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At least 667 records · Page 37Linked to original sources
PubMed2001

Patterns of integrin expression in a human mandibular explant model of osteoblast differentiation.

Cell-matrix interaction is crucial in regulating osteoblast differentiation and function. These interactions are themselves regulated, at least in part, by integrins. Although there are some data from mammalian models, few studies have compared integrin expression at different stages of the osteoblast lineage. Here, primary human mandibular osteoblast cultures were grown in the presence of epidermal growth factor (EGF), giving a proliferative, less differentiated phenotype, or of vitamin D(3) and hydrocortisone (D+Hc), giving a more differentiated phenotype. These cultures were compared with those of cells prepared in the absence of EGF or D+Hc by fluorescence-activated cell sorter using a panel of monoclonal antibodies to specific integrin heterodimers. To provide in vivo correlation, the same panel of antibodies was used to stain fresh-frozen, undemineralised sections of human mandibular bone. Under baseline conditions the alpha(3), alpha(5), alpha(v), alpha(v)beta(3), beta(3) and beta(1) integrin subunits were expressed strongly by the cells, with low-level expression of the alpha(1), alpha(2) and alpha(4) subunits. In the presence of EGF there was increased alpha(2) expression. With D+Hc, alpha(3) and alpha(5) expression was elevated. Immunohistochemical analysis demonstrated alpha(2), alpha(3), alpha(5), alpha(v)beta(3), beta(1) and beta(3) subunits in cells of the osteoblast lineage; alpha(2) staining was restricted to cells close to the bone surface whilst alpha(v)beta(3) and beta(3) were most frequently localised in the osteocytes. The results provide evidence that cells at successive stages of the osteoblast lineage show different patterns of integrin expression. These integrins may be important in cell-matrix interactions leading to osteoblast differentiation.

Antibodies, Monoclonal↗
PubMed2003

Amphiphysin1 inhibits vitronectin-mediated cell adhesion, spreading, and migration in vitro.

To investigate the regulatory mechanism of cell adhesion, we have searched for cellular inhibitory factors which prevent cell adhesion. The brain cytosol was found to inhibit the adhesion of various transformed cells to the substratum. An inhibitory 120-kDa protein was purified by sequential column chromatography. Peptide sequencing revealed that the protein is identical to amphiphysin1. GST-amphiphysin1 suppressed the attachment of HeLa cells to the plate when cells were cultured in the serum-containing medium. Vitronectin, a major cell-adhesive protein in serum and a ligand to alpha(v)beta3 integrin, was responsible for this cell attachment, and the vitronectin action was blocked by GST-amphiphysin1. GST-amphiphysin1 also inhibited the vitronectin-mediated spreading and migration of malignant melanoma cells. Furthermore, GST-amphiphysin1 bound directly to vitronectin. These findings point to the interesting possibility that amphiphysin1 could be a useful tool to inhibit cell-adhesive vitronectin.

Amino Acid Sequence↗
PubMed2003

Disabled-2 small interfering RNA modulates cellular adhesive function and MAPK activity during megakaryocytic differentiation of K562 cells.

Previous studies have shown that Disabled-2 (DAB2) is up-regulated during megakaryocytic differentiation of human K562 cells. To delineate the consequences of DAB2 induction, a DNA vector-based small interfering RNA (siRNA) was designed to intervene in DAB2 expression. We found that DAB2 siRNA specifically inhibited DAB2 induction, resulting in the modulation of cell-cell adhesion and mitogen-activated protein kinase (MAPK) phosphorylation. The morphological changes and beta3 integrin expression associated with megakaryocytic differentiation were not affected. Since the MAPK pathway has been shown to involve DAB2 induction [Tseng et al., Biochem. Biophys. Res. Commun. 285 (2001) 129-135], our results suggest a reciprocal regulation between DAB2 and MAPK in the differentiation of K562 cells. In addition, we have demonstrated for the first time that DAB2 siRNA is a valuable tool for unveiling the biological consequences of DAB2 expression.

Adaptor Proteins, Signal Transducing↗
PubMed1997

A structure prediction for the ligand-binding region of the integrin beta subunit: evidence for the presence of a von Willebrand factor A domain.

The integrins are a family of cell surface receptors that mediate biologically important adhesive interactions. Integrin-ligand binding has been extensively studied because of the potential for the development of anti-adhesive therapies, but the molecular basis of this interaction is still poorly understood. A conserved region near the N-terminus of the beta subunit appears to be of particular importance in ligand binding, but to date this domain has not been expressed in isolation. As a prelude to expression and potential structure determination, we have performed a detailed structure prediction for this region. Primary, secondary and tertiary structure analyses indicate that the region folds into a von Willebrand factor A-domain, thereby potentially placing a previously characterised module at the centre of a key functional region.

