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At least 1,225 records · Page 68Linked to original sources
PubMed2002

Circle of life of secretory vesicles in gastric enterochromaffin-like cells.

Enterochromaffin-like (ECL) cells are neuroendocrine cells in the gastric epithelium characterized by numerous electron-empty, histamine-containing secretory vesicles. The antral hormone gastrin is the key stimulus of histamine secretion from this cell type, thereby controling acid secretion. Following receptor binding, gastrin activates a biphasic calcium signal in ECL cells that involves activation of inositol triphosphate receptors and calcium entry across the plasma membrane. Dihydropyridines block gastrin-induced histamine secretion. However, no depolarization was observed following stimulation with gastrin. Elevation of intracellular calcium by gastrin is an important prerequisite for exocytosis. In permeabilized ECL cells, addition of calcium results in histamine release, which can be inhibited by tetanus toxin and botulinum neurotoxin A, underlining the functional importance of the synaptosome-associated protein of 25 kDa (SNAP-25) and synaptobrevin. Immunocytochemistry also confirmed the presence of these SNAP receptor (SNARE) proteins, as well as synaptophysin, synaptotagmin, and syntaxin. Following 3-6 h of incubation in isolated cells, several transcription factors are induced by gastrin, such as ERK1/2, Sp1, and CRE. Gastrin thereby directly stimulates transcription of the vesicular monoamine transporter subtype 2 (VMAT-2) and chromogranins. Gene expression of histidine decarboxylase (HDC) appears to be stimulated by a putative "gastrin-responsive" element adjacent to the HDC exon 1 gene. ECL cells thereby share several similarities with adrenal chromaffin cells and neurons, but have their own functional properties. Gastrin coordinates secretion, synthesis, and storage by activating diverging signal transducers, leading to a functional synergy in this cell type.

Animals↗
PubMed2005

Identification and characterisation of two runx2 homologues in zebrafish with different expression patterns.

Genome and gene duplications are considered to be the impetus to generate new genes, as the presence of multiple copies of a gene allows for paralogues to adopt novel function. After at least two rounds of genome/gene duplication, the Runt gene family consists of three members in vertebrates, instead of one in invertebrates. One of the family members, Runx2, plays a key role in the development of bone, a tissue that first occurs in vertebrates. The family has thus gained new gene function in the course of evolution. Two Runx2 genes were cloned in the vertebrate model system the zebrafish (Danio rerio). The expression patterns of the two genes differ and their kinetics differ up to four fold. In addition, splice forms exist that are novel when compared with mammals. Together, these findings comprise opportunities for selection and retention of the paralogues towards divergent and possibly new function.

5' Untranslated Regions↗
PubMed2003

Innovation from reduction: gene loss, domain loss and sequence divergence in genome evolution.

Analyses of genome sequences have revealed a surprisingly variable distribution of genes, reflecting the generation of novel genes, lateral gene transfer and gene loss. The impact of gene loss on organisms has been difficult to examine, but the loss of protein coding genes, the loss of domains within proteins and the divergence of genes have made surprising contributions to the differences among organisms. This paper reviews surveys of gene loss and divergence in fungal and archaeal genomes that indicate suites of functionally related genes tend to undergo loss and divergence. Instances of fungal gene loss highlighted here suggest that specific cellular systems have changed, such as Ca 2+ biology in Saccharomyces cerevisiae and peroxisome function in Schizosaccharomyces pombe. Analyses of loss and divergence can provide specific predictions regarding protein-protein interactions, and the relationship between networks of protein interactions and loss may form a part of a parametric model of genome evolution.

Chromosome Mapping↗
PubMed2003

The major tick salivary gland proteins and toxins from the soft tick, Ornithodoros savignyi, are part of the tick Lipocalin family: implications for the origins of tick toxicoses.

