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At least 163 records · Page 9Linked to original sources
PubMed2003

Synapse-associated protein-97 isoform-specific regulation of surface AMPA receptors and synaptic function in cultured neurons.

Members of the synapse-associated protein-97 (SAP97) family of scaffold proteins have been implicated as central organizers of synaptic junctions to build macromolecular signaling complexes around specific postsynaptic neurotransmitter receptors. In this regard, SAP97 has been suggested to regulate the synaptic localization of glutamate receptor type 1 subunits of the AMPA-type glutamate receptors. To test this hypothesis directly, we assessed the effects of SAP97 overexpression on surface expression of synaptic AMPA receptors. We find that recombinant SAP97 not only becomes concentrated at synaptic junctions but also leads to an increase in synaptic AMPA receptors, spine enlargement, and an increase in miniature EPSC (mEPSC) frequency, indicating that SAP97 has both postsynaptic and presynaptic effects on synaptic transmission. Synaptic targeting of SAP97, increased surface AMPA receptors, and increased mEPSC frequency are dependent on the presence of specific alternatively spliced sequences in SAP97 that encode a protein 4.1 binding site. These results suggest that SAP97 can affect the synaptic recruitment of AMPA receptors and spine morphology and that these effects may be regulated by alternative splicing.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Drebrin-dependent actin clustering in dendritic filopodia governs synaptic targeting of postsynaptic density-95 and dendritic spine morphogenesis.

Dendritic spines have two major structural elements: postsynaptic densities (PSDs) and actin cytoskeletons. PSD proteins are proposed to regulate spine morphogenesis. However, other molecular mechanisms should govern spine morphogenesis, because the initiation of spine morphogenesis precedes the synaptic clustering of these proteins. Here, we show that synaptic clustering of drebrin, an actin-binding protein highly enriched in dendritic spines, governs spine morphogenesis. We immunocytochemically analyzed developing hippocampal neurons of low-density cultures. Filopodia-like dendritic protrusions were classified into two types: diffuse-type filopodia, which have diffuse distribution of drebrin, and cluster-type filopodia, which have drebrin clusters with filamentous actin (F-actin). Most cluster-type filopodia were synaptic filopodia. Postsynaptic drebrin clusters were found in both most synaptic filopodia and spines. Postsynaptic PSD-95 clusters, however, were found in only one-half of synaptic filopodia but in most spines. These data indicate that cluster-type filopodia are not mature spines but their precursors. Suppression of the upregulation of drebrin adult isoform (drebrin A) by antisense oligonucleotides against it attenuated synaptic clustering of PSD-95, as well as clustering of drebrin and F-actin. Furthermore, the restoration of drebrin A expression by injection of the expression vectors of drebrin A tagged with green fluorescent protein into the neurons treated with the antisense oligonucleotides induced synaptic reclustering of PSD-95 on clusters of the labeled drebrin A. These data indicated that the synaptic clustering of drebrin is necessary for that of PSD-95 in developing neurons. Together, these data suggest that synaptic clustering of drebrin is an essential step for spine morphogenesis.

Actins↗
PubMed2003

Apoptogenic effect of the lipophilic o-naphthoquinone CG 10-248 on rat hepatocytes: light and electron microscopy studies.

CG 10-248 (3,4-dihydro-2,2-dimethyl-9-chloro-2H-naphtho[1,2b]pyran-5,6-dione; CG-NQ), a beta-lapachone analogue, modified the ultrastructure of rat hepatocytes, as demonstrated by light and electron microscopy. After 4 h incubation with 100 microM CG-NQ, the following effects were observed: (a) nuclear chromatin condensation; (b) chromatin fragmentation; (c) displacement of mitochondria, concentrated around the nucleus; (d) disruption or expansion of mitochondrial outer or inner membranes, respectively; (e) displacement and alteration of endoplasmic reticulum (rough and smooth); (f) decrease of microvilli; (g) blebbing of plasma membrane and production of apoptotic bodies formed by folding of plasma membrane fragments around mitochondria or peroxysomes; and (h) production of hydrogen peroxide. Expression of such effects varied according to hepatocyte samples and taken together strongly support an apoptotic action of CG-NQ dependent on "reactive oxygen species".

