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At least 793 records · Page 44Linked to original sources
PubMed1999

Reduced expression of (alpha)5(beta)1 integrin prevents spreading-dependent cell proliferation.

Cell adhesion to substratum results in the initiation of integrin signaling and an integrin-dependent organization of the cytoskeleton (cell spreading). To address the potential relationships between these events and cell proliferation, we transfected NRK fibroblasts with an antisense cDNA encoding a 1.3 kb ATG-spanning portion of (alpha)5 integrin subunit and obtained stable clones in which the surface expression of (alpha)5(beta)1 integrin was selectively reduced. (alpha)5-antisense NRK cells are less spread than the control transfectants, have poorly defined stress fibers, and an increased amount of cortical actin. The antisense clones remained anchorage-dependent, but they proliferated very slowly. Serum dose-response curves showed that they have an impaired response to mitogens. Importantly, cell spreading and stress fiber formation could be completely restored by plating the antisense cells on collagen, but cell spreading failed to rescue proliferation. These data indicate that cell spreading can be uncoupled from cell proliferation and that cytoskeletal organization is important for NRK cell proliferation because it enforces the proliferative effect of (alpha)5(beta)1 integrin. Our results also indicate that reduced surface expression of (alpha)5(beta)1 integrin is not sufficient to confer the anchorage-independent phenotype to nontransformed cells.

Animals↗
PubMed2001

A functional comparison of mutations in integrin beta cytoplasmic domains: effects on the regulation of tyrosine phosphorylation, cell spreading, cell attachment and beta1 integrin conformation.

Cell adhesion is a multistep process that requires the interaction of integrins with their ligands in cell attachment, the activation of integrin-triggered signals, and cell spreading. Integrin beta subunit cytoplasmic domains (beta tails) participate in regulating each of these steps; however, it is not known whether the same or different regions within beta tails are required. We generated a panel of amino acid substitutions within the beta1 and beta3 cytoplasmic domains to determine whether distinct regions within beta3 tails regulate different steps in adhesion. We expressed these beta cytoplasmic domains in the context of interleukin 2 (IL-2) receptor (tac) chimeras and tested their ability to activate tyrosine phosphorylation, to regulate beta1 integrin conformation and to inhibit beta1 integrin function in cell attachment and spreading. We found that many of the mutant beta3 and beta3 chimeras either had no effect on these parameters or dramatically inhibited the function of the beta tail in most assays. However, one set of analogous Ala substitutions in the beta1 and beta3 tails differentially affected the ability of the tac-beta3 and tac-beta3 chimeras to activate tyrosine phosphorylation. The tac-beta1 mutant containing Ala substitutions for the VTT motif did not signal, whereas the analogous tac-beta3 mutant was able to activate tyrosine phosphorylation, albeit not to wild-type levels. We also identified a few mutations that inhibited beta tail function in only a subset of assays. Ala substitutions for the Val residue in the VTT motif of the beta1 tail or for the conserved Asp and Glu residues in the membrane-proximal region of the beta3 tail greatly diminished the ability of tac-beta1 and tac-beta3 to inhibit cell spreading, but had minimal effects in other assays. Ala substitutions for the Trp and Asp residues in the conserved WDT motif in the beta1 tail had dramatic effects on the ability of tac-beta1 to regulate integrin conformation and function in cell spreading, but had no or intermediate effects in other assays. The identification of mutations in the beta1 and beta3 tails that specifically abrogated the ability of these beta tails to regulate beta1 integrin conformation and function in cell spreading suggests that distinct protein interactions with beta tails regulate beta cytoplasmic domain function in these processes.

Amino Acid Sequence↗
PubMed1991

Vanadate inhibits both intercellular adhesion and spreading on fibronectin of BHK21 cells and transformed derivatives.

