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PubMed2006

A stress response pathway involving sirtuins, forkheads and 14-3-3 proteins.

A conserved sir2 deacetylase gene can determine longevity of yeast, flies and worms. Recently we have reported a molecular mechanism of action of the C. elegans homologue sir-2.1. Our study revealed a novel stress-dependent pathway for lifespan determination in which SIR-2.1 binds to 14-3-3 proteins and a forkhead transcription factor DAF-16 to activate transcription of DAF-16 target genes. DAF-16 has long been known as a central protein in the regulation of lifespan that interfaces with multiple pathways. Recent studies by us and other laboratories suggest that DAF-16 requires co-factors for full activity. In this prospective we review recent literature highlighting the role of SIR-2.1, 14-3-3 and other DAF-16 co-factors in DAF-16 activation.

14-3-3 Proteins↗
PubMed2000

Structural basis for the functional difference between Smad2 and Smad3 in FAST-2 (forkhead activin signal transducer-2)-mediated transcription.

Smad2 and Smad3 are signalling proteins that are involved in mediating the transcriptional regulation of target genes downstream of transforming growth factor-beta and activin receptors. Although they are structurally very similar, Smad2 and Smad3 have some functional differences in transducing signals for these receptors. In FAST-2 (forkhead activin signal transducer-2)-mediated transcriptional regulation using the activin-responsive element derived from Xenopus Mix.2 promoter as a reporter, Smad3 but not Smad2 alone was able to stimulate the transcription. In addition, Smad3 was able to inhibit the transactivation of the promoter induced by co-expression of Smad2, Smad4 and an active activin type-I receptor. We used a series of chimaeras between Smad1 and Smad3 and found that the Mad homology 1 (MH1) domain of Smad3 was indispensable for the dual regulatory function of Smad3. However, this Smad3-specific function could not be manifested in Smad2 mutants that were devoid of the two amino acid insertions (at the MH1 domain) that comprise the major structural difference between Smad2 and Smad3, indicating that other structural motifs are involved in determining the regulatory activity of Smad3. By using chimaeras between Smad2 and Smad3, we found that the most N-terminal portion of Smad3 was crucial for its function. Taken together, these results suggest that, as compared with Smad2, the unique function of Smad3 in modulating the FAST-2-mediated transcription is contributed to by a subtle difference in the structural features at the MH1 domain.

Animals↗
PubMed2003

Negative regulation of forkhead transcription factor AFX (Foxo4) by CBP-induced acetylation.

AFX (also called Foxo4), a member of mammalian FOXO forkhead transcription factors, is the homolog of DAF-16, which contributes longevity and oxidative stress in Caenorhabditis elegans. Here, we show that CREB-binding protein (CBP) interacts with AFX via CH1 region and acetylates it at the three lysine residues (K186, K189, and K408). Trichostatin A (TSA) repressed the AFX-stimulated transcription, and substitution of the lysine residues with arginine (K186, 189, 408R) enhanced the transcriptional activity of AFX. Furthermore, TSA suppressed the expression of p27kip1 gene induced by AFX in HEK293T cells. Compared to the coexpression of CBP wild-type, a HAT activity-deficient mutant (DeltaHAT) efficiently leads the cooperative activation of AFX transcription in HepG2 cells. Taken together, these results demonstrate that CBP-induced acetylation of AFX is a novel modification mechanism by which AFX keeps the transcriptional activity mitigating in the nucleus.

Animals↗
PubMed2006

Association of polymorphisms in forkhead box C2 and perilipin genes with bone mineral density in community-dwelling Japanese individuals.

Evidence suggests the existence of a close relation between lipid metabolism and bone remodeling. We hypothesized that polymorphisms of genes that play a role in lipid metabolism, such as those for forkhead box C2 (FOXC2) and perilipin (PLIN), might affect bone mineral density (BMD). We thus examined the possible relationships between a -512C --> T polymorphism of FOXC2 and a 1243C --> T polymorphism of PLIN to BMD in community-dwelling Japanese women and men. The subjects (1129 men, 1114 women for FOXC2; 1122 men, 1112 women for PLIN) were aged 40 to 79 years and were randomly recruited to a population-based prospective cohort study of aging and age-related diseases in Japan. Genotypes for FOXC2 and PLIN were determined with a fluorescence-based allele-specific DNA primer assay system. The -512C --> T polymorphism of FOXC2 was associated with BMD for the distal and proximal radius in men and in premenopausal women as well as with BMD for the distal radius and total body in postmenopausal women, with the T allele being related to reduced BMD. The 1243C --> T polymorphism of PLIN was associated with BMD for the total body, lumbar spine, femoral neck, and trochanter in men, with the C allele being related to reduced BMD. This polymorphism of PLIN was not associated with BMD in all women. These results suggest that FOXC2 is a susceptibility locus for reduced BMD in Japanese men and women, and that PLIN constitutes such a locus in Japanese men.

