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At least 721 records · Page 40Linked to original sources
PubMed2000

Fast1 is required for the development of dorsal axial structures in zebrafish.

Nodal-related signals comprise a subclass of the transforming growth factor-beta (TGF-beta) superfamily and regulate key events in vertebrate embryogenesis, including mesoderm formation, establishment of left-right asymmetry and neural patterning [1-8]. Nodal ligands are thought to act with EGF-CFC protein co-factors to activate activin type I and II or related receptors, which phosphorylate Smad2 and trigger nuclear translocation of a Smad2/4 complex [8-12]. The winged-helix transcription factor forkhead activin signal transducer-1 (Fast-1) acts as a co-factor for Smad2 [12-20]. Xenopus Fast-1 is thought to function as a transcriptional effector of Nodal signals during mesoderm formation [17], but no mutations in the Fast-1 gene have been identified. We report the identification of the zebrafish fast1 gene and show that it is disrupted in schmalspur (sur) mutants, which have defects in the development of dorsal midline cell types and establishment of left-right asymmetry [21-25]. We find that prechordal plate and notochord are strongly reduced in maternal-zygotic sur mutants, whereas other mesendodermal structures are present - a less severe phenotype than that caused by complete loss of Nodal signaling. These results show that fast1 is required for development of dorsal axial structures and left-right asymmetry, and suggest that Nodal signals act through Fast1-dependent and independent pathways.

Amino Acid Sequence↗
PubMed2001

The OLD-1 positive regulator of longevity and stress resistance is under DAF-16 regulation in Caenorhabditis elegans.

Aging and limited life span are fundamental biological phenomena observed in a variety of species [1]. Approximately 55 genes have been identified that can extend longevity when altered in Caenorhabditis elegans [2-5]. These genes include an insulin-like receptor (daf-2) and a phosphatidylinositol 3-OH kinase (age-1) regulating a forkhead transcription factor (daf-16) [6, 7], as well as genes mediating metabolic throughput [8], sensory perception [9], and reproduction [10]. Moreover, these mutant alleles both extend life span and increase resistance to ultraviolet (UV) radiation [11], heat [12], and oxidative stress [13-15], though the stress resistance of clk-1 is controversial. With the exception of old-1 and perhaps some other genes [16-19], all of the life-extension alleles are hypomorphic or nullomorphic. Here, we show that the OLD-1 transmembrane tyrosine kinase (formerly TKR-1; [16, 20]) is expressed in a variety of tissues, is stress inducible, and is a positive regulator of longevity and stress resistance. The transcription of old-1 is upregulated in long-lived age-1 and daf-2 mutants and is upregulated in response to heat, UV light, and starvation. Both RT-PCR and analysis of an OLD-1::GFP tag suggest that old-1 expression is dependent on daf-16. Importantly, old-1 is required for the life extension of age-1 and daf-2 mutants. This study reveals a new system for specifying longevity and stress resistance and suggests possible mechanisms for mediating life extension by dietary restriction and hormesis.

Animals↗
PubMed2003

Identification of a DAF-16 transcriptional target gene, scl-1, that regulates longevity and stress resistance in Caenorhabditis elegans.

In Caenorhabditis elegans, an insulin-like signaling pathway, which includes the daf-2 and age-1 genes, controls longevity and stress resistance. Downregulation of this pathway activates the forkhead transcription factor DAF-16, whose transcriptional targets are suggested to play an essential role in controlling the phenotypes governed by this pathway. We have surveyed the genes that have the DAF-16 consensus binding element (DBE) within putative regulatory regions. Here, we show that one such gene, termed scl-1, is a positive regulator of longevity and stress resistance. Expression of scl-1 is upregulated in long-lived daf-2 and age-1 mutants and is undetectable in a short-lived daf-16 mutant. SCL-1 is a putative secretory protein with an SCP domain and is homologous to the mammalian cysteine-rich secretory protein (CRISP) family. scl-1 is required for the extension of the life span of daf-2 and age-1 mutants, and downregulation of scl-1 reduces both life span and stress resistance of this animal. SCL-1, whose expression is dependent on DAF-16, is the first example of a putative secretory protein that positively regulates longevity and stress resistance.

