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At least 1,279 records · Page 71Linked to original sources
PubMed1995

Tyrosine phosphorylation-dependent stimulation of amyloid precursor protein secretion by the m3 muscarinic acetylcholine receptor.

Stimulation of m1 and m3 muscarinic acetylcholine receptors, which are coupled to phosphoinositide hydrolysis and protein kinase C activation, has been shown to increase the release of soluble amyloid precursor protein derivatives (APPs). The effect is mimicked by phorbol esters, which directly activate protein kinase C. Using human embryonic kidney cells expressing individual muscarinic receptor subtypes, we found that stimulation of APPs release by the muscarinic agonist carbachol was only partially reduced by a specific inhibitor of protein kinase C (the bisindolylmaleimide GF 109203X), while the response to phorbol 12-myristate 13-acetate (PMA) was abolished. The increase in APPs release elicited by carbachol and PMA was accompanied by elevated tyrosine phosphorylation of several proteins and reduced by tyrosine kinase inhibitors; GF 109203X significantly reduced the stimulation of tyrosine phosphorylation by carbachol and PMA. Inhibition of protein tyrosine phosphatases by vanadyl hydroperoxide markedly increased cellular tyrosine phosphorylation and enhanced APPs release as effectively as PMA and carbachol. Direct phosphorylation of amyloid precursor protein on tyrosine residues following treatment with carbachol, PMA, or vanadyl hydroperoxide was not observed. The results implicate both tyrosine phosphorylation and protein kinase C-dependent mechanisms in the regulation of APPs release by G protein-coupled receptors, and suggest that carbachol and PMA increase APPs release from human embryonic kidney cells expressing m3 muscarinic receptors via partially divergent pathways that converge at a tyrosine phosphorylation-dependent step.

Alkaloids↗
PubMed2000

S100A13. Biochemical characterization and subcellular localization in different cell lines.

S100 proteins became of major interest because of their divergent cell- and tissue-specific expression, their close association with a number of human diseases, and their importance for clinical diagnostics. Here, we report for the first time the purification and characterization of human recombinant S100A13. Flow dialysis revealed that the homodimeric S100A13 binds four Ca(2+) in two sets of binding sites, both displaying positive cooperativity but of very different affinity. Fluorescence and difference spectrophotometry indicate that the Trp/Tyr signal changes are almost complete upon binding of Ca(2+) to the two high affinity sites, which probably correspond to the C-terminal EF-hands in each subunit. The far-UV circular dichroic signal also changes upon binding of the first two Ca(2+). So far, the tissue distribution of S100A13 has not been well characterized. Here, we show that S100A13 is widely expressed in various types of tissues with a high expression level in thyroid gland. Using specific antisera against S100A13, high protein expression was detected in follicle cells of thyroid, Leydig cells of testis, and specific cells of brain. In human smooth muscle cells, which co-express S100A2 in the nucleus and S100A1 in stress fibers, S100A13 shows a unique subcellular localization in the perinuclear area. These data suggest diverse functions for this protein in signal transduction.

Brain Chemistry↗
PubMedDate not supplied

PDGF-BB induces expression of LTBP-1 but not TGF-beta1 in a rat cirrhotic fat storing cell line.

TGF-beta, a profibrogenic cytokine is predominantly secreted as a latent molecule complexed with one of the latent TGF-beta binding proteins (LTBP). Due to the proposed functions of LTBP-1 and -3 in regulating TGF-beta-bioavailability and -activity, we investigated the effects of PDGF-BB and TGF-beta1 on their expression levels in Cirrhotic fat storing cells (CFSC). CFSC basally express LTBP-1 and -3 and TGF-beta1. LTBP-1 colocalizes with LAP and the cells secrete some active TGF-beta1. Promoter studies showed no strong induction of the LTBP-1 promoters after stimulation, although mRNA and protein levels were increased by PDGF-BB treatment without affecting TGF-beta1 expression. Vice versa, TGF-beta1 treatment did not alter LTBP-1 expression while an autocrine induction was found. Our data indicate that LTBP-1 but not TGF-beta1 is induced by PDGF-BB and that TGF-beta1 autoinduction does not affect the expression of LTBP-beta1. This divergent regulation may represent an important mechanism for modulation of TGF-beta bioavailability.