Both intercellular adhesion and spreading on fibronectin of BHK21 hamster cells are inhibited by vanadate at concentrations that cause specific regulatory effects rather than general metabolic inhibition. Inhibition of aggregation of these cells in suspension (half-maximal in 10(-5) M vanadate) is rapid and reversible. The extent of inhibition, and its decline with culture age parallel inhibition by agents that depolymerize microtubules. Vanadate also reversibly inhibits spreading of both BHK cells and transformed derivatives on fibronectin. If 10(-4) M vanadate is added to BHK cells that have spread in its absence, they remain spread, but transformed derivatives are sensitive to rounding by vanadate at 10(-6) M. The mechanisms by which vanadate inhibits both intercellular adhesion and spreading are unknown, and may be different for the two phenomena. Possible sensitive targets include cytoplasmic dynein for the former, and protein tyrosyl phosphatase for the latter.

Adenine↗
PubMed2001

Spread of synaptic potentials through electrical synapses in Retzius neurones of the leech.

We studied the spread of excitatory postsynaptic potentials (EPSPs) through electrical synapses in Retzius neurones of the leech Haementeria officinalis. The pair of Retzius neurones in each ganglion is coupled by a non-rectifying electrical synapse. Both neurones displayed synchronous EPSPs of varying amplitudes and rise times. The kinetics of synchronous EPSPs was similar in 79 % of the EPSP pairs. In the remaining 21 %, one EPSP was smaller and slower than the other, suggesting its passive spread from the other neurone. The proportion of these events increased to 75 % in the presence of Mg(2+) in the bathing fluid. This spread of EPSPs from one neurone to another was tested by producing artificial EPSPs by current injection into the soma of one Retzius neurone. The artificial EPSPs were smaller and arrived more slowly at the soma of the coupled neurone. The coupling ratios for the EPSPs were proportional to the coupling ratio for long steady-state pulses in different neuronal pairs. Our results showed that EPSPs spread from one Retzius neurone to the other and support the idea that EPSP spread between electrically coupled neurones may contribute to the integration processes of neurones.

Animals↗
PubMed1995

Artificial cell-spreading of permeabilized BHK cells on fibronectin-coated substratum.

We developed a cell-spreading model of permeabilized BHK cells to analyze molecular interactions in the cell-spreading machinery. BHK cells in suspension were allowed to attach onto the fibronectin-coated cover slips at 37 degrees C for 20 min. The cells were then permeabilized with 50 micrograms/ml saponin for 10 min at 4 degrees C. Approximately 50 percent of the cell models spread in response to exogenous 1 mM ATP for 90 min at 37 degrees C. Anti-actin antibody penetrated into almost all the cell models which spread ATP-dependently. These indicate that half number of the cell models permeabilized with saponin is spread by the exogenous ATP and has pores larger than an IgG molecule.

Adenosine Triphosphate↗
PubMed2001

The toe-spreading reflex of the rabbit revisited--functional evaluation of complete peroneal nerve lesions.

Although a variety of electrophysiological and morphological tests are available for studying nerve regeneration in animals, these endpoints do not necessarily correlate with the return of muscle function. Recent efforts have focused on the assessment of function as the endpoint of nerve regeneration. One of the best known of these tests is the sciatic function index in rats. For rabbits, the toe-spreading reflex has been suggested as a valuable index of peroneal function. We examined the reliability and sensitivity of the toe-spreading reflex in a study of nerve regeneration of the peroneal nerve in 10 New Zealand White rabbits. Eleven weeks after the transection and immediate suturing of the peroneal nerve in both hind legs (at two slightly different sites), a toe-spreading reflex could always be elicited on that side where the level of the severed nerve was closer to the dependent muscles. Also on this hind leg the muscle weight of the peroneal target muscles was significantly higher (P = 0.031) than on the contralateral side, which corresponds well to the results of the toe-spreading reflex. The toe-spreading reflex is an excellent and sensitive indicator of the onset of motor recovery in the peroneal nerve-dependent muscles of rabbits. Even small differences in the localization of lesions in both hind legs can be differentiated with this test.

Animals↗
PubMed1986

Prognostic implications of perineural spread in squamous carcinomas of the head and neck.

