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PubMed2002

Distribution of the titf2/foxe1 gene product is consistent with an important role in the development of foregut endoderm, palate, and hair.

Titf2/foxe1 is a forkhead domain-containing gene expressed in the foregut, in the thyroid, and in the cranial ectoderm of the developing mouse. Titf2 null mice exhibit cleft palate and either a sublingual or completely absent thyroid gland. In humans, mutations of the gene encoding for thyroid transcription factor-2 (TTF-2) result in the Bamforth syndrome, characterized by thyroid agenesis, cleft palate, spiky hair, and choanal atresia. Here, we report a detailed expression pattern of TTF-2 protein during mouse embryogenesis and show its presence in structures where it has not been described yet. At embryonic day (E) 10.5, TTF-2 is expressed in Rathke's pouch, in thyroid, and in the epithelium of the pharyngeal wall and arches, whereas it is absent in the epithelium of the pharyngeal pouches. According to this expression, at E13.5, TTF-2 is present in endoderm derivatives, such as tongue, palate, epiglottis, pharynx, and oesophagus. Later in embryogenesis, we detect TTF-2 in the choanae and whiskers. This pattern of expression helps to define the complex phenotype displayed by human patients. Finally, we show that TTF-2 is a phosphorylated protein. These results help to characterize the domains of TTF-2 expression, from early embryogenesis throughout organogenesis, providing more detail on the potential role of TTF-2 in the development of endoderm and ectoderm derived structures.

Animals↗
PubMed2004

Differences in the embryonic expression patterns of mouse Foxf1 and -2 match their distinct mutant phenotypes.

Murine genes encoding the forkhead transcription factors Foxf1 and -2 are both expressed in derivatives of the splanchnic mesoderm, i.e., the mesenchyme of organs derived from the primitive gut. In addition, Foxf2 is also expressed in limbs and the central nervous system. Targeted mutagenesis of Foxf1 and -2 suggests that Foxf1 is the more important of the two mammalian FoxF genes with early embryonic lethality of null embryos and a haploinsufficiency phenotype affecting foregut-derived organs. In contrast, the only reported defect in Foxf2 null embryos is cleft palate. To investigate if the differences in mutant phenotype can be attributed to nonoverlapping expression patterns or if distinct functions of the encoded proteins have to be inferred, we analyzed the early embryonic expression of Foxf2 and compared it with that of the better investigated Foxf1. We find that in the early embryo, Foxf1 is completely dominating-in terms of expression-in extraembryonic and lateral plate mesoderm, consistent with the malformations and early lethality of Foxf1 null mutants. Along the developing gut, Foxf1 is highly expressed throughout, whereas Foxf2 expression is concentrated to the posterior part-fitting the foregut haploinsufficiency phenotypes of Foxf1 mutants. Foxf2, on the other hand, is more prominent than Foxf1 in mesenchyme around the oral cavity, as would be predicted from the cleft palate phenotype. The differences in expression pattern also highlight areas where defects should be sought for in the Foxf2 mutant, for example limbs, the posterior gut, genitalia, and derivatives of the neural crest mesenchyme.

Animals↗
PubMed2005

Dynamic regulation of FoxP3 expression controls the balance between CD4+ T cell activation and cell death.

The forkhead-family transcription factor FoxP3 is important for the development and function of CD4+CD25+ regulatory T cells. While the overall phenotypic effects of FoxP3 expression are evident, the mechanism by which FoxP3 regulates T cell activation is not well understood. CD4+ T cells from mice that express a FoxP3 Tg are refractory to TCR-mediated stimulation, failing to proliferate or produce cytokines, but possess suppressive activity towards normal T cells. In this report we show that these T cells express elevated levels of mRNA for pro-apoptotic genes and undergo rapid apoptosis following stimulation. These T cells also display slower cell cycle transit following activation, suggesting that FoxP3 is capable of regulating the ability of T cells to respond to TCR-mediated activation. Lastly, we show that contrary to expected results, under Th1 or Th2 driving conditions, CD4+ T cells from FoxP3 Tg mice differentiate into effector cells. Concomitant with differentiation is a loss of FoxP3 mRNA and protein. These data demonstrate that FoxP3 levels regulate T cell function, and that FoxP3 itself is dynamically regulated during effector T cell differentiation.