Adipocytes↗
PubMed2002

Enhanced inhibition of human immunodeficiency virus type 1 replication by novel lentiviral vectors expressing human immunodeficiency virus type 1 envelope antisense RNA.

We have developed optimized versions of a conditionally replicating human immunodeficiency virus type 1 (HIV-1)-based lentiviral vector for gene therapy of HIV-1 infection. These vectors target HIV-1 RNAs containing sequences of the envelope gene by expressing a 1-kb fragment of the HIV-1 Tat/Rev intron in the antisense orientation. Expression of the envelope antisense gene (envAS) was evaluated under the control of different internal promoters such as the human phosphoglycerate kinase (PGK) promoter, the human EF1-alpha promoter, and the U3 region of the SL3 murine leukemia virus. The U3-SL3 promoter transactivates transcription from the vector HIV-1 LTR and drives higher expression levels of envAS-containing RNAs than other promoters in T-cell lines. The effect of other vector structural features was also evaluated. We found that the central polypurine tract and central termination sequence (cPPT) produce a small increase in vector infectivity of 2-fold to 3-fold and results in a 10-fold higher inhibition of wild-type viral replication in challenge experiments. The woodchuck hepatitis posttranscriptional regulatory element (WPRE) does not increase the cytoplasmic levels of envAS mRNA in T-cell lines. We observed that SupT1 and primary CD4(+) T cells transduced with these vectors showed high inhibition of HIV-1 replication, suppression of syncitium formation, and increased cell viability when infected with several HIV-1 laboratory strains. Our results suggest that higher vector copy number and increased levels of envAS RNA expression contribute to block replication of divergent strains of HIV-1.

CD4-Positive T-Lymphocytes↗
PubMed2025

ScGOclust: leveraging gene ontology to find functionally analogous cell types between distant species.

MOTIVATION: Basic biological processes are shared across animal species, yet their cellular mechanisms are profoundly diverse. Comparing cell-type gene expression between species reveals conserved and divergent cellular functions. However, as phylogenetic distance increases, gene-based comparisons become less informative. The gene ontology (GO) knowledgebase offers a solution by serving as the most comprehensive resource of gene functions across a vast diversity of species, providing a bridge for distant species comparisons. RESULTS: Here, we present scGOclust, a computational tool that constructs de novo cellular functional profiles using GO terms, facilitating systematic and robust comparisons within and across species. We applied scGOclust to analyse and compare the heart, gut, and kidney between mouse and fly, and whole-body data from Caenorhabditis elegans and Hydra vulgaris. We show that scGOclust effectively recapitulates the function spectrum of different cell types, characterizes functional similarities between homologous cell types, and reveals functional convergence between unrelated cell types. Additionally, we identified subpopulations within the fly crop that show circadian rhythm-regulated secretory properties and hypothesize an analogy between fly principal cells from different segments and distinct mouse kidney tubules. We envision scGOclust as an effective tool for uncovering functionally analogous cell types or organs across distant species, offering fresh perspectives on evolutionary and functional biology. AVAILABILITY AND IMPLEMENTATION: ScGOclust is publicly available on CRAN: https://cran.r-project.org/web/packages/scGOclust/index.html and development versions are available on GitHub: github.com/Papatheodorou-Group/scGOclust/.

Animals↗
PubMed1995

The tolkin gene is a tolloid/BMP-1 homologue that is essential for Drosophila development.