Animals↗
PubMed2003

Kalirin, a multifunctional Rho guanine nucleotide exchange factor, is necessary for maintenance of hippocampal pyramidal neuron dendrites and dendritic spines.

The structures of dendritic spines and the dendritic tree, key determinants of neuronal function, are regulated by diverse inputs that affect many scaffolding and signaling molecules. Nevertheless, here we show that reduced expression of a single gene results in loss of dendritic spines and a decrease in dendritic complexity. Kalirin, a dual Rho GDP-GTP exchange factor, causes spine formation when overexpressed. Reduced expression of Kalirin in CA1 hippocampal neurons resulted in a reduction in linear spine density, with dispersion of postsynaptic density markers and elimination of presynaptic endings. Simplification of the apical dendritic tree preceded simplification of basal dendrites. Pyramidal cell axons were not dramatically altered. Although many factors determine dendrite shape and spine formation, expression of Kalirin is necessary for the normal function of these many regulatory elements.

Animals↗
PubMed1978

Epidermal acantholysis induced in vitro by pemphigus autoantibody. An ultrastructural study.

Suprabasilar acantholysis can be produced in organ culture of normal human skin in the presence of pemphigus IgG autoantibody. We have examined this in vitro system by electron microscopy. The earliest ultrastructural changes at 12 hours included widening of the intercellular spaces and disruption of the intercellular cement substance in the nondesmosomal areas. After 24 to 48 hours in culture, the tonofilaments retracted from the cell periphery, desmosomes were lost, and extensive cell surface digitation occurred. By 72 hours, isolated cells without noticeable desmosomes were seen in the suprabasilar areas, whereas basal cells, with intact hemidesmosomes, remained attached to the basal lamina. Control cultures which were grown in the presence of normal IgG or F-10 medium alone did not manifest these changes. The ultrastructural features support the conclusion that the acantholysis produced in this system is similar and probably identical to that of naturally occurring pemphigus.

Acantholysis↗
PubMed1998

C. elegans phagocytosis and cell-migration protein CED-5 is similar to human DOCK180.

During programmed cell death, cell corpses are rapidly engulfed. This engulfment process involves the recognition and subsequent phagocytosis of cell corpses by engulfing cells. How cell corpses are engulfed is largely unknown. Here we report that ced-5, a gene that is required for cell-corpse engulfment in the nematode Caenorhabditis elegans, encodes a protein that is similar to the human protein DOCK180 and the Drosophila melanogaster protein Myoblast City (MBC), both of which have been implicated in the extension of cell surfaces. ced-5 mutants are defective not only in the engulfment of cell corpses but also in the migrations of two specific gonadal cells, the distal tip cells. The expression of human DOCK180 in C. elegans rescued the cell-migration defect of a ced-5 mutant. We present evidence that ced-5 functions in engulfing cells during the engulfment of cell corpses. We suggest that ced-5 acts in the extension of the surface of an engulfing cell around a dying cell during programmed cell death. We name this new family of proteins that function in the extension of cell surfaces the CDM (for CED-5, DOCK180 and MBC) family.

Amino Acid Sequence↗
PubMed1987

Elongation and surface extension of individual cells of Escherichia coli B/r: comparison of theoretical and experimental size distributions.

The way individual cells grow and divide uniquely determines the (time-invariant) cell size distribution of populations in steady-state exponential growth. In the preceding article, theoretical distributions were derived for two exponential and six linear models containing a small number of adjustable parameters but no assumptions other than that all cells obey the same growth law. The linear models differ from each other with respect to the timing of the presumptive doubling in their growth rate, the exponential models--according to whether there is or is not a part of the cell that does not contribute to the growth rate. Here we compared the size distributions predicted by each of these models with those of cell length and surface area measured by electron microscopy; the quality of the fit, as determined by the mean-square successive-differences test and the chi 2 goodness-of-fit test, was taken as a measure of the adequacy of the model. The actual data came from two slow-growing E. coli B/r cultures, an A strain (pi = 125 min) and a K strain (pi = 106 min), and a correction was introduced in each to account for the distortion caused by the finite size of the picture frame. The parameter estimates produced by the various models are quite reliable (cv less than 0.1%); we discuss them briefly and compare their values in the two strains. All the length extension models were rejected outright whereas most of the surface growth versions were not. When the same models were tested on A-strain data from a faster growing culture (tau = 21 min), those models that provided an adequate fit to the cell surface area data proved equally satisfactory in the case of cell length. These findings are evaluated and shown to be consistent with cell surface area rather than cell length being the dimension under active control. Three surface area models, all linear, are rejected--those in which doubling of the growth rate occurs with a constant probability from cell birth, at a particular cell age, and precisely at cell division. The evidence in the literature that appears to contradict this last result, rejection of the simple linear surface growth model, is shown to be faulty. The 16 original models are here reduced to five, two involving exponential surface growth and three linear, and possible reasons are presented for our inability to discriminate further at this stage.

