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Results for “Candidate pathways”

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PubMed2006

Differential expression pattern of coq-8 gene during development in Caenorhabditis elegans.

Coenzyme Q (Q) and the genes involved in its biosynthesis are involved in aging and development of Caenorhabditis elegans. Q is synthesized by at least eight highly conserved nuclear coq genes, but this biosynthesis pathway and its regulation is not known. The coq-8 gene sequence has homology to the ABC-1 family kinases and is the only known candidate for a possible regulation of this pathway. To study coq-8 expression pattern, we have developed a C. elegans transgenic strain expressing ubiquinone biosynthesis coq-8 gene promoter and GFP construct. We show here an age-dependent specific pattern from embryo to senescence for COQ-8 protein expression. Expression in embryo was triggered by a defined group of blastomers before morphogenesis. In elderly nematodes expression was only observed in nervous system, whilst expression in larvae was also detected in hypodermis, muscles and coelomocytes. Global expression provide a regulated pattern during life cycle of the nematode.

Aging↗

PubMed2004

Action of fat, four-jointed, dachsous and dachs in distal-to-proximal wing signaling.

In the Drosophila wing, distal cells signal to proximal cells to induce the expression of Wingless, but the basis for this distal-to-proximal signaling is unknown. Here, we show that three genes that act together during the establishment of tissue polarity, fat, four-jointed and dachsous, also influence the expression of Wingless in the proximal wing. fat is required cell autonomously by proximal wing cells to repress Wingless expression, and misexpression of Wingless contributes to proximal wing overgrowth in fat mutant discs. Four-jointed and Dachsous can influence Wingless expression and Fat localization non-autonomously, consistent with the suggestion that they influence signaling to Fat-expressing cells. We also identify dachs as a gene that is genetically required downstream of fat, both for its effects on imaginal disc growth and for the expression of Wingless in the proximal wing. Our observations provide important support for the emerging view that Four-jointed, Dachsous and Fat function in an intercellular signaling pathway, identify a normal role for these proteins in signaling interactions that regulate growth and patterning of the proximal wing, and identify Dachs as a candidate downstream effector of a Fat signaling pathway.

Animals↗

PubMed2002

Optic lobe commissures in a three-dimensional brain model of the cockroach Leucophaea maderae: a search for the circadian coupling pathways.

The circadian rhythm of locomotor activity in the cockroach Leucophaea maderae is controlled by bilaterally symmetric, apparently directly coupled, circadian pacemakers in the optic lobes. Strong evidence predicts that ventromedial to the medulla, the accessory medulla with associated pigment-dispersing hormone-immunoreactive neurons is this circadian clock. In search for direct coupling pathways between both clocks, we performed horseradish peroxidase backfills from one optic stalk as well as dextran and horseradish peroxidase injections into one accessory medulla. Seven commissures with projections in the contralateral optic lobe were identified and reconstructed. Three of these commissures connected both accessory medullae. Two of these resembled the arborization pattern of the pigment-dispersing hormone-immunoreactive neurons, which are circadian pacemaker candidates in insects. This finding suggests that some of these pacemaker candidates form a direct circadian coupling pathway. For better visualization of reconstructed commissures, we implemented the reconstructions into a three-dimensional model of the cockroach brain.

Animals↗

PubMed1997

Mutagenesis screens for interacting genes reveal three roles for fat facets during Drosophila eye development.

The Drosophila fat facets gene encodes a deubiquitinating enzyme that regulates a cell communication pathway essential early during eye development to inhibit the determination of excess photoreceptors. Ubiquitin is a small polypeptide that tags proteins for degradation by a multisubunit proteolytic complex called the proteasome. The FAT FACETS protein is thought to be required to remove ubiquitin from a particular protein, thereby rescuing if from proteolysis. In order to identify the genes encoding the substrate of FAT FACETS and other components of the neural inhibition pathway, a mutagenesis screen for dominant enhancers of the fat facets mutant eye phenotype was performed. Several genes were identified, one of which is an excellent candidate for encoding a component of the pathway regulated by FAT FACETS. Three different eye phenotypes were observed when the fat facets mutants were dominantly enhanced by different mutations, suggesting that fat facets has other functions in addition to its critical role early in eye development.

