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At least 433 records · Page 24Linked to original sources
PubMed2000

A novel PCR-based technique using expressed sequence tags and gene homology for murine genetic mapping: localization of the complement genes.

The complement system is a cascade of serum proteins and receptors which forms a vital arm of innate immunity and enhances the adaptive immune response. This work establishes the chromosomal localization of four key genes of the murine complement system. Mapping was performed using a novel and rapid PCR restriction length polymorphism method which was developed to exploit the murine expressed sequence tag (EST) database. This technique circumvents the laborious cDNA or genomic cloning steps of other mapping methods by relying on EST data and the prediction of exon-intron boundaries. This method can be easily applied to the genes of other systems, ranging from the interests of the individual researcher to large-scale gene localization projects. Here the complement system, probably one of the most well-characterized areas of immunology, was used as a model system. It was shown that the C3a receptor C1r and C1s genes form an unexpected complement gene cluster towards the telomeric end of chromosome 6. The second mannose binding lectin-associated serine protease gene was mapped to the telomeric end of chromosome 4, which is distinct from other complement-activating serine proteases. These results provide new insights into the evolution of this group of proteins.

Animals↗
PubMed2002

Versatile roles for sonic hedgehog in gut development.

Sonic hedgehog (Shh) is a gene encoding a protein that can be secreted and act as a morphogen. The protein exerts versatile and important effects on the surrounding cells by binding a specific receptor, named patched. So far Shh has been shown to be involved in the morphogenesis and cytodifferentiation of many organ systems, such as notochord, floor plate, limb, pancreas, and pituitary gland, to mention only a few examples. Shh is also involved in the determination of left-right asymmetry, at least in the chicken embryo. Here we present evidence that Shh is one of the key genes whose activity is pivotal for the normal morphogenesis and differentiation of digestive organs. Epithelial Shh regulates the formation of stomach glands and stratification of the mesenchyme into connective tissue and smooth muscle. It exerts its effect often through the induction of bone morphogenetic protein (BMP) genes in the mesenchyme. Thus, Shh is a key player in the epithelial-mesenchymal interactions in the development of the gut.

Animals↗
PubMed2001

The peroxisome proliferator-activated receptor delta promotes lipid accumulation in human macrophages.

The peroxisome proliferator-activated receptors (PPARs) are a family of fatty acid-activated transcription factors which control lipid homeostasis and cellular differentiation. PPARalpha (NR1C1) controls lipid oxidation and clearance in hepatocytes and PPARgamma (NR1C3) promotes preadipocyte differentiation and lipogenesis. Drugs that activate PPARalpha are effective in lowering plasma levels of lipids and have been used in the management of hyperlipidemia. PPARgamma agonists increase insulin sensitivity and are used in the management of type 2 diabetes. In contrast, there are no marketed drugs that selectively target PPARdelta (NR1C2) and the physiological roles of PPARdelta are unclear. In this report we demonstrate that the expression of PPARdelta is increased during the differentiation of human macrophages in vitro. In addition, a highly selective agonist of PPARdelta (compound F) promotes lipid accumulation in primary human macrophages and in macrophages derived from the human monocytic cell line, THP-1. Compound F increases the expression of genes involved in lipid uptake and storage such as the class A and B scavenger receptors (SRA, CD36) and adipophilin. PPARdelta activation also represses key genes involved in lipid metabolism and efflux, i.e. cholesterol 27-hydroxylase and apolipoprotein E. We have generated THP-1 sublines that overexpress PPARdelta and have confirmed that PPARdelta is a powerful promoter of macrophage lipid accumulation. These data suggest that PPARdelta may play a role in the pathology of diseases associated with lipid-filled macrophages, such as atherosclerosis, arthritis, and neurodegeneration.

Animals↗
PubMed2005

New genes tied to endocrine, metabolic, and dietary regulation of lifespan from a Caenorhabditis elegans genomic RNAi screen.

Most of our knowledge about the regulation of aging comes from mutants originally isolated for other phenotypes. To ask whether our current view of aging has been affected by selection bias, and to deepen our understanding of known longevity pathways, we screened a genomic Caenorhabditis elegans RNAi library for clones that extend lifespan. We identified 23 new longevity genes affecting signal transduction, the stress response, gene expression, and metabolism and assigned these genes to specific longevity pathways. Our most important findings are (i) that dietary restriction extends C. elegans' lifespan by down-regulating expression of key genes, including a gene required for methylation of many macromolecules, (ii) that integrin signaling is likely to play a general, evolutionarily conserved role in lifespan regulation, and (iii) that specific lipophilic hormones may influence lifespan in a DAF-16/FOXO-dependent fashion. Surprisingly, of the new genes that have conserved sequence domains, only one could not be associated with a known longevity pathway. Thus, our current view of the genetics of aging has probably not been distorted substantially by selection bias.