The Drosophila decapentaplegic (dpp) gene, a member of the transforming growth factor beta superfamily of growth factors, is critical for specification of the embryonic dorsal-ventral axis, for proper formation of the midgut, and for formation of Drosophila adult structures. The Drosophila tolloid gene has been shown to genetically interact with dpp. The genetic interactions between tolloid and dpp suggests a model in which the tolloid protein participates in a complex containing the DPP ligand, its protease serving to activate DPP, either directly or indirectly. We report here the identification and cloning of another Drosophila member of the tolloid/bone morphogenic protein (BMP) 1 family, tolkin, which is located 700 bp 5' to tolloid. Its overall structure is like tolloid, with an N-terminal metalloprotease domain, five complement subcomponents C1r/C1s, Uegf, and Bmp1 (CUB) repeats and two epidermal growth factor (EGF) repeats. Its expression pattern overlaps that of tolloid and dpp in early embryos and diverges in later stages. In larval tissues, both tolloid and tolkin are expressed uniformly in the imaginal disks. In the brain, both tolloid and tolkin are expressed in the outer proliferation center, whereas tolkin has another stripe of expression near the outer proliferation center. Analysis of lethal mutations in tolkin indicate it is vital during larval and pupal stages. Analysis of its mutant phenotypes and expression patterns suggests that its functions may be mostly independent of tolloid and dpp.

Amino Acid Sequence↗
PubMed2000

The mycarose-biosynthetic genes of Streptomyces fradiae, producer of tylosin.

The tylCK region of the Streptomyces fradiae genome was sequenced, revealing an incomplete set of five tylC genes encoding all-but-one of the enzymes involved in the biosynthesis of mycarose. The latter is a 6-deoxyhexose sugar required during production of the macrolide antibiotic, tylosin. The missing mycarose-biosynthetic gene, tylCVI, was found about 50 kb distant from its functional partners, on the other side of the tylG (polyketide synthase) gene complex. Mutational analysis, involving targeted gene transplacement, was employed to confirm the functions of specific genes, including tylCVI. Particularly interesting was the similarity between the tylosin-biosynthetic mycarosyltransferase enzyme, TylCV, and proteins of the macrolide glycosyltransferase (MGT) family that inactivate macrolides via glycosylation of attached sugar residues and are involved in resistance and/or antibiotic efflux. The arrangement of genes within the 'mycarose cluster' would allow their expression as two short operons with divergent, and perhaps co-regulated, promoters. Whether displacement of tylCVI relative to the other tylC genes provides additional regulatory opportunities remains to be established.

Anti-Bacterial Agents↗
PubMed2005

Genotype-phenotype relationships in a mouse model for human small-cell lung cancer.

Lung tumors are usually classified into small-cell lung cancer (SCLC) or non-SCLC (NSCLC) depending on their pathological and histological characteristics. SCLC is defined not only by its characteristic neuroendocrine differentiation, aggressiveness, and metastatic potential, but also by a specific set of genetic aberrations, including the loss of the tumor suppressor genes p53 and Rb1 and the amplification of any member of the Myc family of oncogenes. We have previously described a mouse model of SCLC by somatic conditional disruption of Trp53 and Rb1 genes that closely resembles the human condition. Based on the possibility to study early tumor lesions and to culture and subclone progressed tumors and metastases, we discuss here a strategy to define genotype-phenotype relationships that can explain the underlying biology of lung neuroendocrine tumors. We have found that tumors may be constituted by genetically variant cell populations, which might represent different progression stages. Interestingly, we observed L-myc amplification and Ascl-1 expression in those populations showing neuroendocrine differentiation. Non-neuroendocrine cell populations from the same tumors did not show L-myc amplification nor Ascl-1 expression. We propose that this genetic divergence can play a relevant role in the definition of some phenotypic characteristics like metastasis potential or chemoresistance.

Animals↗
PubMed2000

Population differentiation in an annual legume: genetic architecture.

The presence or absence of epistasis, or gene interaction, is explicitly assumed in many evolutionary models. Although many empirical studies have documented a role of epistasis in population divergence under laboratory conditions, there have been very few attempts at quantifying epistasis in the native environment where natural selection is expected to act. In addition, we have little understanding of the frequency with which epistasis contributes to the evolution of natural populations. In this study we used a quantitative genetic design to quantify the contribution of epistasis to population divergence for fitness components of a native annual legume, Chamaecrista fasciculata. The design incorporated the contrast of performance of F2 and F3 segregating progeny of 18 interpopulation crosses with the F1 and their parents. Crosses were conducted between populations from 100 m to 2000 km apart. All generations were grown for two seasons in the natural environment of one of the parents. The F1 often outperformed the parents. This F1 heterosis reveals population structure and suggests that drift is a major contributor to population differentiation. The F2 generation demonstrated that combining genes from different populations can sometimes have unexpected positive effects. However, the F3 performance indicated that combining genes from different populations decreased vigor beyond that due to the expected loss of heterozygosity. Combined with previous data, our results suggest that both selection and drift contribute to population differentiation that is based on epistatic genetic divergence. Because only the F3 consistently expressed hybrid breakdown, we conclude that the epistasis documented in our study reflects interactions among linked loci.