Animals↗
PubMed2006

FOXP3+ regulatory T cells: Current controversies and future perspectives.

Regulatory T cells (Treg) provide protection from autoimmune disease, graft-versus-host disease, transplant rejection and overwhelming tissue destruction during infections. Conversely, high Treg numbers enable cancer cells to evade the host immune response. Thus, Treg are seen as an important tool to manipulate the immune response. However, as the immunological community is trying to move this knowledge from mice to humans, contradictory results regarding the number and function of Treg in various diseases are appearing. This problem arises because we cannot clearly define Treg populations on the basis of expression of CD25 and other cell surface markers in humans. This review addresses the utility of the FOXP3 forkhead transcription factor for the identification of Treg populations and summarizes recent data on the expression of FOXP3 in lymphomas. It is crucial to really understand Treg biology before attempting therapies, including (i) the injection of expanded Treg to cure autoimmune disease or prevent graft-versus-host disease or (ii) the depletion or inhibition of Treg in cancer therapy. For instance, new data arising from the study of haematological malignancies highlight the additional complexity of systems where malignant cell populations may also be direct Treg targets.

Animals↗
PubMed2007

FOXP3: not just for regulatory T cells anymore.

The forkhead family transcription factor FOXP3 has been shown to be critical for the development and function of CD4+ CD25+ regulatory T cells. Recently, FOXP3 expression has been shown to be induced upon activation of human CD4+ T cells. A new report in this issue of the European Journal of Immunology shows that expression of FOXP3 in activated T cell leads to hyporesponsiveness, but not necessarily to acquisition of suppressor function. This finding suggests a new role for FOXP3 in human CD4+ T cells: down-modulating responses to TCR-mediated stimulation.

Animals↗
PubMed2006

t(3;14)(p14;q32) results in aberrant expression of FOXP1 in a case of diffuse large B-cell lymphoma.

Strong expression of Forkhead box-P1 (FOXP1), a winged-helix transcription factor, has been identified as an independent prognostic factor in diffuse large B-cell lymphoma (DLBCL). However, possible mechanisms of deregulation of this gene, on 3p14.1, have yet to be elucidated. We have identified a breakpoint at the IGA1 gene in the immunoglobulin heavy chain (IGH) locus at 14q32 that was juxtaposed to the FOXP1 gene locus in a gastric DLBCL that showed strong expression of FOXP1. This may be one possible mechanism of deregulating FOXP1 expression by placing it under the control of IGH enhancers.

Base Sequence↗
PubMed2001

The winged helix/forkhead transcription factor Foxq1 regulates differentiation of hair in satin mice.

Satin (sa) homozygous mice have a silky coat with high sheen arising from structurally abnormal medulla cells and defects in differentiation of the hair shaft. We demonstrate that the winged helix/forkhead transcription factor, Foxq1 (Forkhead box, subclass q, member 1) is mutant in sa mice. An intragenic deletion was identified in the radiation-induced satin mutant of the SB/Le inbred strain; a second allele, identified by an N-ethyl-N-nitrosourea (ENU) mutagenesis screen, has a missense mutation in the conserved winged helix DNA-binding domain. Homozygous mutants of the two alleles are indistinguishable. We show that Foxq1 is expressed during embryogenesis and exhibits a tissue-restricted expression pattern in adult tissues. The hair defects appear to be restricted to the inner structures of the hair; consequently, Foxq1 has a unique and distinct function involved in differentiation and development of the hair shaft. Despite an otherwise healthy appearance, satin mice have been reported to exhibit suppressed NK-cell function and alloimmune cytotoxic T-cell function. We show instead that the immune defects are attributable to genetic background differences.

