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At least 685 records · Page 38Linked to original sources
PubMed2005

Metabolic activity and collagen turnover in human tendon in response to physical activity.

Connective tissue of the human tendon plays an important role in force transmission. The extracellular matrix turnover of tendon is influenced by physical activity. Blood flow, oxygen demand, and the level of collagen synthesis and matrix metalloproteinases increase with mechanical loading. Gene transcription and especially post-translational modifications of proteins of the extracellular matrix are enhanced following exercise. Conversely, inactivity markedly decreases collagen turnover. Training leads to a chronically increased collagen turnover, and dependent on the type of collagen also to some degree of net collagen synthesis. These changes modify the biomechanical properties of the tissue (for example, viscoelastic characteristics) as well as the structural properties of the in collagen (for example, cross-sectional area). Mechanical loading of human tendon does result in a marked interstitial increase in growth factors that are known potentially to stimulate synthesis of collagen and other extracellular matrix proteins. Taken together, human tendon tissue mounts a vigorous acute and chronic response to mechanical loading in terms of metabolic-circulatory changes as well as of extracellular matrix formation. These changes may contribute to training-induced adaptation of biomechanical properties consisting of altered resistance to loading and enhanced tolerance to strenuous exercise. Understanding of such changes is a pre-requisite in the development of measures aimed at prevention of overuse tendon injuries occurring during sport, work or leisure-related activities.

Adaptation, Physiological↗
PubMed2005

The modulation of skeletal muscle glycosylation as a potential therapeutic intervention in muscular dystrophies.

Post-translational modification of proteins following glycosylation is a powerful tool to increase diversity of proteins and ligand interaction. alpha-Dystroglycan, a key muscle fibre receptor for various extracellular matrix ligands, is very heavily glycosylated. In addition heterogeneity of its glycosylation pattern has been described not only in different tissues and organs, but also in different regions of skeletal muscle, such as the sarcolemma and the neuromuscular junction. This review is focused on the potential of hyperglycosylation strategies as a means for therapeutic intervention in several forms of muscular dystrophy. Regarding Duchenne muscular dystrophy (DMD) overexpression of the synaptic CT GalNAc transferase in the sarcolemma of mdx animals was shown to induce the appearance of the CT antigen on the dystroglycan expressed at the sarcolemma. This was followed by the recruitment of utrophin at the sarcolemma and improved muscle pathology in mdx mice. A related strategy has also been used in preclinical models of "dystroglycanopathies". These conditions range in severity from severe and congenital onset to milder forms of limb girdle muscular dystrophy affecting the adult. The mechanism of disease in dystroglycanopathies is presumed to be the uncoupling of the cellular receptor alpha-dystroglycan from its extracellular matrix ligands of which laminin is the most important one. Recent work has demonstrated that the overexpression of 2 related glycosyltransferases, LARGE and LARGE L, results in the hyperglycosylation of alpha-dystroglycan. This hyperglycosylation can also be induced in cells from patients with a dystroglycanopathy, restoring normal dystroglycan ligand binding. LARGE and/or LARGE-L up regulation could therefore represent a therapeutic option for patients affected by dystroglycanopathies, regardless of their primary defect.

Dystroglycans↗
PubMed1991

Role of isoprenoid metabolism in IgE receptor-mediated signal transduction.

