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PubMed2000

FHA domain boundaries of the dun1p and rad53p cell cycle checkpoint kinases.

Dun1p and Rad53p of the budding yeast Saccharomyces cerevisiae are members of a conserved family of cell cycle checkpoint protein kinases that contain forkhead-associated (FHA) domains. Here, we demonstrate that these FHA domains contain 130-140 residues, and are thus considerably larger than previously predicted by sequence comparisons (55-75 residues). In vivo, expression of the proteolytically defined Dun1p FHA domain, but not a fragment containing only the predicted domain boundaries, inhibited the transcriptional induction of repair genes following replication blocks. This indicates that the non-catalytic FHA domain plays an important role in the transcriptional function of the Dun1p protein kinase.

Amino Acid Sequence↗
PubMed2002

The FHA domain.

The forkhead-associated (FHA) domain is a small protein module recently shown to recognize phosphothreonine epitopes on proteins. It is present in a diverse range of proteins in eukaryotic cells, such as kinases, phosphatases, kinesins, transcription factors, RNA-binding proteins, and metabolic enzymes. It is also found in a number of bacterial proteins. This suggests that FHA domain-mediated phospho-dependent assembly of protein complexes is an ancient and widespread regulatory mechanism.

Amino Acid Sequence↗
PubMed1999

TTF-1 and HNF-3beta in the developing tracheoesophageal fistula: further evidence for the respiratory origin of the distal esophagus'.

PURPOSE: Using an established rat model of esophageal atresia with tracheoesophageal fistula (EA-TEF), the authors have studied the organogenesis of this congenital anomaly. The authors previously have proposed that the "distal esophagus" actually is of respiratory lineage. In this report this hypothesis is tested by examining the expression of two foregut patterning transcription factors, thyroid transcription factor-1 (TTF-1) and hepatocyte nuclear factor-3beta (HNF-3beta), within the developing TEF. METHODS: Pregnant Sprague-Dawley rats were injected with 2.2 mg/kg of Adriamycin intraperitoneally on days 6 to 9 of gestation. Using microdissection, the trachea, blind-ending esophagus, TEF, and stomach were isolated from embryos of various gestional ages. Immunohistochemistry was performed using polyclonal antibodies to TTF-1 and HNF-3beta. RESULTS: TTF-1 is a homeodomain protein that previously has been shown to be expressed in the lung and trachea but not in the gastrointestinal tract, and which, when deleted in a developing lung, results in a mouse with no peripheral lung parenchyma. TTF-1 was expressed strongly in the lung, fistula, and distal esophagus, but not in the proximal esophagus. HNF-3beta is a forkhead transcription factor important in foregut patterning that binds and activates the TTF-1 promotor sequence. HNF-3beta was expressed globally in the fistula and lung as well as the esophagus. CONCLUSIONS: The expression of the lung-specific transcription factor TTF-1 within the TEF strongly implies that the "distal esophagus" is a respiratory-derived structure and thus supports our theory of TEF organogenesis. The conservation of HNF-3beta expression both in the TEF as well as the normal developing trachea and esophagus suggests that global foregut patterning is intact in the formation of this anomaly, and the defect lies at the level of the respiratory versus gastrointestinal commitment.

Animals↗
PubMed2002

Infrequent occurrence of age-dependent changes in CpG island methylation as detected by restriction landmark genome scanning.

Hypermethylation of CpG islands, resulting in the inactivation of tumor suppressor genes, is an early event in the development of some malignancies. Recent studies suggest that this abnormal methylation may be a function of aging. The number of CpG islands that methylate with age is unknown. We used restriction landmark genome scanning (RLGS) to approximate the extent to which CpG islands change methylation status during aging. Comparison of more than 2000 loci in T lymphocytes isolated from newborn, middle age, and elderly people revealed that 29 loci ( approximately 1%) changed methylation status during aging, with 23 increasing methylation, and six decreasing. The same subset also changed methylation status with age in the esophagus, lung, and pancreas, but in variable directions. Virtual genome scanning identified one of these loci as a member of the forkhead family, recently implicated in aging, and another as an EST fragment. The methylation status of both correlated with level of expression. Confirming studies in multiple tissues from normal and DNMT1(+/-) mice demonstrated only one age dependent change in the methylation of more than 2000 loci, occurring in liver and kidney. These results indicate that the methylation status of the majority of CpG islands in both mice and humans is tightly controlled during aging, and that changes are infrequent and in humans confined to a specific subset of genes.

Adult↗
PubMed2006

Immunodeficiencies with autoimmune consequences.