Amino Acid Sequence↗
PubMed2000

The thyroid transcription factor 2 (TTF-2) is a promoter-specific DNA-binding independent transcriptional repressor.

The thyroid transcription factor TTF-2 is a forkhead-containing protein involved in thyroid-specific gene expression and necessary for thyroid morphogenesis. In this paper, we demonstrate that TTF-2 is able to inhibit the activity of the thyroid-specific transcription factors TTF-1 and Pax-8 only on certain promoters. We identified the minimal protein domain responsible for repressor activity, which behaves as an independent functional domain, and we show that repression by TTF-2 is DNA-binding independent. We suggest that TTF-2 is able to interfere with a specific cofactor required for TTF-1 and Pax-8 activity.

DNA↗
PubMed2001

Mesenchymal transcription factor Fkh6 is essential for the development and differentiation of parietal cells.

The role of transcription factor forkhead homologue 6 (Fkh6) gene expressed only in gastrointestinal mesenchymes on the differentiation of gastric epithelia was analyzed by inactivating the gene by targeting disruption. Gastric mucosa exhibited hyperplasias with disordered glandular structures in the absence of gene. Measurement of acid secretion in the isolated whole stomach demonstrated that both basal and stimulated secretions were severely suppressed in the Fkh6-/- stomach, while immunohistochemical studies showed that comparable numbers of parietal cells were differentiated in both wild-type and Fkh6-/- stomachs. Ultrastructurally Fkh6-/- parietal cells were furnished with developed intracellular canaliculi and many mitochondria, but their canaluculi were not enlarged nor fully connected to the luminal surface even when animals were treated with histamine, suggesting that Fkh6-/- parietal cells were far less responsive to acid secretion-inducing stimulations. Some parietal cells contained secretory granules positively stained with anti-pepsinogen antibodies, indicating that they retained characteristics of oxynticopeptic cells found in lower vertebrates. We thus concluded that Fkh6 plays essential roles for the development and differentiation of parietal cells via epithelial-mesenchymal interactions.

Animals↗
PubMed2002

T2BP, a novel TRAF2 binding protein, can activate NF-kappaB and AP-1 without TNF stimulation.

TRAF2 is a key molecule involved in TNF signaling, which is crucial for the regulation of inflammatory processes. We have identified a novel TRAF2 binding protein, designated as T2BP (TRAF2 binding protein), by a mammalian two-hybrid screening approach. T2BP is a relatively small protein of 184 amino acids, which includes a forkhead-associated domain, the phosphopeptide binding motif. The interaction domain search showed that the TRAF domain in TRAF2 is required for the binding to T2BP whereas almost the entire protein in T2BP binds to TRAF2. The interaction was further confirmed by co-immunoprecipitation. Expression profiling for T2BP and TRAF2 revealed an ubiquitous expression in adult mouse tissues. Overexpression of T2BP in HEK293 cells activated NF-kappaB and AP-1 in a dose dependent manner as well as seen in the TNF-treated control cells. Our results suggest that T2BP is involved in the TNF-mediated signaling by its interaction with TRAF2.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Notochord-dependent expression of MFH1 and PAX1 cooperates to maintain the proliferation of sclerotome cells during the vertebral column development.

During axial skeleton development, the notochord is essential for the induction of the sclerotome and for the subsequent differentiation of cartilage forming the vertebral bodies and intervertebral discs. These functions are mainly mediated by the diffusible signaling molecule Sonic hedgehog. The products of the paired-box-containing Pax1 and the mesenchyme forkhead-1 (Mfh1) genes are expressed in the developing sclerotome and are essential for the normal development of the vertebral column. Here, we demonstrate that Mfh1 like Pax1 expression is dependent on Sonic hedgehog signals from the notochord, and Mfh1 and Pax1 act synergistically to generate the vertebral column. In Mfh1/Pax1 double mutants, dorsomedial structures of the vertebrae are missing, resulting in extreme spina bifida accompanied by subcutaneous myelomeningocoele, and the vertebral bodies and intervertebral discs are missing. The morphological defects in Mfh1/Pax1 double mutants strongly correlate with the reduction of the mitotic rate of sclerotome cells. Thus, both the Mfh1 and the Pax1 gene products cooperate to mediate Sonic hedgehog-dependent proliferation of sclerotome cells.