Animals↗

PubMed2006

The role of nitric oxide and GluR1 in presynaptic and postsynaptic components of neocortical potentiation.

In this study, we investigated the mechanisms underlying synaptic plasticity at the layer IV to II/III pathway in barrel cortex of mice aged 6-13 weeks. This pathway is one of the likely candidates for expression of experience-dependent plasticity in the barrel cortex and may serve as a model for other IV to II/III synapses in the neocortex. We found that postsynaptic autocamtide-2-inhibitory peptide is sufficient to block long-term potentiation (LTP) (IC50 of 500 nm), implicating postsynaptic calcium/calmodulin-dependent kinase II in LTP induction. AMPA receptor subunit 1 (GluR1) knock-out mice also showed LTP in this pathway, but potentiation was predominantly presynaptic in origin as determined by paired-pulse analysis, coefficient of variation analysis, and quantal analysis, whereas wild types showed a mixed presynaptic and postsynaptic locus. Quantal analysis at this synapse was validated by measuring uniquantal events in the presence of strontium. The predominantly presynaptic LTP in the GluR1 knock-outs was blocked by postsynaptic antagonism of nitric oxide synthase (NOS), either with intracellular N-omega-nitro-L-arginine methyl ester or N-nitro-L-arginine, providing the first evidence for a retrograde transmitter role for NO at this synapse. Antagonism of NOS in wild types significantly reduced but did not eliminate LTP (group average reduction of 50%). The residual LTP formed a variable proportion of the total LTP in each cell and was found to be postsynaptic in origin. We found no evidence for silent synapses in this pathway at this age. Finally, application of NO via a donor induced potentiation in layer II/III cells and caused an increase in frequency but not amplitude of miniature EPSPs, again implicating NO in presynaptic plasticity.

Action Potentials↗

PubMed2004

A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway.

Signal transduction pathways are modular composites of functionally interdependent sets of proteins that act in a coordinated fashion to transform environmental information into a phenotypic response. The pro-inflammatory cytokine tumour necrosis factor (TNF)-alpha triggers a signalling cascade, converging on the activation of the transcription factor NF-kappa B, which forms the basis for numerous physiological and pathological processes. Here we report the mapping of a protein interaction network around 32 known and candidate TNF-alpha/NF-kappa B pathway components by using an integrated approach comprising tandem affinity purification, liquid-chromatography tandem mass spectrometry, network analysis and directed functional perturbation studies using RNA interference. We identified 221 molecular associations and 80 previously unknown interactors, including 10 new functional modulators of the pathway. This systems approach provides significant insight into the logic of the TNF-alpha/NF-kappa B pathway and is generally applicable to other pathways relevant to human disease.

Animals↗

PubMed2001

Lipopeptide presentation pathway in dendritic cells.

Lipopeptides are currently being evaluated as candidate vaccines in human volunteers. They elicit cytotoxic responses from CD8(+) T lymphocytes, whereas peptides without a lipidic moiety usually do not. The exact processing and presentation pathways leading to association with MHC class I molecules has not yet been defined. This is of particular interest in dendritic cells, which are required for primary T cell stimulation. We have tracked lipopeptides derived from an HLA-A2.1-restricted HIV-1 Reverse Transcriptase epitope, by N-terminal addition of an N-epsilon-palmitoyl-lysine. Entry of the lipopeptides into human monocyte-derived dendritic cells (MDC) was mediated by endocytosis, as assessed by colocalization using analogs labelled with rhodamine, and by confocal microscopy. This internalization in DC induced functional stimulation of CD8(+) T lymphocytes specific for the epitopes, quantified by Interferon-gamma ELISPOT assays. The peptide alone was not visualized inside the DC and was only presented through direct surface association to HLA-A*0201. Therefore, lipopeptides provide a model system to define precisely the cross-presentation pathways that lead exogenous proteins to associate with class I MHC molecules within dendritic cells. Using this approach, cross-presentation pathways can be better defined and vaccine lipopeptides can be further optimized for MHC class I association in human dendritic cells.