The origins of tick toxicoses remain a subject of controversy because no molecular data are yet available to study the evolution of tick-derived toxins. In this study we describe the molecular structure of toxins from the soft tick, Ornithodoros savignyi. The tick salivary gland proteins (TSGPs) are four highly abundant proteins proposed to play a role in salivary gland granule biogenesis of the soft tick O. savignyi, of which the toxins TSGP2 and TSGP4 are a part. They were assigned to the lipocalin family based on sequence similarity to known tick lipocalins. Several other tick lipocalins were also identified using Smith-Waterman database searches, bringing the tick lipocalin family up to 20. Phylogenetic analysis showed that most tick lipocalins group within genus-specific clades, suggesting that gene duplication and divergence of tick lipocalin function occurred after tick speciation, most probably during the evolution of a hematophagous lifestyle. TSGP2 and TSGP3 show high sequence identity and group terminal to moubatin, an inhibitor of collagen-induced platelet aggregation from the tick, O. moubata. However, no platelet aggregation inhibitory activity is associated with the TSGPs using ADP or collagen as agonists, suggesting that TSGP2 and TSGP3 duplicated after divergence of O. savignyi and O. moubata. This timing is supported by the absence of TSGP2-4 in the salivary gland extracts of O. moubata. The absence of TSGP2 and TSGP4 in salivary gland extracts from O. moubata correlates with the nontoxicity of this tick species. The implications of this study are that the various forms of tick toxicoses do not have a common origin, but must have evolved independently in those tick species that cause pathogenesis.

Amino Acid Sequence↗
PubMed1980

Origins of metabolic diversity: substitution of homologous sequences into genes for enzymes with different catalytic activities.

Similar amino acid sequences were found in portions of bacterial enzymes that mediate different biochemical transformations. Reaction catalyzed by the enzymes include oxygenation, decarboxylation, isomerization, and hydrolysis. The proteins share a common evolutionary history because they participate in an overall catabolic process known as the beta-ketoadipate pathway. One interpretation of the sequence similarities might be that duplication of a single gene gave rise to ancestral genes for the enzymes with different catalytic activities. According to this view, homologous sequences from the ancestral gene were conserved as the proteins diverged to assume different functions. This hypothesis is vitiated by comparison of the NH2-terminal amino acid sequences of sets of enzymes that mediate identical or analogous metabolic reactions within an organism. Gene duplications giving rise to the enzymes within each set must have followed duplication of a putative ancestral gene for all the sets. Yet the amino acid sequences of the proteins within each set have diverged widely, and against this background of divergence the conservation of sequences from an ancestor common to all the enzymes is unlikely. Rather, it appears that most regions of sequence similarity shared by enzymes from different sets were acquired subsequent to their divergence from any common ancestor. In some cases it appears that relatively short regions of sequence homology were achieved by mutations causing the transfer of sequence information from one set of structural genes to structural genes in another set. Alignment of homologous amino acid sequences within any single set requires the introduction of few gaps. Because gaps are required to align sequences that have been altered by the insertion of genetic material, the evidence indicates that copies of oligonucleotides were exchanged by genetic substitution among different structural genes as they coevolved.

Acinetobacter↗
PubMed2003

Structural and functional characterization of the zebrafish gene for glial fibrillary acidic protein, GFAP.

Glial fibrillary acidic protein, GFAP, is an astrocyte-specific member of the family of intermediate filament proteins which are involved in formation of the cytoskeletal structure. We here present a characterization of the zebrafish GFAP gene and corresponding protein. The zebrafish GFAP gene have the same exon-intron organization as the mammalian orthologoue genes. Comparison of the protein with mammalian GFAP shows that the amino acid sequence is highly conserved in the rod and tail domains whereas the head domain has diverged. Zebrafish GFAP exhibits functional characteristics of an intermediate filament protein such as dimerization potential, capacity to assembly into filaments, and cytoskeletal localization. Mutations in human GFAP have been associated with a severe childhood brain disorder called Alexander disease. Interestingly, the mutations affect preferentially amino acid residues of GFAP that are evolutionarily conserved. This indicates that a change of functionally core residues in GFAP is a prerequisite for the disease phenotype to develop and the initial steps in the pathogenesis may thus be modeled in zebrafish.

Alexander Disease↗
PubMed2004

Functional chimeras between the catalytic domains of the mycobacterial adenylyl cyclase Rv1625c and a Paramecium guanylyl cyclase.

The class IIIa adenylyl cyclase (AC) Rv1625c from Mycobacterium tuberculosis forms homodimers with two catalytic centres, whereas the Paramecium guanylyl and mammalian ACs operate as pseudoheterodimers with one catalytic centre. The functional and structural relationship of the catalytic domains of these related class III cyclases was investigated. Point mutations introduced into Rv1625c to engineer a forskolin-binding pocket created a single heterodimeric catalytic centre, yet did not result in forskolin activation. Chimerization of these Rv1625c point mutants with corresponding mammalian AC domains was impossible. However, it was successful using a complemental Paramecium guanylyl cyclase domain and resulted in an AC. The data signify a divergence of structural and functional evolution in class III Acs.