Animals↗
PubMed2001

Inductive signals from the somatopleure mediated by bone morphogenetic proteins are essential for the formation of the sternal component of avian ribs.

The posterior five pairs of avian ribs are composed of vertebral and sternal components, both derived from the somitic mesoderm. For the patterning of the rib cartilage, inductive signals from neighboring tissues on the somitic mesoderm have been suggested to play critical roles. The notochord and surface ectoderm overlying the somitic mesoderm are essentially required for the development of proximal and distal regions of the ribs, respectively. Involvement of the somatopleure in rib development has already been suggested but is less understood than those of the notochord and surface ectoderm. In this study, we reinvestigated the role of the somatopleure during rib development. We first identified the chicken homologue of the mouse Mesenchymal forkhead-1 (cMfh-1) gene based on sequence similarities. cMfh-1 was observed to be expressed in the nonaxial mesoderm, including the somitic mesoderm, and, subsequently, in cartilage forming the ribs, vertebrae, and appendicular skeletal system. In the interlimb region, corresponding to somites 21-25 (or 26), cMfh-1-positive somitic mesoderm was seen penetrating the somatopleure of E4 embryos, and cMfh-1 was used as a molecular marker demarcating prospective rib cartilage. A series of experiments affecting the penetration of the somitic mesoderm into the somatopleure was performed in the present study, resulting in defects in sternal rib formation. The inductive signals emanating from the somatopleure mediated by BMP family proteins were observed to be essentially involved in the ingrowth of the somitic mesoderm. BMP4 alone, however, could not completely replace inductive signals from the somatopleure, suggesting the involvement of additional signals for rib formation.

Amino Acid Sequence↗
PubMed2000

Structure of the FHA1 domain of yeast Rad53 and identification of binding sites for both FHA1 and its target protein Rad9.

Forkhead-associated (FHA) domains have been shown to recognize both pThr and pTyr-peptides. The solution structures of the FHA2 domain of Rad53 from Saccharomyces cerevisiae, and its complex with a pTyr peptide, have been reported recently. We now report the solution structure of the other FHA domain of Rad53, FHA1 (residues 14-164), and identification of binding sites of FHA1 and its target protein Rad9. The FHA1 structure consists of 11 beta-strands, which form two large twisted anti-parallel beta-sheets folding into a beta-sandwich. Three short alpha-helices were also identified. The beta-strands are linked by several loops and turns. These structural features of free FHA1 are similar to those of free FHA2, but there are significant differences in the loops. Screening of a peptide library [XXX(pT)XXX] against FHA1 revealed an absolute requirement for Asp at the +3 position and a preference for Ala at the +2 position. These two criteria are met by a pThr motif (192)TEAD(195) in Rad9. Surface plasmon resonance analysis showed that a pThr peptide containing this motif, (188)SLEV(pT)EADATFVQ(200) from Rad9, binds to FHA1 with a K(d) value of 0.36 microM. Other peptides containing pTXXD sequences also bound to FHA1, but less tightly (K(d)=4-70 microM). These results suggest that Thr192 of Rad9 is the likely phosphorylation site recognized by the FHA1 domain of Rad53. The tight-binding peptide was then used to identify residues of FHA1 involved in the interaction with the pThr peptide. The results are compared with the interactions between the FHA2 domain and a pTyr peptide derived from Rad9 reported previously.

Amino Acid Motifs↗
PubMed2001

Solution structures of two FHA1-phosphothreonine peptide complexes provide insight into the structural basis of the ligand specificity of FHA1 from yeast Rad53.

