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 91 records · Page 5Linked to original sources
PubMed2002

The forkhead transcription factor FoxO regulates transcription of p27Kip1 and Bim in response to IL-2.

The cytokine IL-2 plays a very important role in the proliferation and survival of activated T cells. These effects of IL-2 are dependent on signaling through the phosphatidylinositol 3-kinase (PI3K) pathway. We and others have shown that PI3K, through activation of protein kinase B/Akt, inhibits transcriptional activation by a number of forkhead transcription factors (FoxO1, FoxO3, and FoxO4). In this study we have investigated the role of these forkhead transcription factors in the IL-2-induced T cell proliferation and survival. We show that IL-2 regulates phosphorylation of FoxO3 in a PI3K-dependent fashion. Phosphorylation and inactivation of FoxO3 appears to play an important role in IL-2-mediated T cell survival, because mere activation of FoxO3 is sufficient to trigger apoptosis in T cells. Indeed, active FoxO3 can induce expression of IL-2-regulated genes, such as the cdk inhibitor p27(Kip1) and the proapoptotic Bcl-2 family member Bim. Furthermore, we show that IL-2 triggers a rapid, PI3K-dependent, phosphorylation of FoxO1a in primary T cells. Thus, we propose that inactivation of FoxO transcription factors by IL-2 plays a critical role in T cell proliferation and survival.

Animals↗
PubMed2002

Regulation of alkaline phosphatase promoter activity by forkhead transcription factor FKHR.

Alkaline phosphatase (ALP) is a basic marker of osteoblast maturation and osteogenesis. However, the mechanisms of the ALP gene regulation in osteoblasts remain elusive. In this study, we examined the expression of forkhead transcription factor FKHR, a regulator of hepatic glucose metabolic and proapoptotic genes, in osteogenic cells and the effect of FKHR on transcription of the ALP gene. RT-PCR and immunoblot analyses revealed the expression of FKHR in osteogenic MC3T3-E1, SaOS2, and UMR 106 cells. Reporter assays demonstrated that the overexpression of FKHR stimulated ALP promoter activity through the forkhead response element in its promoter. These results suggest that ALP is a target gene regulated by FKHR and that FKHR contributes to osteoblast maturation and osteogenesis.

3-Phosphoinositide-Dependent Protein Kinases↗
PubMed2000

Forkhead transcription factor FoxF2 is expressed in mesodermal tissues involved in epithelio-mesenchymal interactions.

The growing family of forkhead transcription factors plays many important roles during embryonic development. In this study we have used in situ hybridization to explore the expression pattern of the forkhead transcription factor gene FoxF2 (FREAC-2, LUN) during mouse and rat embryogenesis, postnatal development, and in adult tissues. We demonstrate that FoxF2 is expressed in the mesenchyme adjacent to the epithelium in alimentary, respiratory, and urinary tracts, similar to FoxF1 (FREAC-1, HFH-8). FoxF2 mRNA was also observed in organs that do not express FoxF1 during embryogenesis, e.g., in the central nervous system, eye, ear, and limb buds. In organs that express both FoxF2 and FoxF1, these transcription factors may have similar functions in epithelio-mesenchymal cross-talk, but the fact that FoxF2 is more widely expressed than FoxF1 suggests that FoxF2 also has an independent role as a developmental regulator.

Age Factors↗
PubMed2004

FoxJ3, a novel mammalian forkhead gene expressed in neuroectoderm, neural crest, and myotome.

Forkhead transcription factors are important regulators of animal development. Here, we describe the embryonic expression pattern for one of the novel forkhead genes that were discovered as a result of the mouse and human genome projects. It is most closely related to FoxJ2 and has been assigned the name FoxJ3. The 100-kb, 13-exon mouse Foxj3 gene on chromosome 4 encodes a 623 amino acid (aa) protein from an mRNA of at least 4.8 kb (Human FOXJ3: Chr 1, 627 aa, 5.3-kb mRNA). During the stages of mouse development investigated (embryonic day [E] 8.5-E12.5) Foxj3 is expressed in neuroectoderm, in neural crest, and in many structures derived from neural crest cells, such as facioacoustic, trigeminal, and dorsal root ganglia. Stripes of expression appear at E10.5 in the location of myotomes and expand ventrally in a pattern similar to the developing body wall musculature. Developing limbs have a complex pattern of Foxj3 expression that at E12.5 colocalizes with the condensed mesenchyme of the skeletal primordia.

Amino Acid Sequence↗
PubMed1998

The two-exon gene of the human forkhead transcription factor FREAC-2 (FKHL6) is located at 6p25.3.