Adenylyl Cyclases↗
PubMed2004

The SUV3 gene from Saccharomyces douglasii is a functional equivalent of its Saccharomyces cerevisiae orthologue and is essential for respiratory growth.

In the yeast Saccharomyces cerevisiae the product of the nuclear gene SUV3 has been shown to be involved in a variety of mitochondrial post-transcriptional processes. We have cloned and sequenced the SUV3 gene from Saccharomyces douglasii, a close relative of S. cerevisiae which has important changes in the organization of its mitochondrial genome and concomitant changes in nucleo-mitochondrial interactions. We show that the S. douglasii SUV3 gene shares considerable structural homology (92% amino acid sequence identity) with its S. cerevisiae counterpart and that their nucleotide sequences display evidence of recent divergence. To determine the function of the S. douglasii SUV3 gene we have constructed a strain carrying an inactive SUV3 gene and analyzed the effect of this inactivation on the integrity of the mitochondrial genome and on the stability of mitochondrial transcripts. We have demonstrated that the S. douglasii SUV3 gene, like the S. cerevisiae gene, is essential for respiratory growth and for stability of the intron-containing mitochondrial transcripts, thus the two genes are functionally equivalent. Also the S. douglasii and S. cerevisiae SUV3 genes are completely interchangeable, despite the differences in the structure of the mitochondrial chromosome in the two yeasts.

Amino Acid Sequence↗
PubMed1995

Reliability and validity of the CSSRD functional assessment survey in rheumatoid arthritis. Cooperative Systematic Studies of Rheumatic Diseases.

OBJECTIVE: To demonstrate the reliability and validity characteristics of a fast, intensively focused functional assessment questionnaire that has been used in rheumatoid arthritis clinical trials by the Cooperative Systematic Studies of Rheumatic Diseases group (CSSRD). METHODS: Data from three double-blind, controlled clinical trials by CSSRD were used to examine the properties of the Functional Assessment Survey as a measure of physiologic function. RESULTS: The Functional Assessment Survey has reasonable test-retest reliability and convergent validity with the Steinbrocker et al. functional class. It demonstrated appropriate divergent validity with other clinical measures of response, as well as discriminant validity. CONCLUSIONS: The CSSRD Functional Assessment Survey is brief, intensive, and focused. Reliability and validity characteristics have been documented.

Activities of Daily Living↗
PubMed2003

Functional complementation between a novel mammalian polygenic transport complex and an evolutionarily ancient organic solute transporter, OSTalpha-OSTbeta.

These studies identify an organic solute transporter (OST) that is generated when two novel gene products are co-expressed, namely human OSTalpha and OSTbeta or mouse OSTalpha and OSTbeta. The results also demonstrate that the mammalian proteins are functionally complemented by evolutionarily divergent Ostalpha-Ostbeta proteins recently identified in the little skate, Raja erinacea, even though the latter exhibit only 25-41% predicted amino acid identity with the mammalian proteins. Human, mouse, and skate OSTalpha proteins are predicted to contain seven transmembrane helices, whereas the OSTbeta sequences are predicted to have a single transmembrane helix. Human OSTalpha-OSTbeta and mouse Ostalpha-Ostbeta cDNAs were cloned from liver mRNA, sequenced, expressed in Xenopus laevis oocytes, and tested for their ability to functionally complement the corresponding skate proteins by measuring transport of [3H]estrone 3-sulfate. None of the proteins elicited a transport signal when expressed individually in oocytes; however, all nine OSTalpha-OSTbeta combinations (i.e. OSTalpha-OSTbeta pairs from human, mouse, or skate) generated robust estrone 3-sulfate transport activity. Transport was sodium-independent, saturable, and inhibited by other steroids and anionic drugs. Human and mouse OSTalpha-OSTbeta also were able to mediate transport of taurocholate, digoxin, and prostaglandin E2 but not of estradiol 17beta-d-glucuronide or p-aminohippurate. OSTalpha and OSTbeta were able to reach the oocyte plasma membrane when expressed either individually or in pairs, indicating that co-expression is not required for proper membrane targeting. Interestingly, OSTalpha and OSTbeta mRNAs were highly expressed and widely distributed in human tissues, with the highest levels occurring in the testis, colon, liver, small intestine, kidney, ovary, and adrenal gland.

Amino Acid Sequence↗
PubMed1994

Homology modeling of divergent proteins.