Algorithms↗
PubMed2002

Collagen suppresses the proliferative phenotype of allylamine-injured vascular smooth muscle cells.

Repeated cycles of oxidative injury by allylamine induce proliferative rat vascular smooth muscle cell (vSMC) phenotypes characterized by enhanced secretion of osteopontin (OPN). The present study was designed to evaluate the role of extracellular matrix (ECM) interactions in the induction of proliferative phenotypes in this model of oxidant injury. Because OPN is involved in ECM/integrin signaling, and may participate in proliferative control, the proliferation profiles of control and allylamine vSMCs seeded on different matrices were compared. Allylamine cells exhibited a proliferative advantage over controls when seeded on plastic, Pronectin, or fibronectin, but not type I collagen. Addition of GRGDS peptide selectively enhanced [3H]-thymidine incorporation in allylamine vSMCs, while anti-OPN antibodies nullified their proliferative advantage. Allylamine cells exhibited altered expression of alpha1, alpha5 and beta3 integrin subunits and enhanced downstream integrin-coupled increases in focal adhesion kinase, AP-1 and NF-kappaB binding activity. Inhibition of NF-kappaB by pyrrolidine dithiocarbamate selectively compromised proliferation of allylamine vSMCs, while seeding on a non-permissive collagen matrix ablated enhancement of NF-kappaB inducibility. These results implicate ECM interactions in the deregulation of vSMC proliferation following repeated cycles of oxidative chemical injury.

Allylamine↗
PubMedDate not supplied

Elevated P-selectin on platelets in depression: response to bupropion.

Increased platelet activation has been suggested as a possible reason for the increased vulnerability of depressed patients to ischemic heart disease (IHD). Translocation of P-selectin, an integral alpha-granule membrane protein, to the platelet surface is a measure of platelet activation. Herein, western blots of platelet plasma membranes containing P-selectin were quantified in patients with major depression (n=19; mean age=39 +/- 2 years) and healthy comparison subjects (n=17; mean age=36 +/- 2 years). None evidenced clinical signs of IHD, and only two patients had a lifestyle IHD risk factor (smoking). Blood was obtained from all 19 depressed patients before treatment, and 15 returned after 6-8 weeks of open-label bupropion treatment. Bupropion was chosen as the antidepressant because it did not elevate plasma norepinephrine or serotonin, endogenous agonists that can induce platelet degranulation. Western blotting revealed more P-selectin immunoreactivity (75 kD band) in depressed patients compared to healthy controls (P=0.003). After bupropion treatment, P-selectin remained high in depressed patients. beta3-Integrin, a reference plasma membrane protein that does not translocate during activation, was of equivalent density in depressed patients and healthy control subjects, and was unchanged after treatment with bupropion. P-Selectin failed to correlate with severity of illness based on the Hamilton Depression scale, or with the post-treatment plasma concentration of bupropion. The results suggest an elevation in P-selectin on platelet plasma membranes might be a trait marker for depression.

Adolescent↗
PubMed2002

Osteopontin gene expression and immunolocalization in the rabbit urinary tract.

PURPOSE: Osteopontin is a highly phosphorylated, calcium binding sialoprotein characterized by a conserved arginine-glycine-aspartate sequence. Vitronectin receptor (alphavbeta3 integrin) and hyaluronan receptor (CD44) are documented as receptors for osteopontin and their expression has been established in the bladder. Based on that finding and the fact that osteopontin protein is present in urine we hypothesized that osteopontin is expressed in the lower urinary tract. MATERIALS AND METHODS: Osteopontin messenger (m)RNA and protein were analyzed in 5 adult urinary tracts and 5 neonatal bladders of New Zealand White rabbits using reverse transcriptase-polymerase chain reaction and immunohistochemical testing. Analysis of mRNA expression and localization of osteopontin receptors, alphavbeta3 integrin and CD44 were also performed in adult bladders and primary cultures of detrusor myocytes. RESULTS: Adult renal pelvis, ureter, bladder and urethra, and neonatal bladders contained significant levels of osteopontin mRNA. Immunohistochemical staining revealed osteopontin expression in all layers of the transitional epithelium of the bladder, co-localizing with alphavbeta3 integrin mainly in the superficial layers and with CD44 mainly in the basal layers. Osteopontin was detected within the cytoplasm of smooth muscle cells, while alphavbeta3 integrin was located closer to the plasmalemma. Furthermore, primary cultured detrusor myocytes expressed osteopontin mRNA in stable fashion for up to 4 passages. Treating bladder myocyte cultures with insulin-like growth factor-1 and 17beta-estradiol resulted in up-regulation and down-regulation of osteopontin mRNA, respectively. CONCLUSIONS: Adult and neonatal rabbit detrusors are a prominent source of osteopontin in vivo and in vitro. Epithelial osteopontin may be a source of osteopontin in urine. The co-localization of osteopontin in the bladder epithelium with alphavbeta3 integrin and CD44 suggests a role in maintaining the integrity of the transitional epithelium by providing the sealing and adhesiveness needed for the impermeable state of the bladder.