The occurrence and prognostic implications of perineural spread were examined in 239 patients with mucosal squamous carcinomas of the head and neck. Perineural spread was demonstrated in resections from 64 patients (27%), the majority having primary tumors at one of three sites: buccal cavity, larynx, and pharynx. Perineural spread near nodal metastases was uncommon. There was no evidence that perineural involvement was more commonly associated with large tumors or less differentiated ones. No association was established between perineural spread and coexistent lymph node deposits in the surgical resections. Perineural spread was, however, shown to be a statistically significant prognostic factor for an increased incidence of subsequent locoregional recurrence and for decreased survival.

Adult↗
PubMed2006

Delaying the international spread of pandemic influenza.

BACKGROUND: The recent emergence of hypervirulent subtypes of avian influenza has underlined the potentially devastating effects of pandemic influenza. Were such a virus to acquire the ability to spread efficiently between humans, control would almost certainly be hampered by limited vaccine supplies unless global spread could be substantially delayed. Moreover, the large increases that have occurred in international air travel might be expected to lead to more rapid global dissemination than in previous pandemics. METHODS AND FINDINGS: To evaluate the potential of local control measures and travel restrictions to impede global dissemination, we developed stochastic models of the international spread of influenza based on extensions of coupled epidemic transmission models. These models have been shown to be capable of accurately forecasting local and global spread of epidemic and pandemic influenza. We show that under most scenarios restrictions on air travel are likely to be of surprisingly little value in delaying epidemics, unless almost all travel ceases very soon after epidemics are detected. CONCLUSIONS: Interventions to reduce local transmission of influenza are likely to be more effective at reducing the rate of global spread and less vulnerable to implementation delays than air travel restrictions. Nevertheless, under the most plausible scenarios, achievable delays are small compared with the time needed to accumulate substantial vaccine stocks.

Disease Outbreaks↗
PubMed2004

Direct comparison of the spread area, contractility, and migration of balb/c 3T3 fibroblasts adhered to fibronectin- and RGD-modified substrata.

Native proteins are often substituted by short peptide sequences. These peptides can recapitulate key, but not all biofunctional properties of the native proteins. Here, we quantify the similarities and differences in spread area, contractile activity, and migration speed for balb/c 3T3 fibroblasts adhered to fibronectin- (FN) and Arg-Gly-Asp (RGD)-modified substrata of varying surface density. In both cases spread area has a biphasic dependence on surface ligand density (sigma) with a maximum at sigma approximately 200 molecules/microm2, whereas the total traction force increases and reaches a plateau as a function of sigma. In addition to these qualitative similarities, there are significant quantitative differences between fibroblasts adhered to FN and RGD. For example, fibroblasts on FN have a spread area that is on average greater by approximately 200 microm2 over a approximately 40-fold change in sigma. In addition, fibroblasts on FN exert approximately 3-5 times more total force, which reaches a maximum at a value of sigma approximately 5 times less than for cells adhered to RGD. The data also indicate that the differences in traction are not simply a function of the degree of spreading. In fact, fibroblasts on FN (sigma approximately 2000 microm(-2)) and RGD (sigma approximately 200 microm(-2)) have both similar spread area (approximately 600 microm2) and migration speed (approximately 11 microm/h), yet the total force production is five times higher on FN than RGD (approximately 0.05 dyn compared to approximately 0.01 dyn). Thus, the specific interactions between fibroblasts and FN molecules must inherently allow for higher traction force generation in comparison to the interactions between fibroblasts and RGD.

Adsorption↗
PubMed2006

Spreading of neutrophils: from activation to migration.

Neutrophils rely on rapid changes in morphology to ward off invaders. Time-resolved dynamics of spreading human neutrophils after activation by the chemoattractant fMLF (formyl methionyl leucyl phenylalanine) was observed by RICM (reflection interference contrast microscopy). An image-processing algorithm was developed to identify the changes in the overall cell shape and the zones of close contact with the substrate. We show that in the case of neutrophils, cell spreading immediately after exposure of fMLF is anisotropic and directional. The dependence of spreading area, A, of the cell as a function of time, t, shows several distinct regimes, each of which can be fitted as power laws (A ~ t(b)). The different spreading regimes correspond to distinct values of the exponent b and are related to the adhesion state of the cell. Treatment with cytochalasin-B eliminated the anisotropy in the spreading.