Biological Evolution↗
PubMed2002

Host defense functions of proteolytically processed and parent (unprocessed) cathelicidins of rabbit granulocytes.

Members of the cathelicidin family are present in all mammals studied. Generally, these proteins contain a conserved N-terminal domain and a structurally and functionally divergent C-terminal region that expresses antibacterial or other activities when proteolytically released. Rabbit granulocytes produce CAP18, a cathelicidin that conforms to this structural and functional organization, and also 15-kDa protein isoforms (p15s) that share several key structural features with other cathelicidins but apparently do not undergo processing with release of an active peptide. To further define the importance of proteolysis in the antibacterial activities of these proteins, we have purified from granulocytes proCAP18, its C-terminal peptide (CAP18p), and two p15 isoforms to apparent homogeneity. Of these four polypeptides, only CAP18p was independently cytotoxic to encapsulated Escherichia coli (90% inhibitory concentration, approximately 600 nM) but it was approximately 50-fold less potent on a molar basis than the bactericidal/permeability-increasing protein (BPI). However, all four cathelicidin species, notably including proCAP18, exhibited antibacterial synergy with BPI, and the p15s also displayed synergy with CAP18p in the absence of BPI. Subnanomolar concentrations of proCAP18 blocked lipopolysaccharide-induced chemiluminescence of human leukocytes, showing a molar potency more than 100-fold greater than that of CAP18p ( approximately 20 nM) or BPI ( approximately 50 nM). Thus, while independent bactericidal activity of cathelicidins requires processing, other host-defense functions do not and are more potently expressed by the unprocessed protein than by the C-terminal peptide.

Animals↗
PubMed2006

Overlapping and specialized functions of the molybdenum-dependent regulators MopA and MopB in Rhodobacter capsulatus.

The phototrophic purple bacterium Rhodobacter capsulatus encodes two similar but functionally not identical molybdenum-dependent regulator proteins (MopA and MopB), which are known to replace each other in repression of the modABC genes (coding for an ABC-type high-affinity Mo transport system) and anfA (coding for the transcriptional activator of Fe-nitrogenase genes). We identified further Mo-regulated (mor) genes coding for a putative ABC-type transport system of unknown function (MorABC) and a putative Mo-binding protein (Mop). The genes coding for MopA and the ModABC transporter form part of a single transcriptional unit, mopA-modABCD, as shown by reverse transcriptase PCR. Immediately upstream of mopA and transcribed in the opposite direction is mopB. The genes coding for the putative MorABC transporter belong to two divergently transcribed operons, morAB and morC. Expression studies based on lacZ reporter gene fusions in mutant strains defective for either MopA, MopB, or both revealed that the regulators substitute for each other in Mo-dependent repression of morAB and morC. Specific Mo-dependent activation of the mop gene by MopA, but not MopB, was found to control the putative Mo-binding protein. Both MopA and MopB are thought to bind to conserved DNA sequences with dyad symmetry in the promoter regions of all target genes. The positions of these so-called Mo boxes relative to the transcription start sites (as determined by primer extension analyses) differed between Mo-repressed genes and the Mo-activated mop gene. DNA mobility shift assays showed that MopA and MopB require molybdenum to bind to their target sites with high affinity.

ATP-Binding Cassette Transporters↗
PubMed2001

Catabolite repression of the citrate fermentation genes in Klebsiella pneumoniae: evidence for involvement of the cyclic AMP receptor protein.