The gene for the human transcription factor forkhead related activator 2 (FREAC-2; HGMW-approved symbol FKHL6) has been characterized and found to consist of two exons separated by an intron of 3.6 kb. The first exon encodes the forkhead DNA-binding domain and one of the transcriptional activation domains, AD2. The second exon contains the coding sequence corresponding to the C-terminal activation domain AD1. The full-length FREAC-2 protein is predicted to be 444 amino acids, which adds 39 amino acids to the previously published partial cDNA sequence. A 2-kb CG island is centered around the 5' end of the FREAC-2 gene. Fluorescence in situ hybridization was used to localize the human FREAC-2 gene to chromosomal position 6p24-p25, and the localization was further refined by radiation hybrid mapping to 6p25.3.

Amino Acid Sequence↗
PubMed2002

Expression of the ctenophore Brain Factor 1 forkhead gene ortholog (ctenoBF-1) mRNA is restricted to the presumptive mouth and feeding apparatus: implications for axial organization in the Metazoa.

Ctenophores are thoroughly modern animals whose ancestors are derived from a separate evolutionary branch than that of other eumetazoans. Their major longitudinal body axis is the oral-aboral axis. An apical sense organ, called the apical organ, is located at the aboral pole and contains a highly innervated statocyst and photodetecting cells. The apical organ integrates sensory information and controls the locomotory apparatus of ctenophores, the eight longitudinal rows of ctene/comb plates. In an effort to understand the developmental and evolutionary organization of axial properties of ctenophores we have isolated a forkhead gene from the Brain Factor 1 (BF-1) family. This gene, ctenoBF-1, is the first full-length nuclear gene reported from ctenophores. This makes ctenophores the most basal metazoan (to date) known to express definitive forkhead class transcription factors. Orthologs of BF-1 in vertebrates, Drosophila, and Caenorhabditis elegans are expressed in anterior neural structures. Surprisingly, in situ hybridizations with ctenoBF-1 antisense riboprobes show that this gene is not expressed in the apical organ of ctenophores. CtenoBF-1 is expressed prior to first cleavage. Transcripts become localized to the aboral pole by the 8-cell stage and are inherited by ectodermal micromeres generated from this region at the 16- and 32-cell stages. Expression in subsets of these cells persists and is seen around the edge of the blastopore (presumptive mouth) and in distinct ectodermal regions along the tentacular poles. Following gastrulation, stomodeal expression begins to fade and intense staining becomes restricted to two distinct domains in each tentacular feeding apparatus. We suggest that the apical organ is not homologous to the brain of bilaterians but that the oral pole of ctenophores corresponds to the anterior pole of bilaterian animals.

Amino Acid Sequence↗
PubMed2006

Expression of the forkhead transcription factor FoxN4 in progenitor cells in the developing Xenopus laevis retina and brain.

Forkhead proteins are involved in gene regulation in a large variety of developmental situations. Several forkhead gene products are expressed in the developing eye and brain. Here we characterize the expression of FoxN4 during Xenopus development. We report that FoxN4 is expressed in the eye from the earliest stages of specification through retinal maturation. FoxN4 is also expressed in the pallium, optic tectum, isthmus, reticular formation, and in cells lining the ventricle of the tadpole brain.

Amino Acid Sequence↗
PubMed2003

Forkhead transcription factor Foxf2 (LUN)-deficient mice exhibit abnormal development of secondary palate.

The forkhead genes encode a transcription factor involved in embryogenesis and pattern formation in multicellular organisms. They are mammalian transcriptional regulators that bind DNA as a monomer through their forkhead domain. The Foxf2 (LUN) mRNA is expressed in the mesenchyme directly adjacent to the ectoderm-derived epithelium in the developing tongue and in the mesenchyme adjacent to the endoderm-derived epithelium in the gastrointestinal (GI) tract, lungs, and genitalia. To investigate the developmental role of the Foxf2 gene during embryogenesis, we disrupted the Foxf2 gene and showed that these mutant mice died shortly after birth. Mice lacking the Foxf2 gene were found to develop cleft palate and an abnormal tongue. In addition, we found that the GI tract and the lungs of Foxf2-deficient newborn mice were normal in both morphology and function. These results suggest that the Foxf2 gene plays key roles in palatogenesis by reshaping the growing tongue.

Animals↗
PubMed2003

FoxP4, a novel forkhead transcription factor.