Actins↗
PubMed2005

Multiple bromodomain genes are involved in restricting the spread of heterochromatic silencing at the Saccharomyces cerevisiae HMR-tRNA boundary.

The transfer RNA gene downstream from the HMR locus in S. cerevisiae functions as part of a boundary (barrier) element that restricts the spread of heterochromatic gene silencing into the downstream region of chromosome III. A genetic screen for identifying additional genes that, when mutated, allow inappropriate spreading of silencing from HMR through the tRNA gene was performed. YTA7, a gene containing bromodomain and ATPase homologies, was identified multiple times. Previously, others had shown that the bromodomain protein Bdf1p functions to restrict silencing at yeast euchromatin-heterochromatin boundaries; therefore we deleted nonessential bromodomain-containing genes to test their effects on heterochromatin spreading. Deletion of RSC2, coding for a component of the RSC chromatin-remodeling complex, resulted in a significant spread of silencing at HMR. Since the bromodomain of YTA7 lacks a key tyrosine residue shown to be important for acetyllysine binding in other bromodomains, we confirmed that a GST-Yta7p bromodomain fusion was capable of binding to histones in vitro. Epistasis analysis suggests that YTA7 and the HMR-tRNA function independently to restrict the spread of silencing, while RSC2 may function through the tRNA element. Our results suggest that multiple bromodomain proteins are involved in restricting the propagation of heterochromatin at HMR.

Amino Acid Sequence↗
PubMed2001

Tracer studies in the rat demonstrate misdirected filtration and peritubular filtrate spreading in nephrons with segmental glomerulosclerosis.

In two genetic models of "classic" focal segmental glomerulosclerosis (FSGS), the Milan normotensive and the Fawn-hooded hypertensive rats, tracer studies were performed to test the hypothesis that misdirected glomerular filtration and peritubular filtrate spreading are relevant mechanisms that contribute to nephron degeneration in this disease. Two exogenous tracers, lissamine green and horse spleen ferritin, were administered by intravenous injection and subsequently traced histologically in serial kidney sections. In contrast to control rats, both tracers in kidneys of Milan normotensive and Fawn-hooded hypertensive rats with established FSGS were found to accumulate extracellularly at the following sites: (1) within tuft adhesions to Bowman's capsule and associated paraglomerular spaces, (2) at the glomerulotubular junction contained within extensions of the paraglomerular spaces onto the tubule, and (3) within subepithelial peritubular spaces eventually encircling the entire proximal convolution of an affected nephron. This distribution strongly suggests the existence of misdirected filtration into tuft adhesions to Bowman's capsule and subsequent spreading of the filtrate around the entire circumference of a glomerulus and, alongside the glomerulotubular junction, onto the outer aspect of the corresponding tubule. This leads to an interstitial response that consists of the formation of a barrier of sheet-like fibroblast processes around the affected nephron, which confines the filtrate spreading and, subsequently, the destructive process to the affected nephron. No evidence was found that either misdirected filtration and peritubular filtrate spreading themselves or the associated tubulo-interstitial process led to the transfer of the injury from an affected nephron to an unaffected nephron. It is concluded that in the context of FSGS development, misdirected filtration and peritubular filtrate spreading are important damaging mechanisms that underlie the extension of glomerular injury to the corresponding tubulointerstitium, thus leading finally to degeneration of both the glomerulus and the tubule of a severely injured nephron.

Animals↗
PubMed2003

Spreading of epithelial cells on machined and sandblasted titanium surfaces: an in vitro study.