In the 2H3 subline of rat basophilic leukemia cells (RBL-2H3), IgE receptor cross-linking stimulates a signal transduction pathway that leads to the secretion of histamine, serotonin, and other inflammatory mediators; the assembly of F-actin; and the transformation of the cell surface from a microvillous to a lamellar or ruffled architecture. We report here that 20 h incubation of RBL-2H3 cells with 10 microM lovastatin, an inhibitor of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMG CoA reductase), inhibits both the secretory and morphologic responses to IgE receptor cross-linking. Ag-induced Ca2+ mobilization, determined from the influx and efflux of 45Ca2+, and Ag-induced 1,4,5-inositol trisphosphate production are also inhibited in lovastatin-treated RBL-2H3 cells. Under the same conditions, lovastatin does not alter cell proliferation or IgE receptor expression, and it causes only a small impairment of responses initiated by drugs that bypass the earliest steps in the receptor-activated transduction pathway (ionomycin-induced secretion and PMA-induced membrane ruffling). Receptor-mediated Ca2+ mobilization, secretion, and ruffling are all restored by 0.5- to 4-h incubation of lovastatin-treated cells with mevalonic acid, the product of HMG CoA reductase and the first committed intermediate of the isoprenoid biosynthetic pathway. In contrast, dolichol and cholesterol, which are synthesized from products of the isoprenoid pathway, do not restore receptor-activated responses. These data implicate an isoprenoid pathway intermediate in an early step in the IgE receptor-activated signal-transduction sequence. We postulate that this intermediate is required for a newly described post-translational modification of proteins, their post-synthetic isoprenylation. The substrates for this modification include the ras family of GTP-binding proteins and the gamma subunits of the heterotrimeric guanine nucleotide-binding protein.

Animals↗
PubMed1989

Polyamine metabolism in chronic lymphocytic leukemia.

We have previously shown that polyamines have profound effects on lymphocyte proliferation and function. We now report that the proliferative response of cultured lymphocytes from patients with chronic lymphocytic leukemia is abrogated by the addition of diacetyldiaminohexane (HMBA), the 6-carbon analogue of diacetylputrescine. In addition, this study demonstrates the post-translational modification of proteins by polyamines in CLL-lymphocytes, a decrease in the uptake of exogenous spermidine by CLL-lymphocytes which have been exposed to HMBA, and the significant conversion of spermidine to N1-acetylspermidine in CLL-lymphocytes.

Acetamides↗
PubMedDate not supplied

[Molecular mechanisms of the action of insulin].

Molecular mechanisms of insulin action on metabolism such as interaction with membrane receptor, autophosphorylation of receptor, internalization of insulin-receptor complexes into cells, changes in the processes of transcription, RNA release from nuclei, translation and post-translation modification of proteins and key enzymes are considered. The role of mediators in realization of biological effects of insulin is analyzed. It is emphasized that insulin action on the gene expression is an important link of its influence on metabolism.

Animals↗
PubMedDate not supplied

[Co-translation folding, compartmentalization and modification of proteins].

Transmembrane transport of polypeptide chains in the process of their synthesis on membrane-bound ribosomes and enzymic modification of the nascent polypeptides on membranes are reviewed. The possible role of ribosomes in protein folding and some other unsolved problems are discussed.

Amino Acid Sequence↗
PubMed1993

[Structure of ADP-ribosylating enzyme and DNA repair].

ADP-ribosylation is a post-translational modification of protein using a respiratory coenzyme, NAD+, as a substrate. Poly(ADP-ribosyl)ation reaction in the nuclei has been thought to be involved in DNA repair. Cloning of poly(ADP-ribose)polymerase cDNA and gene has opened the way for analyzing the structure and functions of poly(ADP-ribose)polymerase at the molecular level. Poly(ADP-ribose)polymerase is a zinc-finger protein and binds to nicks of DNA. This enzyme is activated by binding to DNA and poly(ADP-ribosyl)ates nuclear proteins and poly(ADP-ribose)polymerase itself. Structural analysis of poly(ADP-ribose)polymerase from different classes has shown conserved motifs in the domain structures. In this review, recent advances in this field, including mono-ADP-ribosylation and cyclic ADP-ribose, are described.

ADP Ribose Transferases↗
PubMed1992

Synthesis and modification of D7 protein during Xenopus oocyte maturation.