Journal Article↗
PubMed2000

Nutrient regulation of gene expression by the sterol regulatory element binding proteins: increased recruitment of gene-specific coregulatory factors and selective hyperacetylation of histone H3 in vivo.

We have evaluated the mechanism for sterol-regulated gene expression by the sterol regulatory element binding proteins (SREBPs) in intact cells. We show that activation of SREBPs by sterol depletion results in the increased binding of Sp1 to a site adjacent to SREBP in the promoter for the low density lipoprotein (LDL) receptor gene in vivo. Similarly, sterol depletion resulted in the increased recruitment of two distinct SREBP coregulatory factors, NF-Y and CREB, to the promoter for hydroxymethyl glutaryl CoA reductase, another key gene of intracellular cholesterol homeostasis. Furthermore, increased acetylation of histone H3 but not H4 was also detected in chromatin from both promoters on SREBP activation. Thus, SREBP activation results in the similar selective recruitment of different coregulatory generic transcription factors to two separate cholesterol-regulated promoters. These studies demonstrate the utility of the chromatin immunoprecipitation technique for analyzing the differential action of low-abundance transcription factors in fundamental regulatory events in intact cells. Our results also provide key in vivo support for the mechanism proposed from cell-free experiments, where SREBP increased the binding of Sp1 to the LDL receptor promoter. Finally, our findings also indicate that subtle differences in the pattern of core histone acetylation play a role in selective gene activation.

Acetylation↗
PubMed2004

Mild mutations in the pan neural gene prospero affect male-specific behaviour in Drosophila melanogaster.

The fruitfly Drosophila melanogaster is one of the most appropriate model organisms to study the genetics of behaviour. Here, we focus on prospero (pros), a key gene for the development of the nervous system which specifies multiple aspects from the early formation of the embryonic central nervous system to the formation of larval and adult sensory organs. We studied the effects on locomotion, courtship and mating behaviour of three mild pros mutations. These newly isolated pros mutations were induced after the incomplete excision of a transposable genomic element that, before excision, caused a lethal phenotype during larval development. Strikingly, these mutant strains, but not the strains with a clean excision, produced a high frequency of heterozygous flies, after more than 50 generations in the lab. We investigated the factors that could decrease the fitness of homozygotes relatively to heterozygous pros mutant flies. Flies of both genotypes had slightly different levels of fertility. More strikingly, homozygous mutant males had a lower sexual activity than heterozygous males and failed to mate in a competitive situation. No similar effect was detected in mutant females. These findings suggest that mild mutations in pros did not alter vital functions during development but drastically changed adult male behaviour and reproductive fitness.

Alleles↗
PubMed2003

Xylem-specific and tension stress-responsive expression of cellulose synthase genes from aspen trees.

Genetic improvement of cellulose biosynthesis in woody trees is one of the major goals of tree biotechnology research. Yet, progress in this field has been slow owing to (1) unavailability of key genes from tree genomes, (2) the inability to isolate active and intact cellulose synthase complexes and, (3) the limited understanding of the mechanistic processes involved in the wood cellulose development. Here I report on the recent advances in molecular genetics of cellulose synthases (CesA) from aspen trees. Two different types of cellulose synthases appear to be involved in cellulose deposition in primary and secondary walls in aspen xylem. The three distinct secondary CesAs from aspen- PtrCesA1, PtrCesA2, and PtrCesA3-appear to be aspen homologs of Arabidopsis secondary CesAs AtCesA8, AtCesA7, and AtCesA4, respectively, based on their high identity/similarity (>80%). These aspen CesA proteins share the transmembrane domain (TMD) structure that is typical of all known "true" CesA proteins: two TMDs toward the N-terminal and six TMDs toward the C-terminal. The putative catalytic domain is present between TMDs 2 and 3. All signature motifs of processive glycosyltransferases are also present in this catalytic domain. In a phylogenetic tree based on various predicted CesA proteins from Arabidopsis and aspen, aspen CesAs fall into families similar to those seen with Arabidopsis CesAs, suggesting their functional similarity. The coordinate expression of three aspen secondary CesAs in xylem and phloem fibers, along with their simultaneous tension stress-responsive upregulation, suggests that these three CesAs may play a pivotal role in biosynthesis of better-quality cellulose in secondary cell walls of plants. These results are likely to have a direct impact on genetic manipulation of trees in the future.