BACKGROUND: The purpose of this investigation was to determine the influence of the surface structure of dental implants on epithelial cell spreading and growth in vitro. Cell morphology on machined and sandblasted titanium surfaces was investigated. METHODS: A total of 10 machined and 10 sandblasted discs and 10 glass coverslips were used for the present study. Samples were analyzed using scanning electron microscopy (SEM) and the cell spreading area was determined using a video image analysis system. RESULTS: After 24 hours incubation, keratinocytes grown on sandblasted titanium samples displayed numerous, long, and branched or dendritic filopodia closely adapted to the surface roughness. Filopodia varied from 3 to 12 microm in length and 0.1 to 0.3 microm in width. Cells cultured on a machined surface did not present such cytoplasmic extensions and displayed a round morphology. Keratinocytes seeded on glass coverslips were flat and edged by filopodia (maximum length 7 to 8 microm) on the spreading site of the cluster. Though cell morphology is comparable with that observed on sandblasted specimens, cytoplasmic extensions suggestive of strong adhesion and spreading attitude were less pronounced. CONCLUSION: These results indicate that sandblasted surfaces are the optimal substrata for epithelial cell adhesion and spreading.

Carcinoma, Squamous Cell↗
PubMed2004

Cell spreading controls balance of prestress by microtubules and extracellular matrix.

The controversy surrounds the cellular tensegrity model. Some suggest that microtubules (MTs) must bear a significant portion of cell contractile stress (prestress) if tensegrity is a useful model. Previously we have shown that for highly spread airway smooth muscle cells (areas>2500 microm2) MTs balance a significant but small potion (average 14%) of the prestress. To further explore if controlling the degree of cell spreading could modulate the portion of the prestress balanced by MTs, we utilized a recent method by which tractions are quantified in cells that are constrained within micropatterned adhesive islands of defined sizes on the surface of flexible polyacrylamide gels containing fluorescent microbeads. The prediction is that if MTs balance a portion of the contractile stress, then, upon their disruption, the portion of the stress balanced by MTs would shift to the substrate, causing an increase in traction and strain energy. We first activated the cells maximally with histamine and then disrupted the MTs with colchicine. Histamine resulted in an increase in intracellular calcium whereas ensuing colchicine addition in the presence of histamine did not change intracellular calcium concentration, suggesting there was no additional net increase in contractile stress inside the cell. We found that following disruption of MTs the increase in traction and strain energy varied with the degree of cell spreading: as the cell projected areas increased from 500 micrometer 2 to about 1800 micrometer 2, the percent increase in tractions decreased from 80% to about a few percent and the percent increase in strain energy decreased from 200% to almost zero percent, indicating the portion of the prestress balanced by MTs decreased as the cells increased spreading. These findings demonstrate that complementary role of the extracellular matrix and the MTs in balancing the prestress is controlled by the degree of cell spreading.

Acrylic Resins↗
PubMed1988

Potentiation of fibroblast spreading by extracellular matrix from fibroblasts derived from phenytoin-induced gingival overgrowth.

Cell attachment and spreading appear when a cell, on contact with an appropriate substratum, adheres and changes its shape and accommodates to the substratum. The transition from a non-spreading to a spreading state is a prerequisite for growth. Cell-free extracellular matrix (ECM) was produced by fibroblast-like cells from normal gingiva (N-ECM) and phenytoin-induced gingival overgrowth (PHT-ECM). The effect of the ECM on cell attachment and spreading of human gingival fibroblasts was studied in the presence of 2% serum. Within 30 min after seeding 40% of the normal fibroblast cells showed an advanced flattening on PHT-ECM-prepared dishes, compared with 10% on normal ECM-prepared dishes and 5% on uncoated plastic dishes. The results indicate that cells derived from PHT-induced gingival overgrowth produce an ECM with special properties, which could regulate cell functions such as cell attachment and spreading.

Adolescent↗
PubMed1985

Histogenesis of malignant melanoma with an adjacent component of the superficial spreading type.