Far from being mutually exclusive, immunodeficiency and autoimmunity may occur simultaneously. During the last years, analysis of Autoimmune Polyendocrinopathy--Candidiasis--Ectodermal Dystrophy (APECED) and Immunodysregulation--Polyendocrinopathy--Enteropathy--X-linked (IPEX), two rare monogenic forms of immunodeficiency associated with autoimmunity, has led to the identification of Auto Immune Regulator (AIRE) and Forkhead Box P3 (FOXP3), essential transcriptional regulators, involved in central tolerance and peripheral immune homeostasis, respectively. Characterization of the molecular and cellular mechanisms involved in APECED, and recognition that AIRE expression is sustained by effective thymopoiesis, has recently allowed to define that the autoimmunity of Omenn syndrome, a combined immunodeficiency due to defects of V(D)J recombination, also results from defective expression of AIRE. The implications of identification of the basis of autoimmunity in these rare forms of immunodeficiency have important implications for a better understanding of more common autoimmune disorders, and for development of novel therapeutic approaches.

Animals↗
PubMed2004

Regulation of sensitivity to TRAIL by the PTEN tumor suppressor.

The ability of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to induce apoptosis preferentially in cancer cells is attractive for its development as a novel cancer therapeutic agent, but many cancer cell lines are resistant to TRAIL. While the molecular basis for TRAIL resistance is not always clear, a number of factors have been proposed to mediate TRAIL resistance, including decoy receptor, c-FLIP, nuclear factor (NF)-kappaB, and activation of antiapoptotic kinase signaling. Many growth factor receptors mediate their survival signals through the pathway involving recruitment and activation of phosphatidylinositol (PI) 3-kinase and the serine?threonine kinase Akt. The PTEN tumor suppressor is a phosphatase that dephosphorylates the phospholipids phosphorylated by PI-3 kinase, thereby opposing the action of PI 3-kinase, and acts as the primary negative regulator of the PI-3 kinase?Akt pathway in the cell. Loss of PTEN function occurs frequently in human tumors and leads to constitutive activation of Akt in cancer cells. Constitutively active Akt protects cells from TRAIL-induced apoptosis in multiple tumor types. Growth factors such as epidermal growth factor or insulin-like growth factor-1 also inhibit TRAIL-induced apoptosis through the Akt pathway. Akt exerts its antiapoptotic function by its ability to phosphorylate many key components of the cellular apoptotic regulatory circuit, such as BAD, MDM2, FOXO Forkhead transcription factors, and PED?PEA-15 as well as by its role in activating NF-kappaB. Because PTEN loss is common in tumors, strategies to inactivate Akt may be necessary to overcome TRAIL resistance and make TRAIL-based therapy more effective.

Animals↗
PubMed1998

Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome.

Nijmegen breakage syndrome (NBS) is an autosomal recessive chromosomal instability syndrome characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition. Cells from NBS patients are hypersensitive to ionizing radiation with cytogenetic features indistinguishable from ataxia telangiectasia. We describe the positional cloning of a gene encoding a novel protein, nibrin. It contains two modules found in cell cycle checkpoint proteins, a forkhead-associated domain adjacent to a breast cancer carboxy-terminal domain. A truncating 5 bp deletion was identified in the majority of NBS patients, carrying a conserved marker haplotype. Five further truncating mutations were identified in patients with other distinct haplotypes. The domains found in nibrin and the NBS phenotype suggest that this disorder is caused by defective responses to DNA double-strand breaks.

Amino Acid Sequence↗
PubMed2004

Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy.

Skeletal muscle atrophy is a debilitating response to fasting, disuse, cancer, and other systemic diseases. In atrophying muscles, the ubiquitin ligase, atrogin-1 (MAFbx), is dramatically induced, and this response is necessary for rapid atrophy. Here, we show that in cultured myotubes undergoing atrophy, the activity of the PI3K/AKT pathway decreases, leading to activation of Foxo transcription factors and atrogin-1 induction. IGF-1 treatment or AKT overexpression inhibits Foxo and atrogin-1 expression. Moreover, constitutively active Foxo3 acts on the atrogin-1 promoter to cause atrogin-1 transcription and dramatic atrophy of myotubes and muscle fibers. When Foxo activation is blocked by a dominant-negative construct in myotubes or by RNAi in mouse muscles in vivo, atrogin-1 induction during starvation and atrophy of myotubes induced by glucocorticoids are prevented. Thus, forkhead factor(s) play a critical role in the development of muscle atrophy, and inhibition of Foxo factors is an attractive approach to combat muscle wasting.