AIDS Vaccines↗

PubMed2006

The calmodulin pathway and evolution of elongated beak morphology in Darwin's finches.

A classic textbook example of adaptive radiation under natural selection is the evolution of 14 closely related species of Darwin's finches (Fringillidae, Passeriformes), whose primary diversity lies in the size and shape of their beaks. Thus, ground finches have deep and wide beaks, cactus finches have long and pointed beaks (low depth and narrower width), and warbler finches have slender and pointed beaks, reflecting differences in their respective diets. Previous work has shown that even small differences in any of the three major dimensions (depth, width and length) of the beak have major consequences for the overall fitness of the birds. Recently we used a candidate gene approach to explain one pathway involved in Darwin's finch beak morphogenesis. However, this type of analysis is limited to molecules with a known association with craniofacial and/or skeletogenic development. Here we use a less constrained, complementary DNA microarray analysis of the transcripts expressed in the beak primordia to find previously unknown genes and pathways whose expression correlates with specific beak morphologies. We show that calmodulin (CaM), a molecule involved in mediating Ca2+ signalling, is expressed at higher levels in the long and pointed beaks of cactus finches than in more robust beak types of other species. We validated this observation with in situ hybridizations. When this upregulation of the CaM-dependent pathway is artificially replicated in the chick frontonasal prominence, it causes an elongation of the upper beak, recapitulating the beak morphology of the cactus finches. Our results indicate that local upregulation of the CaM-dependent pathway is likely to have been a component of the evolution of Darwin's finch species with elongated beak morphology and provide a mechanistic explanation for the independence of beak evolution along different axes. More generally, our results implicate the CaM-dependent pathway in the developmental regulation of craniofacial skeletal structures.

Animals↗

PubMed1996

AKR1 encodes a candidate effector of the G beta gamma complex in the Saccharomyces cerevisiae pheromone response pathway and contributes to control of both cell shape and signal transduction.

Mating pheromones of Saccharomyces cerevisiae control both signal transduction events and changes in cell shape. The G beta gamma complex of the pheromone receptor-coupled G protein activates the signal transduction pathway, leading to transcriptional induction and cell cycle arrest, but how pheromone-dependent signalling leads to cell shape changes is unclear. We used a two-hybrid system to search for proteins that interact with the G beta gamma complex and that might be involved in cell shape changes. We identified the ankyrin repeat-containing protein Akr1p and show here that it interacts with the free G beta gamma complex. This interaction may be regulated by pheromone, since Akr1p is excluded from the G alpha beta gamma heterotrimer. Both haploid and diploid cells lacking Akr1p grow slowly and develop deformed buds or projections, suggesting that this protein participates in the control of cell shape. In addition, Akr1p has a negative influence on the pheromone response pathway. Epistasis analysis demonstrates that this negative effect does not act on the G beta gamma complex but instead affects the kinase cascade downstream of G beta gamma, so that the kinase Ste20p and components downstream of Ste20p (e.g., Ste11p and Ste7p) are partially activated in cells lacking Akr1p. Although the elevated signalling is eliminated by deletion of Ste20p (or components downstream of Ste20p), the growth and morphological abnormalities of cells lacking Akr1p are not rescued by deletion of any of the known pheromone response pathway components. We therefore propose that Akr1p negatively affects the activity of a protein that both controls cell shape and contributes to the pheromone response pathway upstream of Ste20p but downstream of G beta gamma. Specifically, because recent evidence suggests that Bem1p, Cdc24p, and Cdc42p can act in the pheromone response pathway, we suggest that Akr1p affects the functions of these proteins, by preventing them from activating mating-specific targets including the pheromone-responsive kinase cascade, until G beta gamma is activated by pheromone.

Base Sequence↗

PubMed2007

Microarray analysis of the fetal hippocampus in the Emx2 mutant.