The Xenopus maternal mRNA D7 is translationally repressed during oogenesis, only becoming recruited into polysomes during oocyte maturation, with D7 protein being detectable for the first time prior to germinal vesicle breakdown (GVBD). The synthesis of D7 protein was found to be induced by a variety of maturation-promoting agents including cyclin, c-mos and crude preparations of MPF. D7 protein induced by all these agents is post-translationally modified and exists as a number of variants of differing molecular weight. In contrast to endogenous D7 mRNA, D7 RNA injected into the stage VI oocyte is efficiently translated, resulting in the accumulation of predominantly unmodified D7 polypeptides, which become increasingly modified during oocyte maturation to produce a pattern of polypeptides similar to those derived from endogenous D7 mRNA. Thus, the system that results in the post-translational modification of the D7 protein is itself activated during oocyte maturation. The nature of the protein modification is not known but does not appear to be phosphorylation. The translation of exogenous D7 RNA in the stage VI oocyte does not lead to translational derepression of endogenous D7 mRNA.

Animals↗
PubMed2004

Transglutaminase-mediated N- and C-terminal fluorescein labeling of a protein can support the native activity of the modified protein.

Fluorescein and its analogs are among the best fluorophores to label proteins and the labeling generally involves chemical modification of a translated protein. Using this methodology, labeling at a specific position remains difficult. It is known that the guinea pig liver transglutaminase (TGase)-catalyzed enzymatic modification method can allow terminal-specific fluorophore labeling of a protein by monodansylcadaverine. However, native activity of the fluorescent protein has not been investigated so far, nor has direct comparison between the chemical modification and the TGase-catalyzed modification been attempted. Therefore, we compared the possibility of fluorescein labeling via chemical labeling and via TGase-catalyzed modification. The latter method was found to be very practical and overcame some of the problems associated with the specificity of the former; fluorescein was covalently attached only to the N- or C-terminal site of glutathione S-transferase when the reaction was catalyzed by TGase and the resulting labeled protein completely retained its native activity. The TGase-mediated labeling occurred not only at room temperature but also at 4 degrees C to the same extent, which is more desirable for preventing the inactivation of proteins.

Base Sequence↗
PubMed2006

Dynamic regulation of effector protein binding to histone modifications: the biology of HP1 switching.

Post-translational modifications of histone proteins, the basic building blocks around which eukaryotic DNA is organized, are crucially involved in the regulation of genome activity as they control chromatin structure and dynamics. The recruitment of specific binding proteins that recognize and interact with particular histone modifications is thought to constitute a fundamental mechanism by which histone marks mediate biological function. For instance, tri-methylation of histone H3 lysine 9 (H3K9me3) is important for recruiting heterochromatin protein 1 (HP1) to discrete regions of the genome, thereby regulating gene expression, chromatin packaging, and heterochromatin formation. Until now, little was known about the regulation of effector-histone mark interactions, and in particular, of the binding of HP1 to H3K9me3. Recently, we and others presented evidence that a "binary methylation-phosphorylation switch" mechanism controls the dynamic release of HP1 from H3K9me3 during the cell cycle: phosphorylation of histone H3 serine 10 (H3S10ph) occurs at the onset of mitosis, interferes with HP1-H3K9me3 interaction, and therefore, ejects HP1 from its binding site. Here, we discuss the biological function of HP1 release from chromatin during mitosis, consider implications why the cell controls HP1 binding by such a methylation-phosphorylation switching mechanism, and reflect on other cellular pathways where binary switching of HP1 might occur.

Animals↗
PubMed1994

A novel RNA-binding motif in omnipotent suppressors of translation termination, ribosomal proteins and a ribosome modification enzyme?

Using computer methods for database search, multiple alignment, protein sequence motif analysis and secondary structure prediction, a putative new RNA-binding motif was identified. The novel motif is conserved in yeast omnipotent translation termination suppressor SUP1, the related DOM34 protein and its pseudogene homologue; three groups of eukaryotic and archaeal ribosomal proteins, namely L30e, L7Ae/S6e and S12e; an uncharacterized Bacillus subtilis protein related to the L7A/S6e group; and Escherichia coli ribosomal protein modification enzyme RimK. We hypothesize that a new type of RNA-binding domain may be utilized to deliver additional activities to the ribosome.