Adenoviridae↗
PubMed2004

FoxOs at the crossroads of cellular metabolism, differentiation, and transformation.

Forkhead transcription factors of the FoxO subfamily are emerging as a shared component among pathways regulating diverse cellular functions, such as differentiation, metabolism, proliferation, and survival. Their transcriptional output is controlled via a two-tiered mechanism of phosphorylation and acetylation. Modest alterations of this balance can result in profound effects. The gamut of phenotypes runs from protection against diabetes and predisposition to neoplasia, conferred by FoxO loss of function, to increased cellular survival and a marked catabolic response associated with gain of function.

Acetylation↗
PubMed2003

Nicotinamide: necessary nutrient emerges as a novel cytoprotectant for the brain.

Although usually identified as an essential cellular nutrient for cellular growth and maintenance, nicotinamide is under development as a novel cytoprotectant for acute and chronic neurodegenerative disorders. Here, we outline support for the premise that nicotinamide both prevents and reverses neuronal and vascular cell injury. Nicotinamide fosters DNA integrity and maintains phosphatidylserine membrane asymmetry to prevent cellular inflammation, cellular phagocytosis and vascular thrombosis. The downstream cellular and molecular cascades are considered vital for the cytoprotection offered by nicotinamide. These pathways encompass the modulation of Akt, the forkhead transcription factor FKHRL1, mitochondrial membrane potential, caspase activities and cellular energy metabolism, but remain independent of intracellular pH and mitogen-activated protein kinases. As both a therapeutic agent and an investigational tool, nicotinamide offers new therapeutic strategies for degenerative disorders of the CNS.

Animals↗
PubMed2004

In silico analysis of the sigma54-dependent enhancer-binding proteins in Pirellula species strain 1.

The planctomycetes are a phylogenetically distinct group of bacteria, widespread in aquatic and terrestrial environments. Their cell walls lack peptidoglycan and their compartmentalised cells undergo a yeast-like budding cell division process. Many bacteria regulate a subset of their genes by an enhancer-dependent mechanism involving the alternative sigma factor sigma54 (RpoN, sigmaN) in association with sigma54-dependent transcriptional activators known as enhancer-binding proteins (EBPs). The sigma54-dependent regulon has previously been studied in several groups of bacteria, but not in the planctomycetes. We wished to exploit the recently published complete genome sequence of Pirellula species strain 1 to predict and analyse the sigma54-dependent regulon in this interesting group of bacteria. The genome of Pirellula species strain 1 encodes one homologue of sigma54, and 16 sigma54-dependent EBPs, including 10 two-component response regulators and a homologue of Escherichia coli RtcR. Two EBPs contain forkhead-associated domains, representing a novel protein domain combination not previously observed in bacterial EBPs and suggesting a novel link between the enhancer-dependent regulon and 'eukaryotic-like' protein phosphorylation in bacterial signal transduction. We identified several potential sigma54-dependent promoters upstream of genes and operons including two homologues of csrA, which encodes the global regulator CsrA, and rtcBA, encoding a RNA 3'-terminal phosphate cyclase. Phylogenetic analysis of EBP sequences from a wide range of bacterial taxa suggested that planctomycete EBPs fall into several distinct clades. Also the phylogeny of the sigma54 factors is broadly consistent with that of the host organisms. These results are consistent with a very ancient origin of sigma54 within the bacterial lineage. The repertoire of functions predicted to be under the control of the sigma54-dependent regulon in Pirellula shares some similarities (e.g. rtcBA) as well as exhibiting differences with that in other taxonomic groups of bacteria, reinforcing the evolutionarily dynamic nature of this regulon.

Bacteria↗
PubMed2003

Cloning and analysis of a FoxO transcription factor from Xiphophorus.

Melanoma development in the fish Xiphophorus is determined, at least in part, by overexpression and activation of the Xmrk-2 oncogene, which triggers a variety of signal transduction pathways resulting in altered cell cycle control. We have begun analysing transcription factors which may link Xmrk-2 with regulation of cell proliferation or apoptosis. Towards this end, we have cloned an FKHR (FoxO sub-family) homolog from Xiphophorus maculatus. The isolated clone is a 2.7 kb cDNA encoding a predicted protein of 664 amino acids. The gene, which we have named FoxO5, maps to Xiphophorus Linkage Group XV. The protein product can be categorized within a branch of the FOXO sub-class, which includes: Danio rerio zFKHR (foxo5), Homo sapiens FKHR-L1 (FoxO3a) and Mus musculus FKHR2 (Foxo3). Notably, the Forkhead DNA binding domain, three Akt consensus phosphorylation sites and a carboxy-terminal minimal activation domain are each highly conserved. A mutated FoxO5 protein with disrupted Akt phosphorylation sites inhibits proliferation, but the wild-type protein fails to do so, when exogenously expressed in Xiphophorus cells derived from a melanoma. The same mutated protein predominantly localizes to the nucleus, yet the wild-type protein seldom does. Further characterization of Xiphophorus FoxO5 will contribute to understanding the molecular basis of carcinogenesis in these species.