Arabidopsis↗
PubMed2003

Regulation of hepatic fasting response by PPARgamma coactivator-1alpha (PGC-1): requirement for hepatocyte nuclear factor 4alpha in gluconeogenesis.

The liver plays several critical roles in the metabolic adaptation to fasting. We have shown previously that the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) is induced in fasted or diabetic liver and activates the entire program of gluconeogenesis. PGC-1alpha interacts with several nuclear receptors known to bind gluconeogenic promoters including the glucocorticoid receptor, hepatocyte nuclear factor 4alpha (HNF4alpha), and the peroxisome proliferator-activated receptors. However, the genetic requirement for any of these interactions has not been determined. Using hepatocytes from mice lacking HNF4alpha in the liver, we show here that PGC-1alpha completely loses its ability to activate key genes of gluconeogenesis such as phosphoenolpyruvate carboxykinase and glucose-6-phosphatase when HNF4alpha is absent. It is also shown that PGC-1alpha can induce genes of beta-oxidation and ketogenesis in hepatocytes, but these effects do not require HNF4alpha. Analysis of the glucose-6-phosphatase promoter indicates a key role for HNF4alpha-binding sites that function robustly only when HNF4alpha is coactivated by PGC-1alpha. These data illustrate the involvement of PGC-1alpha in several aspects of the hepatic fasting response and show that HNF4alpha is a critical component of PGC-1alpha-mediated gluconeogenesis.

Adenoviridae↗
PubMed2026

Integrated multi-omics analysis of fluoroquinolone tolerance mechanisms induced by enrofloxacin in Pasteurella multocida.

BACKGROUND: The global prevalence of multidrug-resistant bacteria has been rising at an alarming rate, posing a serious threat to both human and animal health. However, the mechanisms by which bacteria acquire antibiotic tolerance and subsequently develop resistance remain incompletely understood. METHODS: In this study, Pasteurella multocida, a common pathogen in the animal husbandry industry, was exposed to enrofloxacin, and genome resequencing, transcriptomic, and metabolomic analyses were performed to elucidate the adaptive mechanisms of P. multocida under fluoroquinolone-induced stress. RESULTS: Compared with the wild-type strain, the enrofloxacin-tolerant strain exhibited an extended lag phase, a prolonged logarithmic phase, reduced sensitivity to polymyxin B, reduced biofilm formation, and an elongated cellular morphology. Multi-omics analysis revealed a deletion in the dusB gene of the tolerant strain, resulting in a truncated non-functional protein. The deletion of dusB enhanced tolerance by prolonging the lag phase and reducing the growth rate. Moreover, the expression of genes in the CAMP pathway was up-regulated, and deletion of cpxR further promoted tolerance by modulating ribosome-associated genes. Integrated transcriptomic and metabolomic analyses indicated activation of the tricarboxylic acid (TCA) cycle during tolerance development. CONCLUSION: This study identified dusB and cpxR as key genes mediating enrofloxacin tolerance in P. multocida, elucidated the association between the antibiotic tolerance, growth, and gene expression, and may provide potential targets for future strategies aimed at limiting tolerance-associated resistance development.

Enrofloxacin↗
PubMed2004

In vivo epinephrine-mediated regulation of gene expression in human skeletal muscle.

The stress hormone epinephrine produces major physiological effects on skeletal muscle. Here we determined skeletal muscle mRNA expression profiles before and during a 6-h epinephrine infusion performed in nine young men. Stringent statistical analysis of data obtained using 43000 cDNA element microarrays showed that 1206 and 474 genes were up- and down-regulated, respectively. Microarray data were validated using reverse transcription quantitative PCR. Gene classification was performed through data mining of Gene Ontology annotations, cluster analysis of regulated genes among 14 human tissues, and correlation analysis of mRNA and clinical parameter variations. Evidence of an autoregulatory control was provided by the regulation of key genes of the cAMP-dependent transcription pathway. Genes with known functional cAMP response elements were regulated by the hormone. The impact on metabolism was illustrated by coordinated regulations of genes involved in carbohydrate and protein metabolisms. Epinephrine had a profound effect on genes involved in immunity and inflammatory response, a previously unappreciated aspect of catecholamine action. Information on 526 mRNAs corresponded to genes of unknown function. These data define the molecular signatures of epinephrine action in human skeletal muscle. They may contribute to the understanding of skeletal muscle alterations observed in pathological conditions characterized by sympathetic nervous system overdrive.