Absorptiometry, Photon↗
PubMed1993

Drosophila forkhead homologues are expressed in a lineage-restricted manner in human hematopoietic cells.

The forkhead gene (FKH) regulates morphogenesis in Drosophila. It is the prototype of a new family of transcriptional activators. Partially degenerate oligonucleotides to two conserved amino acid sequences of this family were used to prime a polymerase chain reaction (PCR) amplification of HEL cell cDNA. Two unique clones, designated H3 and H8, were isolated that contained homologies to FKH. A third novel clone, 5-3, was isolated by low stringency screening of a chronic myelogenous leukemia cDNA library using H8 as a probe. H3 and 5-3 are preferentially expressed in restricted hematopoietic lineages, while the expression of H8 was ubiquitous. Southern analysis showed that FKH 5-3 is conserved through yeast, which is rare among tissue-specific transcription factors. The H3 and 5-3 clones provide evidence that FKH family members are present in a tissue-restricted manner in humans.

Amino Acid Sequence↗
PubMed1997

AF6q21, a novel partner of the MLL gene in t(6;11)(q21;q23), defines a forkhead transcriptional factor subfamily.

Fusion genes implicating the MLL gene have been recently demonstrated in various 11q23 chromosomal abnormalities in human hematopoietic malignancies. We analyzed a t(6;11)(q21;q23) translocation detected in a secondary acute myeloblastic leukemia. This translocation results in fusion of the MLL gene on 11q23 to a previously unknown gene on chromosome 6 that differs from the previously reported MLL partner gene AF6q. The novel gene, named AF6q21, encodes a forkhead (FH) protein with strong similarities to the two FH family members whose genes are already known to be involved in chromosomal translocations of human malignancies, AFX and FKHR. Strikingly, in these translocations the breakpoints are located at the same position within the FH domains. Therefore, AF6q21, AFX, and FKHR could define a new FH subfamily particularly involved in human malignancies.

Amino Acid Sequence↗
PubMed1996

Molecular cloning of the forkhead transcription factor HNF-3 alpha from a human pulmonary adenocarcinoma cell line.

We have cloned the human homologue of HNF-3 alpha from the pulmonary adenocarcinoma cell line NCI-H441. Full-length HNF-3 alpha which was found to be 2872 bp encoded a protein of 473 amino acids. The human protein is highly related to the rat and mouse homologues and the forkhead DNA binding domain is highly conserved between all species yet identified. Northern blotting with a variety of human-derived cell lines identified a single 3 kb mRNA species. RNA levels are > 10-fold higher in the H441 cells than in any of the others.

Adenocarcinoma↗
PubMed2004

TIFAB inhibits TIFA, TRAF-interacting protein with a forkhead-associated domain.

Tumor necrosis factor receptor-associated factor 6 (TRAF6) transduces signals that lead to activation of NFkappaB and AP-1, which is essential for cell differentiation and establishment of the immune and inflammatory systems. TRAF-interacting protein with a forkhead-associated domain (TIFA) was identified as a TRAF6-binding protein that could link IRAK-1 to TRAF6 and then activate TRAF6 upon stimulation. We report identification of a TIFA-related protein, TIFAB, that inhibits TIFA-mediated activation of NFkappaB. TIFAB does not associate with members of the TRAF family but does bind TIFA. We analyzed the effect of TIFAB expression on the TRAF6/TIFA interaction by immunoprecipitation of TRAF6 and found that TIFA coprecipitated with TRAF6 was not changed. However, when we analyzed this interaction by immunoprecipitation of TIFA, we found that TIFAB significantly increased the amount of TRAF6 coprecipitated with TIFA. These findings suggest that TIFAB inhibits the TIFA-mediated TRAF6 activation possibly by inducing a conformational change in TIFA.

Amino Acid Sequence↗
PubMed2005

Chromosome-wide mapping of estrogen receptor binding reveals long-range regulation requiring the forkhead protein FoxA1.