There has been a world-wide exponential increase in the incidence of thin malignant melanoma. At the Sydney Melanoma Unit, the proportion of patients diagnosed as having superficial spreading melanoma has more than doubled from 33% prior to 1960 to 78% during 1980-83. A study was made of the non-invasive component of malignant melanoma with an adjacent non-invasive component of the superficial spreading type in an attempt to elucidate the pathogenetic mechanisms involved in these changing trends. In this study on 723 cases of melanoma with a superficial spreading component, there was evidence that 39% originated in a precursor lesion. In the remaining 61%, the adjacent superficial spreading component consisted of melanoma in situ, suggesting that these were melanomas from the beginning. The latter lesions were thinner and had a lower degree of mitotic activity than melanomas commencing in a precursor lesion. Despite the large increase in incidence of superficial spreading melanomas and the shift to thinner lesions over time, there appeared to be no difference in the proportion of lesions commencing de novo to those commencing in a precursor lesion. This suggests that the precursor lesion may be of genetic origin.

Humans↗
PubMed1999

Different integrins mediate cell spreading, haptotaxis and lateral migration of HaCaT keratinocytes on fibronectin.

Collaborative role of various fibronectin-binding integrins (alpha5beta1, alphavbeta1 and alphavbeta6) as mediators of cell adhesion and migration on fibronectin was studied using cultured HaCaT keratinocytes. This cell line spontaneously expressed all three fibronectin-binding integrins. In addition, the expression of alphavbeta6 integrin was strongly and specifically upregulated by transforming growth factor-beta1 (TGFbeta1) whereas the amount of other integrins remained practically unchanged on the cell surface. Adhesion, spreading and motility of HaCaT keratinocytes on fibronectin were promoted by TGFbeta1. Based on antibody blocking experiments, both untreated and TGFbeta1-treated HaCaT cells used alphavbeta6 integrin as their main fibronectin receptor for cell spreading. In contrast to TGFbeta1-treated cells, the untreated cells also needed alpha5beta1 integrin for maximal cell spreading on fibronectin. Combinations of antibodies blocking both of these receptors totally prevented spreading of both untreated and TGFbeta1-treated cells. Haptotactic motility of individual HaCaT cells through fibronectin-coated membranes was again mainly dependent on alphavbeta6 integrin, while alphavbeta1 and alpha5beta1 integrins played a lesser role both in untreated and TGFbeta1-treated HaCaT cells. However, unlike haptotaxis, lateral migration of HaCaT cell sheet was mainly mediated by beta1 integrins, and alphavbeta6 integrin showed a minor role. The migration process appeared to involve a number of beta1 integrins that could adaptively replace each other when blocking antibodies were present. Thus, keratinocytes appear to use different fibronectin receptors for different functions, such as cell spreading, haptotaxis and lateral migration. The cells can also adapt to a situation where one receptor is unfunctional by switching to another receptor of the same ligand.

Antigens, Neoplasm↗
PubMed2001

Intermolecular antigen spreading occurs during the preclinical period of human type 1 diabetes.

Intra- and intermolecular spreading of T cell responses to autoantigens has been implicated in the pathogenesis of autoimmune diseases. Therefore, we questioned whether T cell responses from subjects identified as at-risk (positive for autoantibody reactivity to islet proteins) for the development of type 1 diabetes, a cell-mediated autoimmune disease, would demonstrate intermolecular Ag spreading of T cell responses to islet cell proteins. Previously, we have demonstrated that by the time subjects develop type 1 diabetes, they have T cell responses to numerous islet proteins, whereas T cells from normal controls respond to a limited number of islet proteins. Initial testing of PBMC responses from 25 nondiabetic at-risk subjects demonstrated that 16 of the 25 subjects have PBMC responses to islet proteins similar to controls. Fourteen of these 16 subjects were available for follow-up. Eleven of the 14 developed T cell responses to increasing numbers of islet proteins, and 6 of these subjects developed type 1 diabetes. In the nine subjects who already demonstrated T cell Ag spreading at the initial visit, four were available for follow-up. Of these four, two had increases in T cell reactivity to islet proteins, while two maintained their initial levels of T cell reactivity. We also observed Ag spreading in autoantibody reactivity to islet proteins in nine of the 18 at-risk subjects available for follow-up. Our data strongly support the conclusion that intermolecular spreading of T cell and Ab responses to islet proteins occurs during the preclinical period of type 1 diabetes.

Adolescent↗