Klebsiella pneumoniae is able to grow anaerobically with citrate as a sole carbon and energy source by a fermentative pathway involving the Na(+)-dependent citrate carrier CitS, citrate lyase, and oxaloacetate decarboxylase. The corresponding genes are organized in the divergent citC and citS operons, whose expression is strictly dependent on the citrate-sensing CitA-CitB two-component system. Evidence is provided here that the citrate fermentation genes are subject to catabolite repression, since anaerobic cultivation with a mixture of citrate and glucose or citrate and gluconate resulted in diauxic growth. Glucose, gluconate, and also glycerol decreased the expression of a chromosomal citS-lacZ fusion by 60 to 75%, whereas a direct inhibition of the citrate fermentation enzymes was not observed. The purified cyclic AMP (cAMP) receptor protein (CRP) of K. pneumoniae bound to two sites in the citC-citS intergenic region, which were centered at position -41.5 upstream of the citC and citS transcriptional start sites. Binding was apparently stimulated by the response regulator CitB. These data indicate that catabolite repression of the citrate fermentation genes is exerted by CRP and that in the absence of repressing carbon sources the cAMP-CRP complex serves to enhance the basal, CitB-dependent transcription level.

Anaerobiosis↗
PubMed1990

Secondary structure of the human T-cell leukemia virus type 1 rex-responsive element is essential for rex regulation of RNA processing and transport of unspliced RNAs.

Rex protein of human T-cell leukemia virus type 1 (HTLV-1) induces cytoplasmic expression of unspliced gag/pol mRNA and singly spliced env mRNA and thus is essential for replication of the virus. This regulation requires a cis-acting rex-responsive element (RXE), located in the 3' region of the viral RNA. By external deletion, we have identified RXE composed of 205 nucleotides. The secondary structure of RXE was confirmed by studies on its susceptibility to nuclease digestions to consist of four stem-loops and a long stretch of stem structure. Substitution and deletion mutations revealed that two regions of the stem-loops and their secondary structures are essential for rex regulation. Similar secondary structures were found in the corresponding regions of HTLV-2, bovine leukemia virus and human immunodeficiency virus. Furthermore, a sequence of 11 nucleotides in the RXE was found to be conserved in the secondary structures of HTLV-1, HTLV-2, and bovine leukemia virus. These observations suggest that the secondary structure as well as the conserved sequence may be important in expression of unspliced RNA even with diverged sequences as observed in these viruses.

Base Sequence↗
PubMed2002

Herpes simplex virus type 1 origins of DNA replication play no role in the regulation of flanking promoters.

Herpes simplex virus (HSV) exhibits altered gene regulation in neuronal compared to nonneuronal tissues. It has been hypothesized that initiation of DNA synthesis at the viral origins of replication (oriS and oriL) is a critical step in the upregulation of transcriptional activity of flanking divergent promoters, thereby increasing productive gene expression in neurons. Notably, oriS is flanked by the immediate-early (IE) ICP4 and ICP22/47 promoters, and oriL is flanked by the early (E) UL29 and UL30 promoters. To test this hypothesis further, a series of constructs were generated in which these promoters were placed upstream of luciferase genes. In addition, DNA replication origins were deleted in the context of these promoter constructs. All cassettes were recombined into the viral genome of HSV type 1 strain KOS at a site distal to its native origins. Recombinant reporter expression was monitored in vitro and in vivo to determine the role of viral origins of DNA replication in the regulation of their flanking promoters. Reporter gene expression was unaffected by the presence or absence of oriS or oriL, with the exception of a twofold increase in ICP22/47 promoter activity in the absence of oriS. DNA synthesis inhibitors resulted in a decrease of both IE- and E-promoter activity in primary cells but not continuous cell cultures. Reporter activity was readily assayed in vivo during acute infection and reactivation from latency and was also sensitive to DNA synthesis inhibitors. In all assays, reporter gene expression was unaffected by the presence or absence of either oriS or oriL. These data support the requirement of DNA synthesis for full viral gene expression in vivo but suggest that the origin elements play no role in the regulation of their flanking promoters.

Animals↗
PubMed1992

Intrafamilial heterogeneity in hereditary motor neuron disease.