Deficiency in the transcription factor Emx2 causes a specific alteration of hippocampal development, which has been well analyzed morphologically. We are currently using microarrays and in situ hybridization to characterize gene expression in the Emx2 mutant hippocampus. In this report on our preliminary results for the fetal stage, we identify a group of genes for most of which a putative relation to Emx2 pathways has not been previously recognized. Some candidates are development genes or are involved in functional maturation, and show expression in the hippocampal plate and/or developing dentate gyrus. A second class of candidates label neuronal, glial or vascular structures in the outer marginal zone, and likely represent markers for cell populations specifically absent in the mutant. Our results point at pathways and processes altered in the mutant, particularly the Notch and chemokine pathways, the processes of cell migration, axonal guidance and angiogenesis, and the relation of pia and Cajal-Retzius cells with hippocampal morphogenesis.

Animals↗

PubMed2006

Identification of small molecules that induce apoptosis in a Myc-dependent manner and inhibit Myc-driven transformation.

The Myc transcription factor plays a central role in the regulation of cell cycle progression, apoptosis, angiogenesis, and cellular transformation. Myc is a potent oncoprotein that is deregulated in a wide variety of human tumors and is therefore an attractive target for novel cancer therapies. Using a cellular screening approach, we have identified low-molecular-weight compounds, Myc pathway response agents (MYRAs), that induce apoptosis in a c-Myc-dependent manner and inhibit Myc-driven cellular transformation. MYRA-A inhibits Myc transactivation and interferes with the DNA-binding activity of Myc family proteins but has no effect on the E-box-binding protein USF. In contrast, MYRA-B induces Myc-dependent apoptosis without affecting Myc transactivation or Myc/Max DNA binding. Our data show that cellular screening assays can be a powerful strategy for the identification of candidate substances that modulate the Myc pathway. These compounds can be useful tools for studying Myc function and may also be of therapeutic potential as leads for drug development.

Animals↗

PubMed2026

Searching for New Genes That Cause Usher Syndrome.

PURPOSE: The purpose of this project was to identify novel Usher syndrome (USH) candidate genes from phenotyping data of 9139 knockout (KO) mouse lines. METHODS: We evaluated phenotype data for concurrent retinopathy and hearing abnormalities in single-gene KO mice generated by the International Mouse Phenotyping Consortium (IMPC). A search was performed to determine whether each gene had been previously associated with retinopathy and/or deafness in humans. Bioinformatic tools were used to predict protein interactions, molecular functions, signaling pathways, and the expression of human orthologues of candidate genes in the retina and inner ear. RESULTS: We identified 18 single-gene KO lines exhibiting hearing abnormality and retinopathy after ear and eye examinations, respectively, and/or by histopathology. The molecular functions and signaling pathways of the human orthologues of the 18 candidate genes partially overlapped with those of USH genes. Particularly, FER and DYRK1B proteins were predicted to interact with proteins encoded by known ciliopathy genes. ADIPOR1, ATP8B1, and MPDZ were associated with retinal degeneration in humans. CHSY1 and IDUA may be pathogenic causes of hearing impairment in people. Furthermore, CHSY1, CSTB, and SPRED1 were located adjacent to unsolved genetic loci related to USH. CONCLUSIONS: A screen of 9139 KO mouse lines revealed 18 candidate genes exhibiting both retinal and inner ear abnormalities consistent with the principal clinical features associated with USH. As the observed phenotypes are attributed to gene deletion in mice, these genes warrant further study to determine the causation of retinal degeneration and hearing loss in patients.

Animals↗

PubMed2005

Atg17 regulates the magnitude of the autophagic response.

Autophagy is a catabolic process used by eukaryotic cells for the degradation and recycling of cytosolic proteins and excess or defective organelles. In yeast, autophagy is primarily a response to nutrient limitation, whereas in higher eukaryotes it also plays a role in developmental processes. Due to its essentially unlimited degradative capacity, it is critical that regulatory mechanisms are in place to modulate the timing and magnitude of the autophagic response. One set of proteins that seems to function in this regard includes a complex that contains the Atg1 kinase. Aside from Atg1, the proteins in this complex participate primarily in either nonspecific autophagy or specific types of autophagy, including the cytoplasm to vacuole targeting pathway, which operates under vegetative growth conditions, and peroxisome degradation. Accordingly, these proteins are prime candidates for factors that regulate the conversion between these pathways, including the change in size of the sequestering vesicle, the most obvious morphological difference. The atg17delta mutant forms a reduced number of small autophagosomes. As a result, it is defective in peroxisome degradation and is partially defective for autophagy. Atg17 interacts with both Atg1 and Atg13, via two coiled-coil domains, and these interactions facilitate its inclusion in the Atg1 complex.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Hedgehog signaling pathway as a target for therapeutic intervention in basal cell carcinoma.