Estrogen plays an essential physiologic role in reproduction and a pathologic one in breast cancer. The completion of the human genome has allowed the identification of the expressed regions of protein-coding genes; however, little is known concerning the organization of their cis-regulatory elements. We have mapped the association of the estrogen receptor (ER) with the complete nonrepetitive sequence of human chromosomes 21 and 22 by combining chromatin immunoprecipitation (ChIP) with tiled microarrays. ER binds selectively to a limited number of sites, the majority of which are distant from the transcription start sites of regulated genes. The unbiased sequence interrogation of the genuine chromatin binding sites suggests that direct ER binding requires the presence of Forkhead factor binding in close proximity. Furthermore, knockdown of FoxA1 expression blocks the association of ER with chromatin and estrogen-induced gene expression demonstrating the necessity of FoxA1 in mediating an estrogen response in breast cancer cells.

Animals↗
PubMed2004

Isolation and characterization of five Fox (Forkhead) genes from the sponge Suberites domuncula.

Fox or Forkhead genes constitute a subgroup of the helix-turn-helix class of transcription factors with a characteristic and highly conserved DNA binding domain. To date, around 100 different Fox genes have been reported ranging from yeast to humans; these have been classified into 18 subclasses (A to P). Fox proteins are responsible for a wide range of functions and key roles in early developmental processes, during organogenesis and also for the function of the major organs and tissues in the adult. Here, we report the isolation and phylogenetic characterization of five members of the Fox family from the sponge Suberites domuncula. Four of them (Sd-FoxL2, Sd-FoxP, Sd-FoxD and Sd-FoxF) fall in the root of four of the already established families of vertebrates Fox, suggesting that in sponges, the basal group of metazoans, the main groups of Fox proteins were already established. We also demonstrate that they are differentially regulated during the culture of sponge cells.

Animals↗
PubMed2004

Cloning and characterization of a forkhead transcription factor gene, FoxO1a, from thirteen-lined ground squirrel.

This research analyzes the regulation of ischemic tolerance in hibernating thirteen-lined ground squirrels (Spermophilus tridecemlineatus). Hibernation is studied because it represents a unique state of reversible suspended animation associated with tolerance to an otherwise lethal reduction of core body temperature and metabolism. An integral aspect of hibernation is the profound decrease of cerebral perfusion without neurological damage. As such, hibernation serves as a model for studying natural tolerance to brain ischemia. Identification of regulatory mechanisms that control hibernation in ground squirrels may guide efforts to develop improved treatments for stroke and brain trauma. It was previously shown that phosphorylation of Akt (protein kinase B), an insulin-like growth factor-regulated serine/threonine kinase, was significantly reduced as was its kinase activity in hibernating thirteen-lined ground squirrels. Here we studied the forkhead (FH) in rhabdomyosarcoma (FKHR) transcription factor, which is controlled by Akt signaling and is involved in regulating cell cycle progression and cell death. A cDNA derived from brains of S. tridecemlineatus, encoding a specific FKHR transcription factor, FoxO1a, was cloned and sequenced, and the amino acid sequence of the protein was deduced. FoxO1a is composed of 653 amino acids and has a predicted molecular mass of 69.4 kilodaltons (kDa). Here, for the first time, we report the contrary expression of phosphorylation of two members in the insulin-like growth factor signaling pathway during hibernation (i.e., phosphorylated FKHR was significantly up-regulated as phosphorylation of its upstream kinase, Akt, was significantly down-regulated). Further study is required to identify the possible connection between FoxO1a and Akt activity and the possible of such interactions in hibernation.

Animals↗
PubMed2004

An early pharyngeal muscle enhancer from the Caenorhabditis elegans ceh-22 gene is targeted by the Forkhead factor PHA-4.

Caenorhabditis elegans pharyngeal muscle development involves ceh-22, an NK-2 family homeobox gene related to genes controlling heart development in other species. ceh-22 is the earliest known gene expressed in the pharyngeal muscles and is likely regulated directly by factors specifying pharyngeal muscle fate. We have previously implicated the ceh-22 distal enhancer in initiating ceh-22 expression. Here we analyze the distal enhancer using functional and comparative assays. The distal enhancer contains three subelements contributing additively to its activity, and functionally important regulatory sequences are highly conserved in Caenorhabditis briggsae. One subelement, termed DE3, is strongly active in the pharyngeal muscles, and we identified two short oligonucleotides (de199 and de209) contributing to DE3 activity. Multimerized de209 enhances transcription similarly to DE3 specifically in the pharyngeal muscles, suggesting it may be an essential site regulating ceh-22. de209 binds the pan-pharyngeal Forkhead factor PHA-4 in vitro and responds to ectopic pha-4 expression in vivo, suggesting that PHA-4 directly initiates ceh-22 expression through de209. Because de209 enhancer activity is primarily limited to the pharyngeal muscles, we hypothesize that de209 also binds factors functioning with PHA-4 to specifically activate ceh-22 expression in pharyngeal muscle.