Forkhead proteins have been demonstrated to play key roles in embryonic development, cell cycle regulation, and oncogenesis. We report the characterization of a new forkhead transcription factor, which is a member of the FoxP subfamily. In adult tissues FoxP4 is expressed in heart, brain, lung, liver, kidney, and testis. By Northern hybridization, very low levels of FoxP4 expression were found as early as E7 during embryonic development. Embryonic expression was highest at E11 and subsequently decreased at E15 and E17. In situ hybridization revealed expression of FoxP4 in the developing lung and gut, suggesting a role for FoxP4 during the development of these organs. In addition, FoxP4 was found to be significantly reduced in patients with kidney tumors. Lastly, FoxP4 matches an uncharacterized human EST that has previously been shown to be down-regulated in larynx carcinoma.

Amino Acid Sequence↗
PubMed1996

Spatial expression of a forkhead homologue in the sea urchin embryo.

Echinoderms are the sister group of the chordates and hemichordates within the deuterostomes. They lack a notochord or any structures obviously homologous with it. To gain insight into developmental mechanisms important in the origin and early evolution of chordates, we investigated sea urchin homologues of chordate genes that are implicated in notochord formation, viz. Brachyury and HNF-3 beta. Here we report the pattern of expression of a sea urchin orthologue of forkhead, Hphnf3 which is present as a single copy per haploid genome. An Hphnf3 transcript of 3.0 kb was first detected at the swimming blastula stage, accumulated maximally at the gastrula and prism-embryo stages, and decreased at the pluteus-larva stage. In situ hybridization signals were found in cells of the vegetal plate of the swimming blastula. During gastrulation, intense staining was evident in the cells surrounding the blastopore, whereas weak staining was detected in the invaginating archenteron. At the prism-embryo stage, the entire archenteron stained intensely; then, at pluteus stage, the larva staining decreased in intensity. The forkhead and Brachyury genes begin to be expressed almost simultaneously in sea urchin embryos, in the vegetal plate at the late blastula stage. After the onset of gastrulation, however, Hphnf3 is expressed in the posterior part of the archenteron, whereas the Brachyury orthologue, HpTa, is expressed in the secondary mesenchyme founder cells, which occupy the anterior tip of archenteron. Hphnf3 may contribute to specification of embryonic cells as archenteron, and the role of HpTa may be directed towards specification of mesodermal founder cells. Except for the basal character of expression in endoderm and endomesoderm, these transcription factors are clearly utilized differently in chordates.

Amino Acid Sequence↗
PubMed1998

Mouse Mesenchyme forkhead 2 (Mf2): expression, DNA binding and induction by sonic hedgehog during somitogenesis.

Cloning and sequencing of mouse Mf2 (mesoderm/mesenchyme forkhead 2) cDNAs revealed an open reading frame encoding a putative protein of 492 amino acids which, after in vitro translation, binds to a DNA consensus sequence. Mf2 is expressed at high levels in the ventral region of newly formed somites, in sclerotomal derivatives, in lateral plate and cephalic mesoderm and in the first and second branchial arches. Other regions of mesodermal expression include the developing tongue, meninges, nose, whiskers, kidney, genital tubercule and limb joints. In the nervous system Mf2 is transcribed in restricted regions of the mid- and forebrain. In several tissues, including the early somite, Mf2 is expressed in cell populations adjacent to regions expressing sonic hedgehog (Shh) and in explant cultures of presomitic mesoderm Mf2 is induced by Shh secreted by COS cells. These results suggest that Mf2, like other murine forkhead genes, has multiple roles in embryogenesis, possibly mediating the response of cells to signaling molecules such as SHH.

Amino Acid Sequence↗
PubMed2001

A forkhead-domain gene is mutated in a severe speech and language disorder.

Individuals affected with developmental disorders of speech and language have substantial difficulty acquiring expressive and/or receptive language in the absence of any profound sensory or neurological impairment and despite adequate intelligence and opportunity. Although studies of twins consistently indicate that a significant genetic component is involved, most families segregating speech and language deficits show complex patterns of inheritance, and a gene that predisposes individuals to such disorders has not been identified. We have studied a unique three-generation pedigree, KE, in which a severe speech and language disorder is transmitted as an autosomal-dominant monogenic trait. Our previous work mapped the locus responsible, SPCH1, to a 5.6-cM interval of region 7q31 on chromosome 7 (ref. 5). We also identified an unrelated individual, CS, in whom speech and language impairment is associated with a chromosomal translocation involving the SPCH1 interval. Here we show that the gene FOXP2, which encodes a putative transcription factor containing a polyglutamine tract and a forkhead DNA-binding domain, is directly disrupted by the translocation breakpoint in CS. In addition, we identify a point mutation in affected members of the KE family that alters an invariant amino-acid residue in the forkhead domain. Our findings suggest that FOXP2 is involved in the developmental process that culminates in speech and language.