Rad53, a yeast checkpoint protein involved in regulating the repair of DNA damage, contains two forkhead-associated domains, FHA1 and FHA2. Previous combinatorial library screening has shown that FHA1 strongly selects peptides containing a pTXXD motif. Subsequent location of this motif within the sequence of Rad9, the target protein, coupled with spectroscopic analysis has led to identification of a tight binding sequence that is likely the binding site of FHA1: (188)SLEV(pT)EADATFVQ(200). We present solution structures of FHA1 in complex with this pT-peptide and with another Rad9-derived pT-peptide that has ca 30-fold lower affinity, (148)KKMTFQ(pT)PTDPLE(160). Both complexes showed intermolecular NOEs predominantly between three peptide residues (pT, +1, and +2 residues) and five FHA1 residues (S82, R83, S85, T106, and N107). Furthermore, the following interactions were implicated on the basis of chemical shift perturbations and structural analysis: the phosphate group of the pT residue with the side-chain amide group of N86 and the guanidino group of R70, and the carboxylate group of Asp (at the +3 position) with the guanidino group of R83. The generated structures revealed a similar binding mode adopted by these two peptides, suggesting that pT and the +3 residue Asp are the major contributors to binding affinity and specificity, while +1 and +2 residues could provide additional fine-tuning. It was also shown that FHA1 does not bind to the corresponding pS-peptides or a related pY-peptide. We suggest that differentiation between pT and pS-peptides by FHA1 can be attributed to hydrophobic interactions between the methyl group of the pT residue and the aliphatic protons of R83, S85, and T106 from FHA1.

Amino Acid Motifs↗
PubMed2002

PTEN in neural precursor cells: regulation of migration, apoptosis, and proliferation.

PTEN is a lipid phosphatase, and PTEN mutations are associated with gliomas, macrocephaly, and mental deficiencies. We have used PTEN +/- mice to assess PTEN's role in subventricular zone (SVZ) precursor cells. For cultured SVZ neurosphere cells, haploinsufficiency for PTEN increases phosphorylation of Akt and forkhead transcription factor and slightly enhances proliferation. Based on a filter penetration assay, PTEN +/- cells are substantially more migratory and invasive than +/+ cells. The +/- cells also are more resistant to H(2)O(2)-induced apoptosis. Analysis of PTEN +/- and +/+ mice by BrdU labeling reveals no difference in the rate of cell proliferation in the SVZ. Exit of BrdU-labeled cells from the SVZ and radial migration to the outer layers of the olfactory bulb are more rapid for +/- cells. These observations indicate that PTEN regulates SVZ precursor cell function and is particularly important for migration and apoptosis in response to oxidative stress.

Animals↗
PubMed2025

Reporter Gene Assays to Measure FOXO-Specific Transcriptional Activity.

The forkhead box O (FOXO) family of transcription factors translates environmental cues into precise gene expression patterns maintaining cellular equilibrium while influencing critical determinations of cell destiny and differentiation. FOXO proteins exert their effects through specific consensus binding to promoter sites within target genes. Notably, among the array of techniques available for assessing the transcriptional activity of FOXO factors, the utilization of luciferase-based reporters emerges as particularly distinctive. Luciferase, an enzyme sourced from bioluminescent organisms, instigates the oxidation of luciferin, culminating in the generation of oxyluciferin accompanied by discernible luminescence, a quantifiable event readily gauged using a luminometer. The adoption of luciferase activity as a measure in transcriptional assays is widespread due to its numerous advantages including simplicity, remarkable reproducibility, and high sensitivity. Moreover, the continuous advancements witnessed in luciferase-based vectors and measurement reagents bestow notable flexibility upon this methodology. Luciferase-based reporters offer a powerful tool for uncovering constituents within the signaling pathways governing FOXO factor function. Furthermore, these assays are also suitable for evaluating the efficacy of FOXO-targeting agents, whether they be inhibitors or activators. Here, we present a comprehensive, step-by-step elucidation of a commonly employed assay, adeptly quantifying the potential of small molecular compounds to amplify FOXO-specific transcriptional activity in U2OS cells.