Animals↗
PubMed1999

The forkhead gene FH1 is involved in evolutionary modification of the ascidian tadpole larva.

The forkhead gene FH1 encodes a HNF-3beta protein required for gastrulation and development of chordate features in the ascidian tadpole larva. Although most ascidian species develop via a tadpole larva, the conventional larva has regressed into an anural (tailless) larva in some species. Molgula oculata (the tailed species) exhibits a tadpole larva with chordate features (a dorsal neural sensory organ or otolith, a notochord, striated muscle cells, and a tail), whereas its sister species Molgula occulta (the tailless species) has evolved an anural larva, which has lost these features. Here we examine the role of FH1 in modifying the larval body plan in the tailless species. We also examine FH1 function in tailless speciesxtailed species hybrids, in which the otolith, notochord, and tail are restored. The FH1 gene is expressed primarily in the presumptive endoderm and notochord cells during gastrulation, neurulation, and larval axis formation in both species and hybrids. In the tailless species, FH1 expression is down-regulated after neurulation in concert with arrested otolith, notochord, and tail development. The FH1 expression pattern characteristic of the tailed species is restored in hybrid embryos prior to the development of chordate larval features. Antisense oligodeoxynucleotides (ODNs) shown previously to disrupt FH1 function were used to compare the developmental roles of this gene in both species and hybrids. As described previously, antisense FH1 ODNs inhibited endoderm invagination during gastrulation, notochord extension, and larval tail formation in the tailed species. Antisense FH1 ODNs also affected gastrulation in the tailless species, although the effects were less severe than in the tailed species, and an anural larva was formed. In hybrid embryos, antisense FH1 ODNs blocked restoration of the otolith, notochord, and tail, reverting the larva back to the anural state. The results suggest that changes in FH1 expression are involved in re-organizing the tadpole larva during the evolution of anural development.

Amino Acid Sequence↗
PubMed2000

Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1.

Cell death is regulated mainly through an evolutionarily conserved form of cell suicide termed apoptosis [1]. Deregulation of apoptosis has been associated with cancer, autoimmune diseases and degenerative disorders. Many cells, particularly those of the hematopoietic system, have a default program of cell death and survival that is dependent on the constant supply of survival signals. The Bcl-2 family, which has both pro- and anti-apoptotic members, plays a critical role in regulating cell survival [2]. One family member, the Bcl-2 interacting mediator of cell death (Bim), contains only a protein-interaction motif known as the BH3 domain, allowing it to bind pro-survival Bcl-2 molecules, neutralizing their function [3]. Disruption of the bim gene results in resistance to apoptosis following cytokine withdrawal in leukocytes, indicating that regulation of the pro-apoptotic activity of Bim is critical for maintenance of the default apoptotic program [4]. Here, we report that withdrawal of cytokine results in upregulation of Bim expression concomitant with induction of the apoptotic program in lymphocytes. Activation of the forkhead transcription factor FKHR-L1, previously implicated in regulation of apoptosis in T lymphocytes [5], was sufficient to induce Bim expression. We propose a mechanism by which cytokines promote lymphocyte survival by inhibition of FKHR-L1, preventing Bim expression.

Apoptosis↗
PubMed2002

Cell cycle and death control: long live Forkheads.

The FOXO family of Forkhead transcription factors, FKHR (FOXO1), FKHR-L1 (FOXO3a) and AFX (FOXO4), are regulated by the phosphoinositide-3-kinase-protein-kinase-B (PI3K-PKB/c-Akt) pathway. Direct phosphorylation by PKB results in cytoplasmic retention and inactivation, inhibiting the expression of FOXO-regulated genes, which control the cell cycle, cell death, cell metabolism and oxidative stress. This pathway appears to be well conserved throughout evolution. In the nematode Caenorhabditis elegans, it affects lifespan and controls dauer formation. Recent discoveries about FOXO regulation by PI3K-PKB signalling suggest that the PI3K-PKB-FOXO pathway might participate in similar processes in higher eukaryotes.