Cell Division↗
PubMed1997

Antigen-unspecific B cells and lymphoid dendritic cells both show extensive surface expression of processed antigen-major histocompatibility complex class II complexes after soluble protein exposure in vivo or in vitro.

Intravenous (i.v.) injection of high amounts of soluble proteins often results in the induction of antigen-specific tolerance or deviation to helper rather than inflammatory T cell immunity. It has been proposed that this outcome may be due to antigen presentation to T cells by a large cohort of poorly costimulatory or IL-12-deficient resting B cells lacking specific immunoglobulin receptors for the protein. However, previous studies using T cell activation in vitro to assess antigen display have failed to support this idea, showing evidence of specific peptide-major histocompatibility complex (MHC) class II ligand only on purified dendritic cells (DC) or antigen-specific B cells isolated from protein injected mice. Here we reexamine this question using a recently derived monoclonal antibody specific for the T cell receptor (TCR) ligand formed by the association of the 46-61 determinant of hen egg lysozyme (HEL) and the mouse MHC class II molecule I-Ak. In striking contrast to conclusions drawn from indirect T cell activation studies, this direct method of TCR ligand analysis shows that i.v. administration of HEL protein results in nearly all B cells in lymphoid tissues having substantial levels of HEL 46-61-Ak complexes on their surface. DC readily isolated from spleen also display this TCR ligand on their surface. Although the absolute number of displayed ligands is greater on such DC, the relative specific ligand expression compared to total MHC class II levels is similar or greater on B cells. These results demonstrate that in the absence of activating stimuli, both lymphoid DC and antigen-unspecific B cells present to a similar extent class II-associated peptides derived from soluble proteins in extracellular fluid. The numerical advantage of the TCR ligand-bearing B cells may permit them to interact first or more often with naive antigen-specific T cells, contributing to the induction of high-dose T cell tolerance or immune deviation.

Animals↗
PubMed1993

Redox-linked ligand-independent cell surface triggering for extensive protein tyrosine phosphorylation.

Exposure of lymphocytes to 0.2-2 mM HgCl2, a thiol-reactive heavy metal, induced extensive tyrosine phosphorylation of multiple cellular proteins. The phosphorylation started as quickly as 5 s after exposure to HgCl2, and was irreversible. Another 3 thiol-reactive chemicals also displayed similar, though less marked, actions, whereas dithiothreitol, a reducing agent, antagonized the HgCl2 action. The demonstrated new action of HgCl2 indispensably required membrane-intact cells as a target. Whereas exposure of lymphocytes to > 0.2 mM HgCl2 caused rapid cell death, 0.01-0.1 mM HgCl2 affected the cells so as to accelerate their c-fos transcription. These results suggest a novel redox-linked mechanism of cell surface triggering of intracellular protein kinase activity, which is independent of receptor-ligand interactions.

4-Chloromercuribenzenesulfonate↗
PubMed1975

Anucleate cell production and surface extension in a temperature-sensitive chromosome initiation mutant of Bacillus subtilis.

