 in a 14-3-3-dependent manner. By contrast, low insulin-like signaling does not promote SIR-2.1/DAF-16 interaction, and sir-2.1 and the 14-3-3 genes are not required for the regulation of life span by the insulin-like signaling pathway. We propose the existence of a stress-dependent pathway in which SIR-2.1 and 14-3-3 act in parallel to the insulin-like pathway to activate DAF-16 and extend life span.

14-3-3 Proteins↗
PubMed2006

FOXP3 controls regulatory T cell function through cooperation with NFAT.

Antigen stimulation of immune cells activates the transcription factor NFAT, a key regulator of T cell activation and anergy. NFAT forms cooperative complexes with the AP-1 family of transcription factors and regulates T cell activation-associated genes. Here we show that regulatory T cell (Treg) function is mediated by an analogous cooperative complex of NFAT with the forkhead transcription factor FOXP3, a lineage specification factor for Tregs. The crystal structure of an NFAT:FOXP2:DNA complex reveals an extensive protein-protein interaction interface between NFAT and FOXP2. Structure-guided mutations of FOXP3, predicted to progressively disrupt its interaction with NFAT, interfere in a graded manner with the ability of FOXP3 to repress expression of the cytokine IL2, upregulate expression of the Treg markers CTLA4 and CD25, and confer suppressor function in a murine model of autoimmune diabetes. Thus by switching transcriptional partners, NFAT converts the acute T cell activation program into the suppressor program of Tregs.

Amino Acid Sequence↗
PubMed2005

All roads lead to FoxO.

Stress-activated kinases control metabolism by antagonizing the early steps of insulin signal transduction. Two papers now demonstrate that Jnk, the prototypical stress-activated kinase, controls life span in Drosophila and C. elegans by promoting phosphorylation of the forkhead protein FoxO (Oh et al., 2005; Wang et al., 2005). The findings provide yet another mechanism by which metabolic and stress responses are integrated via phosphorylation of FoxO proteins.

Animals↗