Aging↗
PubMed2002

Bacterial FHA domains: neglected players in the phospho-threonine signalling game?

Forkhead-associated (FHA) domains bind phospho-threonine peptides and are known to mediate phosphorylation-dependent protein-protein interactions in a variety of eukaryotic settings. However, their role in bacterial physiology and signalling has been largely neglected. We have surveyed bacterial FHA domains and discovered that they are implicated in many bacterial processes, including regulation of cell shape, type III secretion, sporulation, pathogenic and symbiotic host-bacterium interactions, carbohydrate storage and transport, signal transduction and ethambutol resistance. The way is now open to identify the targets of each FHA domain, and their roles in cellular physiology, and perhaps even to develop novel FHA-blocking antibacterial agents.

Amino Acid Sequence↗
PubMed2000

The molecular basis of FHA domain:phosphopeptide binding specificity and implications for phospho-dependent signaling mechanisms.

Forkhead-associated (FHA) domains are a class of ubiquitous signaling modules that appear to function through interactions with phosphorylated target molecules. We have used oriented peptide library screening to determine the optimal phosphopeptide binding motifs recognized by several FHA domains, including those within a number of DNA damage checkpoint kinases, and determined the X-ray structure of Rad53p-FHA1, in complex with a phospho-threonine peptide, at 1.6 A resolution. The structure reveals a striking similarity to the MH2 domains of Smad tumor suppressor proteins and reveals a mode of peptide binding that differs from SH2, 14-3-3, or PTB domain complexes. These results have important implications for DNA damage signaling and CHK2-dependent tumor suppression, and they indicate that FHA domains play important and unsuspected roles in S/T kinase signaling mechanisms in prokaryotes and eukaryotes.

14-3-3 Proteins↗
PubMed1998

Characterization of human FAST-1, a TGF beta and activin signal transducer.

We have identified a human homolog of the Xenopus forkhead activin signal transducer-1 (xFAST-1). Although significantly different in sequence from its Xenopus counterpart, hFAST-1 shared with xFAST-1 the ability to bind to human Smad2 and activate an activin response element (ARE). The hFAST-1-dependent activation of ARE was completely dependent on endogenous Smad4 and stimulation by a TGF beta-like ligand. The hFAST-1 protein was shown to bind to a novel DNA motif, TGT (G/T) (T/G)ATT, an exact copy of which was present within the ARE. A single copy of this motif could activate a reporter in a TGF beta-dependent fashion but only when an adjacent Smad-binding element was present in the construct. These data suggest that responses to TGF beta family members may be mediated by a DNA-binding complex formed by hFAST-1, hSmad2, and hSmad4.

Activins↗
PubMed2002

Rad9 phosphorylation sites couple Rad53 to the Saccharomyces cerevisiae DNA damage checkpoint.

Rad9 is required for the MEC1/TEL1-dependent activation of Saccharomyces cerevisiae DNA damage checkpoint pathways mediated by Rad53 and Chk1. DNA damage induces Rad9 phosphorylation, and Rad53 specifically associates with phosphorylated Rad9. We report here that multiple Mec1/Tel1 consensus [S/T]Q sites within Rad9 are phosphorylated in response to DNA damage. These Rad9 phosphorylation sites are selectively required for activation of the Rad53 branch of the checkpoint pathway. Consistent with the in vivo function in recruiting Rad53, Rad9 phosphopeptides are bound by Rad53 forkhead-associated (FHA) domains in vitro. These data suggest that functionally independent domains within Rad9 regulate Rad53 and Chk1, and support the model that FHA domain-mediated recognition of Rad9 phosphopeptides couples Rad53 to the DNA damage checkpoint pathway.

Binding Sites↗
PubMed2003

An FHA phosphoprotein recognition domain mediates protein EmbR phosphorylation by PknH, a Ser/Thr protein kinase from Mycobacterium tuberculosis.