A method is presented for homology modeling of proteins bearing weak sequence identity to proteins of known tertiary structure. To accommodate non-identical amino acids in the core region, the backbone of the structurally conserved core of the model protein is allowed to deviate from that of the template protein. We have expanded FOLDER, a distance geometry-based homology modeling method, to allow for such displacements in the structurally conserved core. Models are built by rigidly constraining the interatomic distances within a structurally conserved segment and by allowing the interatomic distances between these segments to vary by a "divergence factor". We test this method by simulating models of the beta-barrel domain D1 of CD4 and a four-helix bundle protein cytochrome b562 using the crystal structures of Bence-Jones protein and cytochrome c' as templates, respectively. In both cases, previously published structure-based sequence alignments were used for simulating models. The root-mean-square (r.m.s.) deviation of the backbone atoms in the common core between the templates and models was found to be a function of the imposed divergence factor. Our results demonstrate that this r.m.s. deviation results from the relative displacements of structurally conserved segments to accommodate the amino acid replacements in the core of the model protein. To test the integrity of the simulated structures we compared them with their respective crystal structures. The r.m.s. deviation of the backbone atoms in the core regions of the simulated models and their respective crystal structures is approximately 1.4 A. The r.m.s. deviation for all the backbone atoms in the models, including those in the structurally variable regions, which are modeled de novo, is 2.4 A for CD4 and 3.2 A for cytochrome b562 when compared with their respective X-ray structures.

Animals↗
PubMed2003

Finding functional features in Saccharomyces genomes by phylogenetic footprinting.

The sifting and winnowing of DNA sequence that occur during evolution cause nonfunctional sequences to diverge, leaving phylogenetic footprints of functional sequence elements in comparisons of genome sequences. We searched for such footprints among the genome sequences of six Saccharomyces species and identified potentially functional sequences. Comparison of these sequences allowed us to revise the catalog of yeast genes and identify sequence motifs that may be targets of transcriptional regulatory proteins. Some of these conserved sequence motifs reside upstream of genes with similar functional annotations or similar expression patterns or those bound by the same transcription factor and are thus good candidates for functional regulatory sequences.

Algorithms↗
PubMed1997

Isolation of cDNA for an NADP-malic enzyme from Aloe arborescens.

NADP-malic enzyme catalyzes the reaction of decarboxylation from malate. In CAM plants, functions of this enzyme diverged to include both photosynthetic and non-photosynthetic roles. A full length cDNA for an NADP-malic enzyme was isolated from an 'obligate' CAM plant aloe (Aloe arborescens). The cDNA contains an ORF encoding 592 amino acid residues, whose sequence is highly homologous to the known plant NADP-malic enzymes. This gene is constitutively expressed in all organs in a low level. The amount of the transcript exhibited no diurnal variation, suggesting that this gene is not involved in photosynthetic functions.

Aloe↗
PubMed1996

Higher-plant chloroplast and cytosolic fructose-1,6-bisphosphatase isoenzymes: origins via duplication rather than prokaryote-eukaryote divergence.

Full-size cDNAs encoding the precursors of chloroplast fructose-1,6-bisphosphatase (FBP), sedoheptulose-1,7-bisphosphatase (SBP), and the small subunit of Rubisco (RbcS) from spinach were cloned. These cDNAs complete the set of homologous probes for all nuclear-encoded enzymes of the Calvin cycle from spinach (Spinacia oleracea L.). FBP enzymes not only of higher plants but also of non-photosynthetic eukaryotes are found to be unexpectedly similar to eubacterial homologues, suggesting a eubacterial origin of these eukaryotic nuclear genes. Chloroplast and cytosolic FBP isoenzymes of higher plants arose through a gene duplication event which occurred early in eukaryotic evolution. Both FBP and SBP of higher plant chloroplasts have acquired substrate specificity, i.e. have undergone functional specialization since their divergence from bifunctional FBP/SBP enzymes of free-living eubacteria.

Amino Acid Sequence↗
PubMed2001

A lineage-restricted and divergent beta-tubulin isoform is essential for the biogenesis, structure and function of blood platelets.