At 45 C, in a temperature-sensitive initiation mutant (TsB134) of Bacillus subtilis 168 Thy- tryp-, growing in a glucose-arginine minimal medium, chromosome completion occurred over a period of 80 to 90 min, after which there was no further nuclear division. Normal symmetrical cell divisions continued for a generation afterwards, so that nuclei were segregated into separate cells. During this period asymmetric divisions started to occur. Septa appeared at 25 to 30% from one end of the cell, giving a small anucleate cell and a larger nucleate cell. During inhibition of deoxyribonucleic acid (DNA) synthesis by thymine starvation under the restrictive conditions, asymmetrical division also occurred until there was approximately one nucleus per cell (about one generation time). Asymmetric division, giving anucleate cells, then occurred. Similar results were obtained when DNA synthesis was inhibited by nalidixic acid. After 3 h at 45 C, the rate of anucleate cell production in the presence and absence of thymine was constant at one division per 85 min per chromosome terminus present when DNA synthesis stopped. In the absence of DNA synthesis (during thymine starvation) at 35 C, growth in cell length was linear (i.e., the rate was constant), but at 45 C during thymine starvation the rate gradually increased by more than twofold. It is suggested that this was due to the establishment of new sites of growth associated with anucleate cell production. In the presence of thymine at 45 C, the rate of length extension increased by more than fourfold, which it is suggested was caused by the appearance of new growth zones as a result of chromosome termination and a contribution associated with anucleate cell production. If the mutant was incubated at 45 C for 90 min, both in the presence and absence of thymine, then anucleate cell formation could continue on restoration to 35 C in the absence of thymine...

Bacillus subtilis↗
PubMed2005

Unconventional mode of attachment of the Ruminococcus flavefaciens cellulosome to the cell surface.

Sequence extension of the scaffoldin gene cluster from Ruminococcus flavefaciens revealed a new gene (scaE) that encodes a protein with an N-terminal cohesin domain and a C terminus with a typical gram-positive anchoring signal for sortase-mediated attachment to the bacterial cell wall. The recombinant cohesin of ScaE was recovered after expression in Escherichia coli and was shown to bind to the C-terminal domain of the cellulosomal structural protein ScaB, as well as to three unknown polypeptides derived from native cellulose-bound Ruminococcus flavefaciens protein extracts. The ScaB C terminus includes a cryptic dockerin domain that is unusual in its sequence, and considerably larger than conventional dockerins. The ScaB dockerin binds to ScaE, suggesting that this interaction occurs through a novel cohesin-dockerin pairing. The novel ScaB dockerin was expressed as a xylanase fusion protein, which was shown to bind tenaciously and selectively to a recombinant form of the ScaE cohesin. Thus, ScaE appears to play a role in anchoring the cellulosomal complex to the bacterial cell envelope via its interaction with ScaB. This sortase-mediated mechanism for covalent cell-wall anchoring of the cellulosome in R. flavefaciens differs from those reported thus far for any other cellulosome system.

Amino Acid Sequence↗
PubMed2004

Effect of some volatile oils on the affinity of intact and oxidized low-density lipoproteins for adrenal cell surface receptors.

Extensive research has shown that a high plasma concentration and oxidation of low-density lipoproteins (LDL) has an important role in atherogenesis. The affinity of LDL to its classic receptor is reduced due to oxidation. Instead, it is taken up by scavenger molecules in macrophages, as a result of which foam cells are formed that have a major role in increasing the subendothelial fat layers of the blood vessels. In the present study the antioxidant effect of eight volatile compounds in plant essences, namely, anethol, eugenol, limonen, linalool, p-cymol, pulegon, thymol, and geraniol, and their effect on the affinities of intact and oxidized (with Cu(+2)) LDL for LDL receptor in sheep adrenal tissue cells in the presence of labeled LDL with fluorescein isothiocynate (FITC) were investigated. The results obtained show that eugenol and thymol have the highest antioxidant effect, on the uptake of LDL (intact and oxidized) by the adrenal cells. The order of the compounds studied with regard to their antioxidant effect on intact and oxidized LDL is as follows: On intact LDL: eugenol > or = thymol > linalool > p-cymol > limonen > geraniol > anethol; on oxidized LDL: thymol > or = eugenol > geraniol > p-cymol > linalool > pulegon. Our findings also show that the compounds, particularly thymol and eugenol, have an antioxidant property and can change the affinity of the LDL particles for the LDL receptor probably due to their lipophylic property. Further research may prove that these compounds can be used clinically, especially in atherosclerotic and hypercholesterolemic cases.

Adrenal Glands↗
PubMed1991

Surface extensions of 3T3 cells towards distant infrared light sources.