Adrenergic Agonists↗
PubMed1993

Virus infections in mice with targeted gene disruptions.

The experimental dissection of the ways that the various cells and molecules of the immune system interact to promote virus clearance has been greatly facilitated by the availability of mice with targeted disruptions of key genes. New insights are emerging, and details of host resistance mechanisms that could only be inferred for the in vivo situation are now being clearly established.

Animals↗
PubMed1997

daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans.

A C. elegans neurosecretory signaling system regulates whether animals enter the reproductive life cycle or arrest development at the long-lived dauer diapause stage. daf-2, a key gene in the genetic pathway that mediates this endocrine signaling, encodes an insulin receptor family member. Decreases in DAF-2 signaling induce metabolic and developmental changes, as in mammalian metabolic control by the insulin receptor. Decreased DAF-2 signaling also causes an increase in life-span. Life-span regulation by insulin-like metabolic control is analogous to mammalian longevity enhancement induced by caloric restriction, suggesting a general link between metabolism, diapause, and longevity.

Adipose Tissue↗
PubMed1993

Modulation of the H2O2-induced SOS response in Escherichia coli PQ300 by amino acids, metal chelators, antioxidants, and scavengers of reactive oxygen species.

The SOS chromotest is a simple colorimetric genotoxicity assay that monitors DNA repair by measuring the induction of the gene sfiA in Escherichia coli K-12. E. coli PQ300, a diagnostic SOS tester strain for the detection of oxidative genotoxins, carries a mutation in a key gene for antioxidative defense, oxyR. This mutation renders PQ300 more sensitive to oxidative genotoxins, particularly to H2O2. We found that induction of the SOS response by H2O2 in E. coli PQ300 is dependent on the composition of the incubation medium; a substantially reduced response was obtained in minimal phosphate buffered saline (PBS) as opposed to complex Luria broth (LB) medium. Supplementation of PBS with histidine or cysteine stimulated H2O2-induced SOS induction to levels exceeding those found in LB medium. Low concentrations of glutathione (20-70 microM) also enhanced the H2O2-induced SOS response in E. coli PQ300, whereas higher concentrations (> 150 microM) were protective. Preincubation of tester cells with the chelators o-phenanthroline, 2,2-dipyridyl, and ethylenediaminetetraacetic acid (EDTA) protected cells from the effects of H2O2, although EDTA was only partially effective. Pretreatment of PQ300 with the antioxidant ascorbic acid or the hydroxyl radical scavenger dimethyl sulfoxide also diminished the SOS response, whereas mannitol and glucose were ineffective. The results show that the net effect of H2O2-induced DNA damage is influenced by the balance of oxidative and antioxidative factors and, furthermore, can be modulated by constituents of the extracellular milieu.

Amino Acids↗
PubMed2002

Inhibition of cartilage destruction by double gene transfer of IL-1Ra and IL-10 involves the activin pathway.

The objective of the study was to determine the effects and the molecular background of interleukin-1 receptor antagonist (IL-1Ra) and vIL-10 double gene transfer into human synovial fibroblasts from patients with rheumatoid arthritis (RA) using the SCID mouse model for cartilage erosion in RA. RA synovial fibroblasts were transduced with retro- or adenoviruses encoding IL-1Ra and/or viral IL-10 (vIL-10). SCID mice were engrafted subcutaneously with IL-1Ra and vIL-10 transduced human rheumatoid synovial fibroblasts and normal cartilage. In parallel, gene expression analysis before and after gene transfer using RNA arbitrarily primed PCR in combination with cDNA array was performed. vIL-10 and IL-1Ra double gene transfer resulted in inhibition of cartilage invasion and degradation by RA synovial fibroblasts when compared with control transduced and non-transduced implants. Expression of key genes that were altered after double gene transfer were related to the activin pathway. The results demonstrate not only that virus-based gene transfer using a combination of two joint-protective genes is a feasible approach to inhibit cartilage degradation by activated RA synovial fibroblasts, but also that the underlying molecular effects include modulation of the activin pathway.

Actins↗
PubMed2026

Expression and mutation characteristics of mitochondrial genes in PBMCs of SLE patients: Implications for SLE pathogenesis.