In bacteria, regulatory phosphorylation of proteins at serine and/or threonine residues by Ser/Thr protein kinase (STPK) is an emerging theme in prokaryotic signaling, particularly since the prediction of the occurrence of several STPKs from genome sequencing and sequence surveys. Here we show that protein PknH possesses an autokinase activity and belongs to the large STPK family found in Mycobacterium tuberculosis. Evidence is presented that PknH can also phosphorylate EmbR, a protein suspected to modulate the level of arabinosyltransferase activity involved in arabinan biosynthesis of arabinogalactan, a key molecule of the mycobacterial cell wall. Interestingly, EmbR possesses an FHA (forkhead-associated) domain, a newly described phosphoprotein recognition domain, which plays an essential role in PknH-EmbR interaction and phosphorylation of EmbR by PknH. It is demonstrated that mutation of each of three particular residues of this FHA domain, Arg312, Ser326, and Asn348, totally abolishes the PknH-mediated phosphorylation of EmbR, thus highlighting the critical role of this domain in the direct interaction between EmbR and PknH.

Bacterial Proteins↗
PubMed2004

The ligand specificity of yeast Rad53 FHA domains at the +3 position is determined by nonconserved residues.

On the basis of the results from our laboratory and others, we recently suggested that the ligand specificity of forkhead-associated (FHA) domains is controlled by variations in three major factors: (i) residues interacting with pThr, (ii) residues recognizing the +1 to +3 residues from pThr, and (iii) an extended binding surface. While the first factor has been well established by several solution and crystal structures of FHA-phosphopeptide complexes, the structural bases of the second and third factors are not well understood and are likely to vary greatly between different FHA domains. In this work, we proposed and tested the hypothesis that nonconserved residues G133 and G135 of FHA1 and I681 and D683 of FHA2, located outside of the core FHA region of yeast Rad53 FHA domains, contribute to the specific recognition of the +3 position of different phosphopeptides. By rational mutagenesis of these residues, the specificity of FHA1 has been changed from predominantly pTXXD to be equally acceptable for pTXXD, pTXXL, and pYXL, which are similar to the specificities of the FHA2 domain of Rad53. Conversely, the +3 position specificity of FHA2 has been engineered to be more like FHA1 with the I681A mutation. These results were based on library screening as well as binding analyses of specific phosphopeptides. Furthermore, results of structural analyses by NMR indicate that some of these residues are also important for the structural integrity of the loops.

Arginine↗
PubMed2003

Involvement of the Akt/PKB signaling pathway with disease processes.

Akt/PKB is a serine/threonine kinase, which controls vital cellular functions such as cell survival/apoptosis, cell cycle progression and glucose metabolism. Akt/PKB acts down-stream from growth factors and hormones and is a key mediator of their pro-survival, proliferative and metabolic effects. Akt/PKB carries out these diverse tasks through phosphorylation of a number of cellular substrates. The substrates of Akt/PKB, which promote the inhibition of apoptosis after being phosphorylated by Akt, include the Forkhead transcription factors and the Bcl-2 family member Bad. The cyclin dependent kinase inhibitors are substrates of Akt which when phosphorylated relinquish their inhibitory influence on cell cycle progression. Akt mediates many of the stimulatory effects of insulin on glucose metabolism through deactivation of glycogen synthase kinase, activation of phosphofructokinase, and modulation of glucose transporter activity. Consequently, Akt can be implicated in the pathological processes, which are associated with defects in regulation of apoptosis/survival and energy metabolism.

Animals↗
PubMed2001

The nude gene and the skin.

The nude mutation has been known for a long time. Nevertheless, the gene responsible for the defect has been identified only recently. It encodes a transcriptional activator of the family of forkhead proteins mainly expressed in thymic epithelium and distinct keratinocyte populations in the epidermis and hair follicles. The present review focuses on the molecular and functional characterization of the nude gene and its product and gives an overview as to its role in skin biology and the first identified target genes in the skin. In addition, evolutionary aspects are highlighted stressing the importance of such investigations for a comprehensive understanding of the nude gene product and the regulation of its expression. Furthermore, these studies give a hint as to when the nude gene has occurred first and how it has developed in molecular and functional terms since then.

Alternative Splicing↗
PubMed1998

A mouse model for hereditary thyroid dysgenesis and cleft palate.