Animals↗
PubMed2000

A nodal signaling pathway regulates the laterality of neuroanatomical asymmetries in the zebrafish forebrain.

Animals show behavioral asymmetries that are mediated by differences between the left and right sides of the brain. We report that the laterality of asymmetric development of the diencephalic habenular nuclei and the photoreceptive pineal complex is regulated by the Nodal signaling pathway and by midline tissue. Analysis of zebrafish embryos with compromised Nodal signaling reveals an early role for this pathway in the repression of asymmetrically expressed genes in the diencephalon. Later signaling mediated by the EGF-CFC protein One-eyed pinhead and the forkhead transcription factor Schmalspur is required to overcome this repression. When expression of Nodal pathway genes is either absent or symmetrical, neuroanatomical asymmetries are still established but are randomized. This indicates that Nodal signaling is not required for asymmetric development per se but is essential to determine the laterality of the asymmetry.

Animals↗
PubMed1998

BMP-2 induces ectopic expression of cardiac lineage markers and interferes with somite formation in chicken embryos.

In Drosophila induction of the homeobox gene tinman and subsequent heart formation are dependent on dpp signaling from overlying ectoderm. In order to define vertebrate heart-inducing signals we screened for dpp-homologues expressed in HH stage 4 chicken embryos. The majority of transcripts were found to be BMP-2 among several other members of the BMP family. From embryonic HH stage 4 onwards cardiogenic mesoderm appeared to be in close contact to BMP-2 expressing cells which initially were present in lateral mesoderm and subsequently after headfold formation in the pharyngeal endoderm. In order to assess the role of BMP-2 for heart formation, gastrulating chick embryos in New culture were implanted with BMP-2 producing cells. BMP-2 implantation resulted in ectopic cardiac mesoderm specification. BMP-2 was able to induce Nkx2-5 expression ectopically within the anterior head domain, while GATA-4 was also induced more caudally. Cardiogenic induction by BMP-2, however remained incomplete, since neither Nkx2-8 nor the cardiac-restricted structural gene VMHC-1 became ectopically induced. BMP-2 expressing cells implanted adjacent to paraxial mesoderm resulted in impaired somite formation and blocked the expression of marker genes, such as paraxis, Pax-3, and the forkhead gene cFKH-1. These results suggest that BMP-2 is part of the complex of cardiogenic signals and is involved in the patterning of early mesoderm similar to the role of dpp in Drosophila.

Animals↗
PubMed1999

A double interaction screen identifies positive and negative ftz gene regulators and ftz-interacting proteins.

Regulatory genes directing embryonic development are expressed in complex patterns. The Drosophila homeobox gene fushi tarazu (ftz) is expressed in a striped pattern that is controlled by several discrete and large cis- regulatory elements. One key cis-element is the ftz proximal enhancer which is required for stripe establishment and which mediates autoregulation by direct binding of Ftz protein. To identify the trans-acting factors that regulate ftz expression and autoregulation, we developed a modified yeast two hybrid screen, the Double Interaction Screen (DIS). The DIS was designed to isolate both DNA binding transcriptional regulators that interact with the proximal enhancer and proteins that interact with Ftz itself when it is bound to the enhancer. The screen identified two candidate Ftz protein cofactors as well as activators and repressors of ftz transcription that bind directly to the enhancer. One of these (Tramtrack (Ttk)) was previously shown to bind to at least five sites in the proximal enhancer; genetic studies suggested that Ttk acts as a repressor of ftz in the embryo. Here we show that, in yeast cells, Ttk protein strongly activates transcription, suggesting that yeast may be missing a necessary co-repressor which is present in Drosophila embryos. Further, we have characterized the activity of a second candidate ftz repressor isolated in the screen - the product of the pair-rule gene sloppy paired - a member of the forkhead family. We show that Slp1 is a DNA binding protein. We have identified a high affinity binding site for Slp1 in the ftz proximal enhancer. Slp1 represses transcription via this binding site in yeast cells, consistent with its role as a direct repressor of ftz stripes in interstripe regions during late stages of embryogenesis. The DIS should be a generally useful method to identify DNA binding transcriptional regulators and protein partners of previously characterized DNA binding proteins.