Amino Acid Sequence↗
PubMed1995

Novel protein families in archaean genomes.

In a quest for novel functions in archaea, all archaean hypothetical open reading frames (ORFs), as annotated in the Swiss-Prot protein sequence database, were used to search the latest databases for the identification of characterized homologues. Of the 95 hypothetical archaean ORFs, 25 were found to be homologous to another hypothetical archaean ORF, while 36 were homologous to non-archaean proteins, of which as many as 30 were homologous to a characterized protein family. Thus the level of sequence similarity in this set reaches 64%, while the level of function assignment is only 32%. Of the ORFs with predicted functions, 12 homologies are reported here for the first time and represent nine new functions and one gene duplication at an acetyl-coA synthetase locus. The novel functions include components of the transcriptional and translational apparatus, such as ribosomal proteins, modification enzymes and a translation initiation factor. In addition, new enzymes are identified in archaea, such as cobyric acid synthase, dCTP deaminase and the first archaean homologues of a new subclass of ATP binding proteins found in fungi. Finally, it is shown that the putative laminin receptor family of eukaryotes and an archaean homologue belong to the previously characterized ribosomal protein family S2 from eubacteria. From the present and previous work, the major implication is that archaea seem to have a mode of expression of genetic information rather similar to eukaryotes, while eubacteria may have proceeded into unique ways of transcription and translation. In addition, with the detection of proteins in various metabolic and genetic processes in archaea, we can further predict the presence of additional proteins involved in these processes.

Animal Population Groups↗
PubMed2000

Translation initiation factor modifications and the regulation of protein synthesis in apoptotic cells.

The rate of protein synthesis is rapidly down-regulated in mammalian cells following the induction of apoptosis. Inhibition occurs at the level of polypeptide chain initiation and is accompanied by the phosphorylation of the alpha subunit of initiation factor eIF2 and the caspase-dependent cleavage of initiation factors eIF4G, eIF4B, eIF2alpha and the p35 subunit of eIF3. Proteolytic cleavage of these proteins yields characteristic products which may exert regulatory effects on the translational machinery. Inhibition of caspase activity protects protein synthesis from long-term inhibition in cells treated with some, but not all, inducers of apoptosis. This review describes the initiation factor modifications and the possible signalling pathways by which translation may be regulated during apoptosis. We discuss the significance of the initiation factor cleavages and other changes for protein synthesis, and the implications of these events for our understanding of the cellular changes associated with apoptosis.

Animals↗
PubMed2005

Stem cell proteomes: a profile of human mesenchymal stem cells derived from umbilical cord blood.

Multipotent mesenchymal stem cells (MSCs) derived from human umbilical cord blood (UCB) represent promising candidates for the development of future strategies in cellular therapy. To create a comprehensive protein expression profile for UCB-MSCs, one UCB unit from a full-term delivery was isolated from the unborn placenta, transferred into culture, and their whole-cell protein fraction was subjected to two-dimensional electrophoresis (2-DE). Unambiguous protein identification was achieved with peptide mass fingerprinting matrix-assisted laser desorption/ionization - time of flight - mass spectrometry (MALDI-TOF-MS), peptide sequencing (MALDI LIFT-TOF/TOF MS), as well as gel-matching with previously identified databases. In overall five replicate 2-DE runs, a total of 2037 +/- 437 protein spots were detected of which 205 were identified representing 145 different proteins and 60 isoforms or post-translational modifications. The identified proteins could be grouped into several functional categories, such as metabolism, folding, cytoskeleton, transcription, signal transduction, protein degradation, detoxification, vesicle/protein transport, cell cycle regulation, apoptosis, and calcium homeostasis. The acquired proteome map of nondifferentiated UCB-MSCs is a useful inventory which facilitates the identification of the normal proteomic pattern as well as its changes due to activated or suppressed pathways of cytosolic signal transduction which occur during proliferation, differentiation, or other experimental conditions.