Alteration of thyroid gland morphogenesis (thyroid dysgenesis) is a frequent human malformation. Among the one in three to four thousand newborns in which congenital hypothyroidism is detected, 80% have either an ectopic, small and sublingual thyroid, or have no thyroid tissue. Most of these cases appear sporadically, although a few cases of recurring familial thyroid dysgenesis have been described. The lack of evidence for hereditary thyroid dysgenesis may be due to the severity of the hypothyroid phenotype. Neonatal screening and early thyroid hormone therapy have eliminated most of the clinical consequences of hypothyroidism such that the heritability of this condition may become apparent in the near future. We have recently cloned cDNA encoding a forkhead domain-containing transcription factor, TTF-2, and have located the position of the gene, designated Titf2, to mouse chromosome 4 (ref. 3). Titf2 is expressed in the developing thyroid, in most of the foregut endoderm and in craniopharyngeal ectoderm, including Rathke's pouch. Expression of Titf2 in thyroid cell precursors is down-regulated as they cease migration, suggesting that this factor is involved in the process of thyroid gland morphogenesis. Here we show that Titf2-null mutant mice exhibit cleft palate and either a sublingual or completely absent thyroid gland. Thus, mutation of Titf2-/- results in neonatal hypothyroidism that shows similarity to thyroid dysgenesis in humans.

Animals↗
PubMed1998

Mutation of the gene encoding human TTF-2 associated with thyroid agenesis, cleft palate and choanal atresia.

Congenital hypothyroidism occurs in one of every three to four thousand newborns, owing to complete or partial failure of thyroid gland development. Although thyroid hypoplasia has recently been associated with mutations in the thyrotropin (TSH) receptor, the cause of thyroid agenesis is unknown. Proteins including thyroid transcription factors 1 (TTF-1; refs 4,5) and 2 (TTF-2; refs 6,7) and Pax8 (refs 8,9) are abundant in the developing mouse thyroid and are known to regulate genes expressed during its differentiation (for example, thyroid peroxidase and thyroglobulin genes). TTF-2 is a member of the forkhead/winged-helix domain transcription factor family, many of which are key regulators of embryogenesis. Here we report that the transcription factor FKHL15 (ref. 11) is the human homologue of mouse TTF-2 (encoded by the Titf2 gene) and that two siblings with thyroid agenesis, cleft palate and choanal atresia are homozygous for a missense mutation (Ala65Val) within its forkhead domain. The mutant protein exhibits impaired DNA binding and loss of transcriptional function. Our observations represent the first description of a genetic cause for thyroid agenesis.

Abnormalities, Multiple↗
PubMed2001

Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans.

In Caenorhabditis elegans, mutations that reduce the activity of an insulin-like receptor (daf-2) or a phosphatidylinositol-3-OH kinase (age-1) favour entry into the dauer state during larval development and extend lifespan in adults. Downregulation of this pathway activates a forkhead transcription factor (daf-16), which may regulate targets that promote dauer formation in larvae and stress resistance and longevity in adults. In yeast, the SIR2 gene determines the lifespan of mother cells, and adding an extra copy of SIR2 extends lifespan. Sir2 mediates chromatin silencing through a histone deacetylase activity that depends on NAD (nicotinamide adenine dinucleotide) as a cofactor. We have surveyed the lifespan of C. elegans strains containing duplications of chromosomal regions. Here we report that a duplication containing sir-2.1-the C. elegans gene most homologous to yeast SIR2-confers a lifespan that is extended by up to 50%. Genetic analysis indicates that the sir-2.1 transgene functions upstream of daf-16 in the insulin-like signalling pathway. Our findings suggest that Sir2 proteins may couple longevity to nutrient availability in many eukaryotic organisms.

Animals↗
PubMed2001

Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse.