Animals↗
PubMed2000

The molecular basis of lung morphogenesis.

To form a diffusible interface large enough to conduct respiratory gas exchange with the circulation, the lung endoderm undergoes extensive branching morphogenesis and alveolization, coupled with angiogenesis and vasculogenesis. It is becoming clear that many of the key factors determining the process of branching morphogenesis, particularly of the respiratory organs, are highly conserved through evolution. Synthesis of information from null mutations in Drosophila and mouse indicates that members of the sonic hedgehog/patched/smoothened/Gli/FGF/FGFR/sprouty pathway are functionally conserved and extremely important in determining respiratory organogenesis through mesenchymal-epithelial inductive signaling, which induces epithelial proliferation, chemotaxis and organ-specific gene expression. Transcriptional factors including Nkx2.1, HNF family forkhead homologues, GATA family zinc finger factors, pou and hox, helix-loop-helix (HLH) factors, Id factors, glucocorticoid and retinoic acid receptors mediate and integrate the developmental genetic instruction of lung morphogenesis and cell lineage determination. Signaling by the IGF, EGF and TGF-beta/BMP pathways, extracellular matrix components and integrin signaling pathways also directs lung morphogenesis as well as proximo-distal lung epithelial cell lineage differentiation. Soluble factors secreted by lung mesenchyme comprise a 'compleat' inducer of lung morphogenesis. In general, peptide growth factors signaling through cognate receptors with tyrosine kinase intracellular signaling domains such as FGFR, EGFR, IGFR, PDGFR and c-met stimulate lung morphogenesis. On the other hand, cognate receptors with serine/threonine kinase intracellular signaling domains, such as the TGF-beta receptor family are inhibitory, although BMP4 and BMPR also play key inductive roles. Pulmonary neuroendocrine cells differentiate earliest in gestation from among multipotential lung epithelial cells. MASH1 null mutant mice do not develop PNE cells. Proximal and distal airway epithelial phenotypes differentiate under distinct transcriptional control mechanisms. It is becoming clear that angiogenesis and vasculogenesis of the pulmonary circulation and capillary network are closely linked with and may be necessary for lung epithelial morphogenesis. Like epithelial morphogenesis, pulmonary vascularization is subject to a fine balance between positive and negative factors. Angiogenic and vasculogenic factors include VEGF, which signals through cognate receptors flk and flt, while novel anti-angiogenic factors include EMAP II.

Animals↗
PubMed2000

Conserved and divergent genes in apex and axis development of cnidarians.

Despite their radial organization and their sister group position in the life tree, cnidarian species express during morphogenesis a large number of genes that are related to bilaterian developmental genes. Among those, homologs to forkhead, emx, aristaless, goosecoid, brachyury, wnt and nanos genes are regulated during apical patterning in cnidarians, suggesting that key components of early organizer activity were conserved across evolution and recruited for either anterior, axial, or dorso-ventral patterning in bilaterians. In contrast, the expression patterns of the cnidarian Hox-related genes suggest that the apical-basal axis of the cnidarian polyp and the anterior-posterior axis of bilaterians do not differentiate following homologous processes.

Animals↗
PubMed1999

Induction of NF-kappaB by the Akt/PKB kinase.

The serine/threonine kinase Akt (also known as protein kinase B, PKB) is activated by numerous growth-factor and immune receptors through lipid products of phosphatidylinositol (PI) 3-kinase. Akt can couple to pathways that regulate glucose metabolism or cell survival [1]. Akt can also regulate several transcription factors, including E2F, CREB, and the Forkhead family member Daf-16 [2] [3] [4]. Here, we show that Akt can regulate signaling pathways that lead to induction of the NF-kappaB family of transcription factors in the Jurkat T-cell line. This induction occurs, at least in part, at the level of degradation of the NF-kappaB inhibitor IkappaB, and is specific for NF-kappaB, as other inducible transcription factors are not affected by Akt overexpression. Furthermore, the effect requires the kinase activity and pleckstrin homology (PH) domain of Akt. Also, Akt does not act alone to induce cytokine promoters and NF-kappaB reporters, because signals from other pathways are required to observe the effect. These studies uncover a previously unappreciated connection between Akt and NF-kappaB induction that could have implications for the control of T-cell growth and survival.

DNA-Binding Proteins↗