BACKGROUND: Mammalian megakaryocytes release blood platelets through a remarkable process of cytoplasmic fragmentation and de novo assembly of a marginal microtubule band. Cell-specific components of this process include the divergent beta-tubulin isoform beta1 that is expressed exclusively, and is the predominant isoform, in platelets and megakaryocytes. The functional significance of this restricted expression, and indeed of the surprisingly large repertoire of metazoan tubulin genes, is unclear. Fungal tubulin isoforms appear to be functionally redundant, and all mammalian beta-tubulins can assemble in a variety of microtubules, whereas selected fly and worm beta-tubulins are essential in spermatogenesis and neurogenesis. To address the essential role of beta1-tubulin in its natural context, we generated mice with targeted gene disruption. RESULTS: beta1-tubulin(-/-) mice have thrombocytopenia resulting from a defect in generating proplatelets, the immediate precursors of blood platelets. Circulating platelets lack the characteristic discoid shape and have defective marginal bands with reduced microtubule coilings. beta1-tubulin(-/-) mice also have a prolonged bleeding time, and their platelets show an attenuated response to thrombin. Two alternative tubulin isoforms, beta2 and beta5, are overexpressed, and the total beta-tubulin content of beta1-tubulin(-/-) megakaryocytes is normal. However, these isoforms assemble much less efficiently into platelet microtubules and are thus unable to compensate completely for the absence of beta1-tubulin. CONCLUSIONS: This is the first genetic study to address the essential functions of a mammalian tubulin isoform in vivo. The results establish a specialized role for beta1-tubulin in platelet synthesis, structure, and function.

Animals↗
PubMed1976

Agonist and antimineralocorticoid activities of spirolactones.

To investigate the mechanism of action of antimineralocorticoids, a series of spirolactone analogues was evaluated for both mineralocorticoid antagonist and agonist activity. Antagonist activity was assessed by inhibition of aldosterone stimulated sodium transport employing toad bladder short-circuit current (SCC) measurements. Agonist activity was assessed in the same system by the direct effect of spirolactones on SCC. Opening of the gamma-lactone ring of a spirolactone dramatically decreased antagonist activity in the compound studied. Several C-7 chi-substitutions resulted in either enhanced or diminished activity, whereas deletion of the C-10 methyl group (i.e., 19-nor compound) had only minimal effects on antagonist potency. Agonist activity was demonstrable for three of the analogues studied: the 19-nor compound, and those containing a C-7 chi-substitution with a carboxyl isopropyl ester or a C-6-7 cyclopropyl linkage. The functional activity in toad bladder was compared to previous measurements of the relative binding affinity of the same spirolactones for mineralocorticoid receptors in rat kidney. Although there was some correlation between binding to rat kidney receptors and antagonist activity in the toad bladder, the results did not coincide in the case of the three spirolactones that possessed partial agonist activity. Some of the discrepancy may have resulted from differences between mammalian and amphibian receptors; however, intrinsic agonist activity limits antagonist potency and thus may cause a divergence between binding and functional studies limited to antagonist activity alone. Binding affinity, although indicative of total activity, fails to distinguish agonist from antagonist potency.

Aldosterone↗
PubMed2000

p73-deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours.

p73 (ref. 1) has high homology with the tumour suppressor p53 (refs 2-4), as well as with p63, a gene implicated in the maintenance of epithelial stem cells. Despite the localization of the p73 gene to chromosome 1p36.3, a region of frequent aberration in a wide range of human cancers, and the ability of p73 to transactivate p53 target genes, it is unclear whether p73 functions as a tumour suppressor. Here we show that mice functionally deficient for all p73 isoforms exhibit profound defects, including hippocampal dysgenesis, hydrocephalus, chronic infections and inflammation, as well as abnormalities in pheromone sensory pathways. In contrast to p53-deficient mice, however, those lacking p73 show no increased susceptibility to spontaneous tumorigenesis. We report the mechanistic basis of the hippocampal dysgenesis and the loss of pheromone responses, and show that new, potentially dominant-negative, p73 variants are the predominant expression products of this gene in developing and adult tissues. Our data suggest that there is a marked divergence in the physiological functions of the p53 family members, and reveal unique roles for p73 in neurogenesis, sensory pathways and homeostatic control.

Abnormalities, Multiple↗
PubMed1999

Mapping of semantic, phonological, and orthographic verbal working memory in normal adults with functional magnetic resonance imaging.

Twelve neurologically normal participants (4 men and 8 women) performed semantic, phonological, and orthographic working memory tasks and a control task during functional magnetic resonance imaging. Divergent regions of the posterior left hemisphere used for decoding and storage of information emerged in each working memory versus control task comparison. These regions were consistent with previous literature on processing mechanisms for semantic, phonological, and orthographic information. Further, working memory versus control task differences extended into the left frontal lobe, including premotor cortex, and even into subcortical structures. Findings were consistent with R. C. Martin and C. Romani's (1994) contention that different forms of verbal working memory exist and further suggest that a reconceptualization of premotor cortex functions is needed.

Adolescent↗