This study aimed to investigate mitochondrial gene mutations and expression in peripheral blood mononuclear cells (PBMCs) of systemic lupus erythematosus (SLE) patients, focusing on MT-ND5, and assess expression changes under lipopolysaccharide (LPS), tumor necrosis factor-α (TNF-α), and dexamethasone stimulation. Peripheral blood was collected from female SLE patients. Mitochondrial DNA (mtDNA) from PBMCs was sequenced using the HiSeq PE150 platform. Quantitative reverse transcription PCR and western blotting were used to evaluate mRNA and protein expression of the most frequently mutated mitochondrial genes. Cultured PBMCs were treated with LPS, TNF-α, or dexamethasone to examine regulatory effects. A total of 589 mtDNA mutation sites were detected in SLE patients. Among 13 protein-coding genes, MT-ND5, MT-CYB, MT-CO1, MT-ND4, and MT-CO3 exhibited the highest mutation frequencies. Expression analysis revealed significantly reduced mRNA and protein levels of these genes in SLE PBMCs compared with controls, with further decreases after stimulation with LPS, TNF-α, or dexamethasone. SLE PBMCs display extensive mitochondrial mutations and downregulation of key genes, particularly MT-ND5. Inflammatory and therapeutic stimuli exacerbate this suppression, suggesting mitochondrial dysfunction contributes to SLE susceptibility and progression.

Humans↗
PubMed2006

Gene expression profiles of Arabidopsis Cvi seeds during dormancy cycling indicate a common underlying dormancy control mechanism.

Physiologically dormant seeds, like those of Arabidopsis, will cycle through dormant states as seasons change until the environment is favourable for seedling establishment. This phenomenon is widespread in the plant kingdom, but has not been studied at the molecular level. Full-genome microarrays were used for a global transcript analysis of Arabidopsis thaliana (accession Cvi) seeds in a range of dormant and dry after-ripened states during cycling. Principal component analysis of the expression patterns observed showed that they differed in newly imbibed primary dormant seeds, as commonly used in experimental studies, compared with those in the maintained primary and secondary dormant states that exist during cycling. Dormant and after-ripened seeds appear to have equally active although distinct gene expression programmes, dormant seeds having greatly reduced gene expression associated with protein synthesis, potentially controlling the completion of germination. A core set of 442 genes were identified that had higher expression in all dormant states compared with after-ripened states. Abscisic acid (ABA) responsive elements were significantly over-represented in this set of genes the expression of which was enhanced when multiple copies of the elements were present. ABA regulation of dormancy was further supported by expression patterns of key genes in ABA synthesis/catabolism, and dormancy loss in the presence of fluridone. The data support an ABA-gibberelic acid hormone balance mechanism controlling cycling through dormant states that depends on synthetic and catabolic pathways of both hormones. Many of the most highly expressed genes in dormant states were stress-related even in the absence of abiotic stress, indicating that ABA, stress and dormancy responses overlap significantly at the transcriptome level.

Abscisic Acid↗
PubMed2001

Molecular mechanism of cardiac hypertrophy and development.

Congestive heart failure is a major issues for cardiologists and to fully understand heart failure, it is important to understand the mechanism of the development of cardiac hypertrophy. Hemodynamic overload, namely mechanical stress, is a major cause of cardiac hypertrophy and to dissect the signaling pathways from mechanical stress to cardiac hypertrophy, an in-vitro device by which mechanical stress can be imposed on cardiac myocytes of neonatal rats cultured in serum-free conditions has been developed. Passively stretching cardiac myocytes cultured on silicone membranes induced various hypertrophic responses, such as activation of the phosphorylation cascades of many protein kinases, expression of specific genes and an increase in protein synthesis. During this process, secretion and production of vasoactive peptides, such as angiotensin II and endothelin-1, were increased and they played critical roles in the induction of these hypertrophic responses. Candidates for the 'mechanoreceptor' that receives the mechanical stress and converts it into intracellular biochemical signals have been recently demonstrated. Gene therapy and cell transplantation are hopeful strategies for the treatment of heart failure and require an understanding of how normal cardiac myocytes are differentiated. A key gene that plays a critical role in cardiac development has been isolated. The cardiac homeobox-containing gene Csx is expressed in the heart and the heart progenitor cells from the very early developmental stage, and targeted disruption of the murine Csx results in embryonic lethality because of the abnormal looping morphogenesis of the primary heart tube. With a cardiac zinc finger protein GATA4, Csx induces cardiomyocyte differentiation of teratocarcinoma cells as well as upregulation of cardiac genes. Mutations of human CSX cause various congenital heart diseases including atrial septal defect, ventricular septal defect, tricuspid valve abnormalities and atrioventricular block.

Animals↗