Scurfy (sf) is an X-linked recessive mouse mutant resulting in lethality in hemizygous males 16-25 days after birth, and is characterized by overproliferation of CD4+CD8- T lymphocytes, extensive multiorgan infiltration and elevation of numerous cytokines. Similar to animals that lack expression of either Ctla-4 or Tgf-beta, the pathology observed in sf mice seems to result from an inability to properly regulate CD4+CD8- T-cell activity. Here we identify the gene defective in sf mice by combining high-resolution genetic and physical mapping with large-scale sequence analysis. The protein encoded by this gene (designated Foxp3) is a new member of the forkhead/winged-helix family of transcriptional regulators and is highly conserved in humans. In sf mice, a frameshift mutation results in a product lacking the forkhead domain. Genetic complementation demonstrates that the protein product of Foxp3, scurfin, is essential for normal immune homeostasis.

Amino Acid Motifs↗
PubMed2004

Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body.

In Drosophila melanogaster, ageing is slowed when insulin-like signalling is reduced: life expectancy is extended by more than 50% when the insulin-like receptor (InR) or its receptor substrate (chico) are mutated, or when insulin-producing cells are ablated. But we have yet to resolve when insulin affects ageing, or whether insulin signals regulate ageing directly or indirectly through secondary hormones. Caenorhabditis elegans lifespan is also extended when insulin signalling is inhibited in certain tissues, or when repressed in adult worms, and this requires the forkhead transcription factor (FOXO) encoded by daf-16 (ref. 6). The D. melanogaster insulin-like receptor mediates phosphorylation of dFOXO, the equivalent of nematode daf-16 and mammalian FOXO3a. We demonstrate here that dFOXO regulates D. melanogaster ageing when activated in the adult pericerebral fat body. We further show that this limited activation of dFOXO reduces expression of the Drosophila insulin-like peptide dilp-2 synthesized in neurons, and represses endogenous insulin-dependent signalling in peripheral fat body. These findings suggest that autonomous and non-autonomous roles of insulin signalling combine to control ageing.

Aging↗
PubMed2004

The transcription factor Ifh1 is a key regulator of yeast ribosomal protein genes.

Ribosomal protein (RP) genes in eukaryotes are coordinately regulated in response to growth stimuli and environmental stress, thereby permitting cells to adjust ribosome number and overall protein synthetic capacity to physiological conditions. Approximately 50% of RNA polymerase II transcription is devoted to RP genes. The transcriptional regulator Rap1 binds most yeast RP promoters, and Rap1 sites are important for coordinate regulation of RP genes. However, Rap1 is not the specific regulator that controls RP transcription because it also functions as a repressor, and many Rap1-activated promoters are not coordinately regulated with RP promoters. Here we show that the transcription factors Fhl1 and Ifh1 associate almost exclusively with RP promoters; association depends on Rap1 and (to a lesser extent) a DNA element at many RP promoters. Ifh1 is recruited to promoters via the forkhead-associated (FHA) domain of Fhl1; the level of Ifh1 associated with RP promoters determines the level of transcription; and environmental stress causes a marked reduction in the association of Ifh1, but not Fhl1 or Rap1. Thus, Ifh1 association with promoters is the key regulatory step for coordinate expression of RP genes.

Base Sequence↗
PubMed2004

Growth-regulated recruitment of the essential yeast ribosomal protein gene activator Ifh1.

Regulation of ribosome biogenesis is central to the control of cell growth. In rapidly growing yeast cells, ribosomal protein (RP) genes account for approximately one-half of all polymerase II transcription-initiation events, yet these genes are markedly and coordinately downregulated in response to a number of environmental stress conditions, or during the transition from fermentation to respiration. Although several conserved signalling pathways (TOR, RAS/protein kinase A and protein kinase C) impinge upon RP gene transcription, little is known about how initiation at these genes is controlled. Rap1 (refs 6, 7) and more recently Fhl1 (ref. 8) were shown to bind upstream of many RP genes. Here we show that the essential protein Ifh1 binds to and activates many RP gene promoters under optimal growth conditions in Saccharomyces cerevisiae. Ifh1 is recruited to RP gene promoters through the forkhead-associated domain of Fhl1. Ifh1 binding decreases when RP genes are downregulated either by TOR inhibition or nutrient depletion, and is restored after release from starvation or upon regulated induction of IFH1 expression. These findings indicate a central role for Ifh1 and Fhl1 in RP gene regulation.

Forkhead Transcription Factors↗