Databases, Protein↗
PubMed2003

Functional profiling of the proteome with affinity labels.

The analysis of proteomic samples with affinity labels has been firmly established as a tool for the post-genomic researcher. Recent examples highlight the advantages of profiling functionally active members of specific protein families to identify therapeutically relevant protein targets that have escaped normal physiological regulation leading to increased or decreased activity. This dysregulation may result from any number of biological changes that modulate a protein's activity; for example, post-translational modifications of the protein or an imbalance between the protein and its endogenous inhibitor(s). By providing a direct measure of a protein's functional activity, affinity probe analysis identifies these changes and allows investigators to focus their research efforts upon those proteins that are most likely to be responsible for the biological changes under evaluation.

Affinity Labels↗
PubMed1996

Maize chromosomal HMGc. Two closely related structure-specific DNA-binding proteins specify a second type of plant high mobility group box protein.

The chromosomal high mobility group (HMG) proteins are small and abundant non-histone proteins common to eukaryotes. We have purified the maize HMGc protein from immature kernels and characterized it by mass spectrometry and amino acid sequence analysis. HMGc could be resolved into two similar proteins by reversed phase chromatography. Cloning and characterization of the corresponding cDNAs revealed that they encode two closely related maize HMGc proteins, now termed HMGc1 and HMGc2. Their theoretical masses of 15,316 and 15,007 Da are >300 Da lower than the masses determined for the proteins purified from maize, indicating post-translational modifications of the proteins. Despite sequence similarity to maize HMGa (and previously described homologous proteins of other species) amino acid sequence alignments reveal that HMGc is in several conserved regions distinct from these proteins. Consequently, we have identified a novel type of plant protein containing an HMG box DNA binding domain and belonging to the HMG1 protein family. HMGc1 and HMGc2 were expressed in Escherichia coli, purified to homogeneity, and analyzed for their DNA binding properties. They proved to bind to DNA structure-specifically since they formed complexes with DNA minicircles at concentrations approximately 100-fold lower than the concentrations required to form complexes with linear fragments of identical sequence. Furthermore, HMGc1 and HMGc2 can constrain negative superhelical turns in plasmid DNA.

Amino Acid Sequence↗
PubMed2003

p73 is regulated by phosphorylation at the G2/M transition.

p73 is a p53 paralog that encodes proapoptotic (transactivation-competent (TA)) and antiapoptotic (dominant negative) isoforms. TAp73 transcription factors mediate cell cycle arrest and/or apoptosis in response to DNA damage and are involved in developmental processes in the central nervous system and the immune system. p73 proteins may also play a role in the regulation of cell growth. Indeed, p73 expression is itself modulated during the cell cycle and TAp73 proteins accumulate in S phase cells. In addition, the function of p73 proteins is also regulated by post-translational modifications and protein-protein interactions in different cellular and pathophysiological contexts. Here we show that p73 is a physiological target of the p34cdc2-cyclin B mitotic kinase complex in vivo. Both p73beta and p73alpha isoforms are hyperphosphorylated in normal mitotic cells and during mitotic arrest induced by microtubule-targeting drugs. p34cdc2-cyclin B phosphorylates and associates with p73 in vivo, which results in a decreased ability of p73 to both bind DNA and activate transcription in mitotic cells. Indeed, p73 is excluded from condensed chromosomes in meta- and anaphase, redistributes throughout the mitotic cytoplasm, and unlike p53, shows no association with centrosomes. Together these results indicate that M phase-specific phosphorylation of p73 by p34cdc2-cyclin B is associated with negative regulation of its transcriptional activating function.

Cell Line, Tumor↗