Using a specially designed phase-contrast light microscope with an infrared spot illuminator we found that approximately 25% of 3T3 cells were able to extend pseudopodia towards single microscopic infrared light sources nearby. If the cells were offered a pair of such light sources next to each other, 47% of the cells extended towards them. In the latter case 30% of the responding cells extended separate pseudopodia towards each individual light source of a pair. The strongest responses were observed if the infrared light sources emitted light of wavelengths in the range of 800-900 nm intermittently at rates of 30-60 pulses per min. The temperature increases of the irradiated spots can be shown to be negligible. The results suggest that the cells are able to sense specific infrared wavelengths and to determine the direction of individual sources.

Animals↗
PubMed2006

Junctional adhesion molecule-A regulates cell migration and resistance to shear stress.

Junctional adhesion molecule-A (JAM-A) is an adhesive protein expressed in endothelial cells, epithelial cells, platelets, and some leukocytes. JAM-A localizes to the tight junctions between contacting endothelial and epithelial cells, where it contributes to cell-cell adhesion and to the control of paracellular permeability. JAM-A also regulates cell motility, even though the quantitative biophysical features have not been characterized. In this study, we evaluated the role of JAM-A in the regulation of cell motility using JAM-A-expressing and JAM-A-deficient murine endothelial cells. We report that, in the absence of shear stress, JAM-A absence increases cell motility by increasing directional persistence but not cell speed. In addition, in the presence of shear stress, JAM-A absence increases protrusion extension in the direction of flow and increased downstream cellular displacement (while, conversely, decreasing upstream displacement). All these effects of JAM-A absence are mitigated by the microtubule-stabilizing compound taxol. A motility- and microtubule-related function, integrin-mediated adhesiveness, was only slightly reduced in JAM-A-deficient cells compared with JAM-A-expressing cells. However, overexpression of JAM-A in the JAM-A-deficient cells increased integrin adhesiveness to the same levels as those observed in taxol-treated JAM-A-deficient cells. Taken together, these data indicate that JAM-A regulates cell motility by cooperating with microtubule-stabilizing pathways.

Animals↗
PubMed2004

Activation of endogenous Cdc42 visualized in living cells.

Signaling proteins are tightly regulated spatially and temporally to perform multiple functions. For Cdc42 and other guanosine triphosphatases, the subcellular location of activation is a critical determinant of cell behavior. However, current approaches are limited in their ability to examine the dynamics of Cdc42 activity in living cells. We report the development of a biosensor capable of visualizing the changing activation of endogenous, unlabeled Cdc42 in living cells. With the use of a dye that reports protein interactions, the biosensor revealed localized activation in the trans-Golgi apparatus, microtubule-dependent Cdc42 activation at the cell periphery, and activation kinetics precisely coordinated with cell extension and retraction.

Actins↗
PubMed2005

Expression of junctional adhesion molecule-A prevents spontaneous and random motility.

Junctional adhesion molecule-A (JAM-A) is a cell-surface glycoprotein that localizes to intercellular junctions and associates with intracellular proteins via PSD95-Dlg-ZO1-binding residues. To define the functional consequences of JAM-A expression, we have produced endothelial cells from JAM-A-deficient mice. We report here that the absence of JAM-A enhanced spontaneous and random motility. In turn, the enhanced motility of JAM-A-negative cells was abrogated either on transfection of exogenous JAM-A or on treatment with inhibitors of glycogen synthase kinase-3beta (GSK-3beta). In addition, in JAM-A-positive cells, motility was enhanced on inactivation of protein kinase Czeta (PKCzeta), which is an inhibitor of GSK-3beta. Although these findings suggested that JAM-A might inhibit GSK-3beta, we found that expression per se of JAM-A did not change the levels of inactive GSK-3beta. Thus, JAM-A expression may regulate effectors of motility that are also downstream of the PKCzeta/GSK-3beta axis. In support of this view, we found that JAM-A absence increased the number of actin-containing protrusions, reduced the stability of microtubules and impaired the formation of focal adhesions. Notably, all the functional consequences of JAM-A absence were reversed either on treatment with GSK-3beta inhibitors or on transfection of full-length JAM-A, but not on transfection of a JAM-A deletion mutant devoid of the PSD95-Dlg-ZO1-binding residues. Thus, by regulating cytoskeletal and adhesive structures, JAM-A expression prevents cell motility, probably in a PSD95-Dlg-ZO1-dependent manner.

Animals↗