Animals↗
PubMed1997

Immunolocalization of integrins in the normal lung and in pulmonary carcinomas.

Cryosections of normal adult lung (n = 7) and pulmonary epithelial tumors, including squamous (n = 8), adeno (n = 8), bronchioloalveolar (n = 5), and large cell (n = 4) carcinomas (SCC, ACC, BAC, LCC), carcinoids (Cd, n = 7), and neuroendocrine carcinomas (NEC) of variable grades (n = 14) were immunostained by the avidin-biotin peroxidase (ABC) method with monoclonal antibodies to the alpha1-6 and alpha(v) and the beta1-4 integrin subunits. Normal adult alveolar septae showed variably intense immunoreactivity for alpha1,3,6 and beta1, whereas reactions for alpha5 and alpha(v) were weaker and uneven; the remaining integrin subunits were not detected. Bronchial and bronchiolar epithelium showed variably intense staining for alpha2.3,6,v and beta1,4. Reactions were often, though not invariably, basally polarized. SCC, ADC, and LCC showed variably intense reactions for alpha2.3,6,v and beta1,4. BAC were strongly and uniformly stained for alpha1.3 and beta1. In Cd, alpha1,2,3,v and beta1 reactions were noted, whereas in NEC, weak alpha1,3 and beta1 staining was detected with only traces of alpha6 and alpha(v). We conclude that alveolar epithelial cells do not express the hemidesmosome-associated, laminin-binding integrin alpha6beta4 of the bronchial epithelium but rather the alpha1beta1 and alpha3beta1, collagen IV, and laminin receptors, respectively. SCC, ADC, and sampled LCC express an integrin repertory qualitatively similar to that of the bronchial epithelium. Distinct from the latter, the integrin repertory of BAC parallels that of the alveolar epithelium by its strong expression of the multipotential alpha1beta1 and alpha3beta1 integrins. NEC tumors do not display the laminin receptors alpha6beta4 and alpha6beta1 shown by SCC and ADC but express instead alpha1beta1, a collagen IV-laminin receptor rarely found in epithelial neoplasms except for BAC. In NEC tumors, integrins, especially alpha2, decrease with dedifferentiation. Notably distinct from epithelial mesotheliomas, the major fibronectin-binding integrin alpha5beta1 was not found in any type of lung carcinoma.

Adenocarcinoma↗
PubMed1997

Interaction of beta 3 integrin-derived peptides 214-218 and 217-231 with alpha IIb beta 3 complex and with fibrinogen A alpha-chain.

beta 3 integrin-derived peptides 214-218 and 217-231 have been shown previously to inhibit platelet aggregation and fibrinogen binding to platelets and to purified receptor. In this paper we study the activity of both peptides in inhibition of binding of biotinylated fibrinogen to activated platelets and to immobilized alpha IIb beta 3 receptor. We found that the mechanism of this inhibition by both peptides is different 125I-labeled 214-218 peptide binds to alpha IIb beta 3 but in contrast, 125I-labeled 217-231 peptide binds to the A alpha-chain of native and gamma' fibrinogen, as judged by the cross-linking study. In solid phase assay both purified alpha IIb beta 3 and 217-231 peptide bound extensively to native and recombinant fibrinogen, and to fibrinogen with either D574E or D97E mutations in the A alpha-chain. Binding of purified alpha IIb beta 3 to gamma' fibrinogen was markedly impaired whereas binding of 217-231 was only slightly impaired in comparison with native fibrinogen. Binding of 217-231 to fibrinogen fragment X was also reduced suggesting that sequences other than RGDS and RGDF may represent binding sites for this peptide. We hypothesize that the close vicinity of fibrinogen binding site (217-231) and of the site participating in conformational changes of the alpha IIb beta 3 receptor (214-218) may facilitate fibrinogen interaction with its receptor.

Adenosine Diphosphate↗
PubMed1999

The prothrombin gene G20210A mutation and the platelet glycoprotein IIIa polymorphism PlA2 in patients with central retinal vein occlusion.