Although there are varied inheritance patterns in motor neuron disease (MND), the phenotype of MND is reported to be constant within these families, ie, cases of amyotrophic lateral sclerosis or primary lateral sclerosis do not occur in pedigrees with cases of spinal muscular atrophy. We describe four pedigrees whose members diverged in the phenotype of MND expressed. The intrafamilial variation of phenotype suggests a similar pathogenesis for some of the varied types of familial MND and the need for careful inquiry of family history in all patients with MND.

Aged↗
PubMed2006

The divergent TGF-beta ligand Dawdle utilizes an activin pathway to influence axon guidance in Drosophila.

Axon guidance is regulated by intrinsic factors and extrinsic cues provided by other neurons, glia and target muscles. Dawdle (Daw), a divergent TGF-beta superfamily ligand expressed in glia and mesoderm, is required for embryonic motoneuron pathfinding in Drosophila. In daw mutants, ISNb and SNa axons fail to extend completely and are unable to innervate their targets. We find that Daw initiates an activin signaling pathway via the receptors Punt and Baboon (Babo) and the signal-transducer Smad2. Furthermore, mutations in these signaling components display similar axon guidance defects. Cell-autonomous disruption of receptor signaling suggests that Babo is required in motoneurons rather than in muscles or glia. Ectopic ligand expression can rescue the daw phenotype, but has no deleterious effects. Our results indicate that Daw functions in a permissive manner to modulate or enable the growth cone response to other restricted guidance cues, and support a novel role for activin signaling in axon guidance.

Activin Receptors↗
PubMed1995

DWnt-4, a novel Drosophila Wnt gene acts downstream of homeotic complex genes in the visceral mesoderm.

Wnt genes encode putative cell signalling proteins which play crucial roles during development. From a library of DNA fragments associated, in vivo, with Ultrabithorax proteins, we isolated a novel Drosophila Wnt gene, DWnt-4. Neither a paralog nor an ortholog of the gene exist in the current repertoire of full-length Wnt sequences. DWnt-4 maps close (30 kb) to wingless, suggesting that the two Wnt genes derive from a duplication that occurred early in evolution, since they are significantly diverged in sequence and structure. Developmental expression of DWnt-4 partially overlaps that of wingless. The gene is transcribed following a segment polarity-like pattern in the posterior-most cells of each parasegment of the ectoderm, and at two locations that correspond to parasegments 4 and 8 of the visceral mesoderm. The control of DWnt-4 expression in the visceral mesoderm involves a network of regulatory molecules that includes Ultrabithorax and other proteins from the homeotic complex (HOM-C), as well as the TGF-beta decapentaplegic gene product.

Animals↗
PubMed2000

Copurification of brain G-protein beta5 with RGS6 and RGS7.

A structurally divergent G-protein beta subunit expressed in brain and retina, Gbeta5, exhibits functional specialization in its protein-protein interactions in vitro. In retina, Gbeta5 has been isolated in a soluble complex with regulator of G-protein signaling RGS7. The function and molecular associations of Gbeta5 in brain are unknown. To identify tightly bound proteins associated with Gbeta5 in the brain, it was immunoaffinity-purified from a nonionic detergent extract of washed mouse brain membranes using an antibody directed against its N terminus. Elution with cognate peptide revealed a broad band of 55 kDa that coeluted with Gbeta5 on SDS-PAGE. The copurifying 55 kDa band was identified as an approximately 1:1 mixture of RGS6 and RGS7 by matrix-assisted laser desorption ionization mass spectroscopic analysis of tryptic peptides. Gbeta5 and RGS7 could be reciprocally coimmunoprecipitated from unfractionated brain membrane extracts confirming the tight association of native proteins. In contrast, immunoblotting of the peptide eluate revealed no copurifying Galphaq/11, Galphai1/2, Ggamma2, Ggamma3, or Ggamma7. These findings implicate RGS6 and RGS7 in the function of Gbeta5 in the brain and suggest that a large fraction of membrane-targeted Gbeta5 has no associated G subunit and therefore functions outside the canonical framework of G(beta)(gamma) interactions.

Animals↗