Basal cell carcinomas (BCC) are slow-growing skin tumors that rarely metastasize but frequently recur, most often around the face, head and neck. Currently, surgery is the only treatment practice, which can be painful and leave scars. However, several years ago it was discovered that almost all forms of BCC result from mutations in a signaling pathway controlled by a protein called Hedgehog (Hh). Recently, a novel small-molecule drug candidate, CUR-61414, has been identified that blocks this pathway and could potentially be effective for the treatment of BCC. CUR-61414 was reported to prevent the proliferation and selectively induce the death of the tumor cells, while not harming adjacent normal skin cells in two different models of BCC. These findings directly demonstrate that the use of Hh inhibitors could be a valid novel therapeutic approach for treating BCC.

Animals↗

PubMed2002

The mechanism and pathway of pH induced swelling in cowpea chlorotic mottle virus.

Normal mode analysis based on a simplified energy function was used to study the swelling process of the icosahedral virus, cowpea chlorotic mottle virus (CCMV). Native state virus particles (coat proteins) of this T=3 icosahedral virus have been shown to undergo a large conformational change to a swollen state when metal ions are removed or the pH is raised. A normal mode analysis based on the native state capsid showed one preferential direction, a breathing mode, that explains the majority of the structural rearrangement necessary to bring the native structure close to the swollen state. From the native form of CCMV, the structure can be displaced along the direction of a single breathing mode by different amounts to create several candidate swollen structures and a putative pathway for virus expansion. The R-factor between these predicted swollen capsid structures and experimental electron density from cryoelectron microscopy (cryo-EM) measurements is then calculated to indicate how well each structure satisfies the experimental measurements on the swollen capsid state. A decrease of the crystallographic R-factor value from approximately 72% to approximately 49% was observed for these simple incremental displacements along the breathing mode. The simultaneous displacement of the native structure along other relevant (symmetric, non-degenerate) modes produce a structure with an R-factor of 45%, which is further reduced to 43.9% after minimization: a value in good accord with models based on the EM data at 28 A resolution. Based on the incrementally expanded structures, a pathway for the swelling process has been proposed. Analysis of the intermediate structures along this pathway indicates a significant loss of interactions at the quasi-3-fold interfaces occurs in the initial stages of the swelling process and this serves as a trigger for the compact to swollen transition. Furthermore, the pH dependent swelling appears to be triggered by the titration of a single residue with an anomalous pK(a) value in the unswollen particle.

Binding Sites↗

PubMed2026

Identification of putative causal associations between MicroRNAs and breast cancer via Mendelian randomization and bioinformatic analysis.

MicroRNAs (miRNAs) are implicated in breast cancer progression and prognosis. This study employed a Mendelian randomization (MR) framework to investigate causal relationships between plasma circulating miRNAs and breast cancer. miRNA expression quantitative trait loci were extracted from 2 independent cohorts. High-confidence miRNAs and their associated single-nucleotide polymorphisms were selected for 2-sample MR analyses using inverse-variance weighted and MR-Egger methods. Differential expression analysis and univariate Cox regression identified survival-associated genes in breast cancer, while enrichment analyses revealed pathways and biological processes linked to candidate targets. Pan-cancer analyses of miRNAs and targets were conducted via the ENCORI platform. Initial MR analyses in the discovery phase identified hsa-miR-100-5p, hsa-miR-125b-5p, and hsa-miR-339-5p as significantly associated with reduced breast cancer risk (P < .05), suggesting potential protective roles. A total of 1291 survival-associated differentially expressed genes were identified, with 39 overlapping targets implicated in miRNA-mediated breast cancer intervention. Enrichment analyses highlighted their involvement in cell cycle regulation and p53 signaling pathway. In the validation cohort, only hsa-miR-339-5p confirmed a protective effect on breast cancer risk, while hsa-miR-100-5p and hsa-miR-125b-5p did not reach significance. Pan-cancer profiling demonstrated aberrant miRNA expression across malignancies, prognostic relevance in multiple cancers, and significant negative correlations between miRNAs and target genes in breast tumors. Our findings provide novel insights into the causal roles of miRNAs in breast cancer pathogenesis and underscore their potential as noninvasive biomarkers and therapeutic targets. Future studies should prioritize functional validation and clinical translation of these miRNAs.