Amino Acid Sequence↗
PubMed1996

Characterization of the human forkhead gene FREAC-4. Evidence for regulation by Wilms' tumor suppressor gene (WT-1) and p53.

We describe the cloning and sequence analysis of a nearly full-length cDNA as well as a corresponding 5.2-kilobase pair genomic fragment encoding FREAC-4, a member of the forkhead family of transcription factors. The cDNA is collinear with respect to the coding region of the intronless genomic clone. The conceptual translation product predicts a protein of 465 amino acids with a hyperacidic amino-terminal end, a DNA binding forkhead domain and a carboxyl-terminal part that is rich in homopolymeric runs of prolines and alanines. The transcription start is identified using an RNase protection assay. A 2.7-kilobase pair genomic DNA fragment, located immediately upstream of the translation start, was fused to a luciferase reporter gene. Significant levels of luciferase activity were detected when this construct was transfected into two kidney-derived cell lines, 293 and COS-7 cells, whereas only background reporter gene expression was observed in a cell line of nonkidney origin. Cotransfections with plasmids expressing WT-1, WTAR (a mutated form of WT-1), p53, and a mutated form of p53 revealed a complex pattern of regulation with a 3-fold induction with WT-1, a 7-fold induction with mutated p53, and a 4-fold repression with wild-type p53. A 5'-promoter deletion series delimits a DNA fragment necessary for WT-1 inducibility in cotransfection experiments. This fragment is shown to contain at least one cis-element that is capable of interacting with recombinant WT-1.

Amino Acid Sequence↗
PubMed1999

Insulin stimulates phosphorylation of the forkhead transcription factor FKHR on serine 253 through a Wortmannin-sensitive pathway.

In the nematode Caenorhabditis elegans, mutations of the insulin/insulin-like growth factor-1 receptor homologue Daf-2 gene cause developmental arrest at the dauer stage. The effect of Daf-2 mutations is counteracted by mutations in the Daf-16 gene, suggesting that Daf-16 is required for signaling by Daf-2. Daf-16 encodes a forkhead transcription factor. Based on sequence similarity, the FKHR genes are the likeliest mammalian Daf-16 homologues. FKHR proteins contain potential sites for phosphorylation by the serine/threonine kinase Akt. Because Akt is phosphorylated in response to insulin and has been implicated in a variety of insulin effects, we investigated whether insulin affects phosphorylation of FKHR. Insulin stimulated phosphorylation of endogenous FKHR and of a recombinant c-Myc/FKHR fusion protein transiently expressed in murine SV40-transformed hepatocytes. The effect of insulin was inhibited by wortmannin treatment, suggesting that PI 3-kinase activity is required for FKHR phosphorylation. Mutation of serine 253, located in a consensus Akt phosphorylation site at the carboxyl-terminal end of the forkhead domain, abolished the effect of insulin on FKHR phosphorylation. In contrast, mutation of two additional Akt phosphorylation sites, at amino acids threonine 24 or serine 316, did not abolish insulin-induced phosphorylation. These data indicate that FKHR may represent a distal effector of insulin action.

Amino Acid Substitution↗
PubMed2000

Forkhead genes in transcriptional silencing, cell morphology and the cell cycle. Overlapping and distinct functions for FKH1 and FKH2 in Saccharomyces cerevisiae.

The SIR1 gene is one of four specialized genes in Saccharomyces cerevisiae required for repressing transcription at the silent mating-type cassettes, HMLalpha and HMRa, by a mechanism known as silencing. Silencing requires the assembly of a specialized chromatin structure analogous to heterochromatin. FKH1 was isolated as a gene that, when expressed in multiple copies, could substitute for the function of SIR1 in silencing HMRa. FKH1 (Forkhead Homologue One) was named for its homology to the forkhead family of eukaryotic transcription factors classified on the basis of a conserved DNA binding domain. Deletion of FKH1 caused a defect in silencing HMRa, indicating that FKH1 has a positive role in silencing. Significantly, deletion of both FKH1 and its closest homologue in yeast, FKH2, caused a form of yeast pseudohyphal growth, indicating that the two genes have redundant functions in controlling yeast cell morphology. By several criteria, fkh1Delta fkh2Delta-induced pseudohyphal growth was distinct from the nutritionally induced form of pseudohyphal growth observed in some strains of S. cerevisiae. Although FKH2 is redundant with FKH1 in controlling pseudohyphal growth, the two genes have different functions in silencing HMRa. High-copy expression of CLB2, a G2/M-phase cyclin, prevented fkh1Delta fkh2Delta-induced pseudohyphal growth and modulated some of the fkhDelta-induced silencing phenotypes. Interestingly, deletions in either FKH1 or FKH2 alone caused subtle but opposite effects on cell-cycle progression and CLB2 mRNA expression, consistent with a role for each of these genes in modulating the cell cycle and having opposing effects on silencing. The differences between Fkh1p and Fkh2p in vivo were not attributable to differences in their DNA binding domains.