Genes, Reporter↗
PubMed2006

Prostaglandin E2 regulates Foxo activity via the Akt pathway: implications for pancreatic islet beta cell dysfunction.

AIMS/HYPOTHESIS: Prostaglandin E(2) (PGE(2)) is a well-recognised inhibitor of glucose-stimulated insulin secretion (GSIS). The aim of this study was to investigate the signalling pathway of PGE(2) in beta cell function regulation in HIT-T15 cells and isolated rat islets. MATERIALS AND METHODS: mRNA levels of the prostaglandin E receptor 3 (Ptger3) were measured by real-time PCR. Western blot analysis was used to detect changes in the levels of PTGER3, phosphorylated and total Akt, phosphorylated and total forkhead box 'Other' (Foxo). Transient transfection and reporter assays were used to measure Foxo transcriptional activity. The biological significance of PGE(2) in beta cell function was analysed using MTT, flow cytometry and GSIS assays. RESULTS: We found that treating HIT-T15 cells with exogenous PGE(2) stimulated Ptger3 gene expression specifically, and diminished cAMP generation. These were accompanied by the downregulation of Akt and Foxo phosphorylation in HIT-T15 cells and isolated rat islets. Moreover, PGE(2) upregulated basal and partially reversed constitutively active Akt-inactivated Foxo transcriptional activity. Furthermore, GSIS was impaired in PGE(2)-treated HIT-T15 cells and isolated islets. However, the dosage used in the above experiments did not affect beta cell viability and apoptosis. In addition, insulin-like growth factor 1 (IGF-1) pretreatment reversed the effects of PGE(2), and wortmannin treatment abolished the preventive effects of IGF-1. CONCLUSIONS/INTERPRETATION: Our observations strongly suggest that PGE(2) can induce pancreatic beta cell dysfunction through the induction of Ptger3 gene expression and inhibition of Akt/Foxo phosphorylation without impacting beta cell viability. These results shed light on the mechanisms of PGE(2) actions in pancreatic beta cell dysfunction.

Androstadienes↗
PubMed2006

Dendritic cell based antitumor vaccination: impact of functional indoleamine 2,3-dioxygenase expression.

BACKGROUND: Recent reports have demonstrated that the enzyme indoleamine 2,3-dioxygenase (IDO) is upregulated in human dendritic cells (DCs) upon in vitro maturation. IDO is supposed to convey immunosuppressive effects by degrading the essential amino acid tryptophan, thereby downregulating T-cell functions. Hence, we evaluated IDO expression in DC preparations used for therapeutic DC vaccination and its in vivo effects. PATIENTS, METHODS AND RESULTS: IDO expression was detected by real-time-PCR in a series of human clinical grade DCs (n = 28) prior to vaccination of advanced melanoma patients (n = 11). These analyses revealed an intra- and interpersonal variation in IDO mRNA levels. IDO was strongly upregulated in human DCs on RNA and on protein level upon in vitro maturation by Interleukin-1beta (IL-1beta), tumour necrosis factor-alpha (TNF-alpha), Interleukin-6 (IL-6) and Prostaglandin E2 (PGE2) over a time course of 24 h. The enzymatic activity of induced IDO was demonstrated by measuring tryptophan degradation. Moreover, in biopsies obtained 24 h after application of the DC vaccine a prominent infiltrate of IDO-positive cells was observed by immunohistochemistry. The inflammatory infiltrate of these sites stained positive for the transcription factor Forkhead box P3 (FoxP3), suggesting an IDO-mediated induction of regulatory T-cells. All analysed melanoma patients (n = 11) receiving DC based immunotherapy exhibited rapid disease progression with a short overall survival due to advanced tumour stage. CONCLUSION: The presented observations suggest a potential clinical relevance of IDO expression in DC-based therapeutic vaccines via the attraction or induction of FoxP3(+) T-cells.

Adult↗