Humans↗

PubMed2000

Prospects for gene therapy for inherited cardiomyopathies.

Over the last few years the genes responsible for a number of genetic diseases of the cardiovascular system have been identified. These have included X-linked and autosomal dominant dilated cardiomyopathy, and hypertrophic cardiomyopathy. Genetic heterogeneity has been described in both of these diseases but a commonality of function has been apparent: defects in cytoskeletal proteins cause dilated cardiomyopathy and mutations in sarcomeric proteins cause hypertrophic cardiomyopathy. This led us to develop a 'final common pathway' hypothesis as a framework for selecting candidate genes for mutation screening in families with these diseases. The characterization of gene mutations has led to the development of therapies specifically targeting the defective protein or the pathway in which it is involved. These have included the use of pharmaceutical agents to replace or to antagonize the mutated protein, and replacement of the defective gene with a functional one (gene therapy). While early studies using gene therapy vectors were promising, translating studies in animals to viable therapeutic options for humans has remained problematic. There have been many publications describing the use of vectors to transduce target cells for the correction of gene defects, including recombinant retroviruses, adenoviruses, and adeno-associated viruses, as well as non-viral vectors. In this review we will discuss the identification of gene defects associated with cardiomyopathies, and the potential of gene therapy for the treatment of these diseases, as well as addressing some concerns related to the use of adenovirus-based vectors, a virus known to be an etiologic agent of acquired dilated cardiomyopathy.

Journal Article↗

PubMed2004

Transcriptional dysregulation in striatal projection- and interneurons in a mouse model of Huntington's disease: neuronal selectivity and potential neuroprotective role of HAP1.

Transcriptional dysregulation has been described as a central mechanism in the pathogenesis of Huntington's disease (HD), in which medium spiny projection neurons (MSN) selectively degenerate whereas neuronal nitric-oxide-synthase-positive interneurons (nNOS-IN) survive. In order to begin to understand this differential vulnerability we compared mRNA levels of selected genes involved in N-methyl-D-aspartate (NMDA) glutamate receptor and calcium (Ca2+) signaling pathways in MSN and nNOS-IN from 12-week-old R6/2 mice, a transgenic mouse model of HD and wild-type littermates. We undertook a laser capture microdissection (LCM) study to examine the contribution of transcriptional dysregulation in candidate genes involved in these two signaling pathways in discrete populations of striatal neurons. The use of LCM in combination with quantitative real-time polymerase chain reaction (Q-PCR) allowed us to quantify the neuronal abundance of candidate mRNAs. We found different transcriptional alterations in R6/2 neurons for both MSN and nNOS-IN, indicating that global transcriptional dysregulation alone does not account for selective vulnerability. Further, we observed a striking enrichment of several mRNAs in the nNOS-IN population, including that for the NMDA receptor subunit NR2D, the postsynaptic density protein 95 (PSD-95) and the huntingtin-associated protein 1 (HAP1) as well as nitric-oxide-synthase (nNOS) mRNA itself. The higher expression levels of these molecules in nNOS-IN when compared with MSN together with an association of nNOS, NR2D and HAP1 in a protein complex with PSD-95 suggest that these proteins may be involved in protective pathways that contribute to the resistance of this interneuron population to neurodegeneration in HD.

Animals↗