Cell Cycle↗
PubMed2003

OutFOXing the grim reaper: novel mechanisms regulating longevity by forkhead transcription factors.

Studies in the nematode Caenhorhabditis elegans have contributed to understanding the mechanisms that control life-span and aging. Recent experiments have employed RNAi to knock down gene expression, microarray analysis to identify genes involved in the insulin/insulin-like growth factor pathway, and bioinformatics screening to identify new Forkhead-regulated genes. The results from these experiments suggest that members of the Forkhead transcription factor family along with heat shock factors may coordinately regulate production of small heat shock proteins to control how cell stress influences life-span, and provide new links between metabolism and longevity, as well as indicate that antimicrobial genes may be involved in the aging process.

Animals↗
PubMed2002

A forkhead transcription factor is important for true hyphal as well as yeast morphogenesis in Candida albicans.

Candida albicans is an important pathogen of immunocompromised patients which grows with true hyphal, pseudohyphal, and yeast morphologies. The dynamics of cell cycle progression are markedly different in true hyphal relative to pseudohyphal and yeast cells, including nuclear movement and septin ring positioning. In Saccharomyces cerevisiae, two forkhead transcription factors (ScFKH1 and ScFKH2) regulate the expression of B-cyclin genes. In both S. cerevisiae and Schizosaccharomyces pombe, forkhead transcription factors also influence morphogenesis. To explore the molecular mechanisms that connect C. albicans morphogenesis with cell cycle progression, we analyzed CaFKH2, the single homolog of S. cerevisiae FKH1/FKH2. C. albicans cells lacking CaFkh2p formed constitutive pseudohyphae under all yeast and hyphal growth conditions tested. Under hyphal growth conditions levels of hyphae-specific mRNAs were reduced, and under yeast growth conditions levels of several genes encoding proteins likely to be important for cell wall separation were reduced. Together these results imply that Fkh2p is required for the morphogenesis of true hyphal as well as yeast cells. Efglp and Cphlp, two transcription factors that contribute to C. albicans hyphal growth, were not required for the pseudohyphal morphology of fkh2 mutants, implying that Fkh2p acts in pathways downstream of and/or parallel to Efglp and Cphlp. In addition, cells lacking Fkh2p were unable to damage human epithelial or endothelial cells in vitro, suggesting that Fkh2p contributes to C. albicans virulence.

Candida albicans↗
PubMed2003

Identification and analysis of a novel mutation in the FOXC1 forkhead domain.

PURPOSE: To determine the genetic and biochemical defects that underlie Axenfeld-Rieger malformations, identify the pathogenic mutation causing these malformations, and understand how these mutations alter protein function. METHODS: FOXC1 was amplified from a proband with Axenfeld-Rieger malformations and the proband's mother. PCR products were sequenced to identify the pathogenic mutation. Site-directed mutagenesis was used to introduce this mutation into the FOXC1 cDNA. A synthetic mutation at the same position was also introduced, and both natural and synthetic proteins were tested for their ability to localize to the nucleus, bind DNA, and transactivate gene expression. RESULTS: A novel missense mutation (L86F) was identified in FOXC1 in this family. The mutation is located in alpha-helix 1 of the forkhead domain. Biochemical assays showed that the L86F mutation does not affect nuclear localization of FOXC1, but reduces DNA binding and significantly reduces transactivation. The severity of the disruption to FOXC1 protein activity does not appear to correspond well with the severity of the phenotype in the patient. Analogous studies using a L86P, a known alpha-helix breaker, severely disrupts FOXC1 function, revealing the importance of helix 1 in FOXC1 structure and function. CONCLUSIONS: A novel mutation in helix 1 of the FOXC1 forkhead domain has been identified and the importance of position 86 in FOXC1 activity demonstrated. These studies also identified the role of helix 1 in FOXC1 function and provide further evidence for the lack of strong genotype-phenotype correlation in FOXC1 pathogenesis. Normal development appears to be dependent on tight upper and lower thresholds of FOXC1 activity.

Adult↗