Animals↗
PubMed2003

Elevated hepatocyte levels of the Forkhead box A2 (HNF-3beta) transcription factor cause postnatal steatosis and mitochondrial damage.

The Forkhead box (Fox) transcription factor Foxa2 (HNF-3beta) and related family members Foxa1 (HNF-3alpha) and Foxa3 (HNF-3gamma) act in concert with other hepatocyte nuclear factors (HNF) to coordinately regulate liver-specific gene expression. To circumvent the hepatic functional redundancy of the Foxa proteins, we used the T-77 transgenic (TG) mouse line in which the -3-kb transthyretin (TTR) promoter functioned to increase hepatocyte expression of the Foxa2 cDNA. Adult TG mice exhibited reduced hepatic glycogen and progressive liver injury, but maintained normal serum levels of glucose, insulin, and glucagon. In this study, we further characterized the postnatal liver defect in TTR-FoxA2 TG mice. The postnatal TG mice displayed significant reduction in serum glucose levels and in hepatocyte glycogen storage without increased serum levels of ketone bodies and free fatty acid suggesting that they are not undergoing a starvation response. We show that TG liver developed a substantial transient steatosis, which reached a maximum at postnatal day 5 and is associated with increased expression of hepatic genes involved in fatty acid and triglyceride synthesis, lipid beta-oxidation, and amino acid biosynthesis. Furthermore, transmission electron microscopy analysis of postnatal TG liver revealed extensive mitochondrial membrane damage, which is likely due to reactive oxygen species generated from lipid beta-oxidation. In conclusion, our model proposes that in response to reduction in hepatocyte glycogen storage, the TTR-Foxa2 TG mice survive by maintaining sufficient serum levels of glucose through gluconeogenesis using deaminated amino acids with dicarboxylate products of peroxisomal lipid beta-oxidation shuttled through the tricarboxylic acid cycle.

Animals↗
PubMed2005

Enhancer-binding proteins with a forkhead-associated domain and the sigma54 regulon in Myxococcus xanthus fruiting body development.

In response to starvation, Myxococcus xanthus initiates a developmental program that results in the formation of spore-filled, multicellular fruiting bodies. Many developmentally regulated genes in M. xanthus are transcribed from sigma(54) promoters, and these genes require enhancer-binding proteins. Here we report the finding of an unusual group of 12 genes encoding sigma(54)-dependent enhancer-binding proteins containing a forkhead-associated (FHA) domain as their N-terminal sensory domain. FHA domains in other proteins recognize phosphothreonine residues. An insertion mutation in one of these genes, Mx4885, caused a cell autonomous aggregation and sporulation defect. In-frame deletion mutants showed that the FHA domain is necessary for proper Mx4885 function. The altered pattern of developmental gene expression in the mutant implied that Mx4885 is on the pathway of response to the morphogenetic C-signal. Immunoblots specific for C-signal and FruA imply that the site of Mx4885 action is downstream of FruA synthesis on the C-signal transduction pathway. Mx4885 may help to coordinate the level of intracellular phosphorylated FruA (FruA-P) with the level of C-signal displayed on the signal donor cell. Because FHA domains respond to phosphothreonine-containing proteins, these results suggest a regulatory link to the abundant Ser/Thr protein kinases in M. xanthus.

Amino Acid Sequence↗
PubMed2003

Cytokines and BCR-ABL mediate suppression of TRAIL-induced apoptosis through inhibition of forkhead FOXO3a transcription factor.

Cytokine-provided survival signals are known to suppress apoptosis through inhibition of mitochondrial pathways that involve Bcl-2 family members. Here we show that in hematopoietic cells, cytokines also regulate death receptor-mediated pathways. We demonstrate that hematopoietic cytokines such as IL-3 and erythropoietin in normal cells, as well as BCR-ABL oncoprotein in transformed cells, inhibit transcription of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Using small interfering RNAs, we show that the inhibition of TRAIL function is sufficient to partially rescue cytokine-deprived cells from apoptosis. Finally, we demonstrate that cytokine and BCR-ABL suppression of TRAIL transcription is mediated through phosphorylation and inhibition of the forkhead FOXO3a transcription factor. BCR-ABL-induced inhibition of TRAIL transcription in hematopoietic cells may provide a novel mechanism for tumorigenicity in chronic myeloid leukemia.

Apoptosis↗