The prothrombin gene G20210A mutation and the platelet glycoprotein IIIa polymorphism PlA2 have been shown to be associated with thromboembolic disease. We wondered if mutations were overrepresented in patients with central retinal vein occlusion. We studied 129 consecutive patients with a history of central retinal vein occlusion. We analysed for the prothrombin gene G20210A mutation and the platelet glycoprotein IIIa polymorphism PlA2 and compared the results to controls with no history of thrombosis. For the platelet glycoprotein IIIa polymorphism PlA2, 69% were normal, 26% were heterozygous, and 5% were homozygous. For the G20210A prothrombin mutation, 97% were normal and 3% were heterozygous. Neither the prothrombin gene G20210A mutation nor the platelet glycoprotein IIIa polymorphism PlA2 seem to be associated with central retinal vein occlusion.

Adult↗
PubMed2000

Mechanism of calcium oscillations in migrating human astrocytoma cells.

Numerous studies show that intracellular calcium controls the migration rate of different mobile cell types. We studied migrating astrocytoma cells from two human cell lines, U-87MG and A172, in order to clarify the mechanisms by which calcium potentially influences cell migration. Using the wound-healing model to assay migration, we showed that four distinct components of migration could be distinguished: (i) a Ca(2+)/serum-dependent process; (ii) a Ca(2+)-dependent/serum-independent process; (iii) a Ca(2+)/serum-independent process; (iv) a Ca(2+)-independent/serum-dependent process. In U-87MG cells which lack a Ca(2+)-dependent/serum-independent component, we found that intracellular Ca(2+) oscillations are involved in Ca(2+)-dependent migration. Removing extracellular Ca(2+) greatly decreased the frequency of migration-associated Ca(2+) oscillations. Furthermore, non-selective inhibition of Ca(2+) channels by heavy metals such as Cd(2+) or La(3+) almost completely abolished changes in intracellular Ca(2+) observed during migration, indicating an essential role for Ca(2+) channels in the generation of these Ca(2+) oscillations. However, specific blockers of voltage-gated Ca(2+) channels, including nitrendipine, omega-conotoxin GVIA, omega-conotoxin MVIIC or low concentrations of Ni(2+) were without effect on Ca(2+) oscillations. We examined the role of internal Ca(2+) stores, showing that thapsigargin-sensitive Ca(2+) stores and InsP(3) receptors are involved in Ca(2+) oscillations, unlike ryanodine-sensitive Ca(2+) stores. Detailed analysis of the spatio-temporal aspect of the Ca(2+) oscillations revealed the existence of Ca(2+) waves initiated at the leading cell edge which propagate throughout the cell. Previously, we have shown that the frequency of Ca(2+) oscillations was reduced in the presence of inhibitory antibodies directed against beta3 integrin subunits. A simple model of a Ca(2+) oscillator is proposed, which may explain how the generation of Ca(2+) oscillations is linked to cell migration.

Astrocytoma↗
PubMed1994

Serum levels of integrins in chronic liver diseases.

The serum levels of beta 1 integrin (microgram/ml) were significantly higher in the patients with chronic persistent hepatitis (2.59 +/- 0.04), chronic active hepatitis (3.45 +/- 0.13), cirrhosis (4.77 +/- 0.30) and hepatocellular carcinoma (4.71 +/- 0.49) than in normal subjects (2.11 +/- 0.08). Serum levels of beta 3 integrin (microgram/ml) were significantly higher in the patients with chronic active hepatitis (10.48 +/- 1.22), liver cirrhosis (13.55 +/- 1.54) and hepatocellular carcinoma (14.1 +/- 1.77) when compared with normal subjects (5.51 +/- 0.52). A positive correlation was found between serum levels of beta 1 and beta 3 integrins (p < 0.001). A strong positive correlation was observed between serum levels of beta 1 integrin and histologic features, particularly in the degree of hepatic fibrosis, while no correlation was found between serum levels of beta 3 integrin and hepatic fibrosis. Immunohistochemical studies revealed that the beta 1 integrin was present on the plasma membranes of hepatocytes and sinusoidal lining cells in the normal liver, and was increased in fibrotic areas, and on the plasma membranes of hepatocytes and sinusoidal lining cells of the chronic liver disease. However, no positive staining for beta 3 integrin was observed in fibrotic area. The serum level of beta 1 integrin in patients with chronic liver diseases may therefore be a useful marker of hepatic fibrosis.

Chronic Disease↗
PubMed2000

PlA polymorphism of glycoprotein IIIa and risk of adverse events after coronary stent placement.

OBJECTIVE: We designed this prospective study to test the hypothesis that platelet antigen (PlA) polymorphism of glycoprotein (GP) IIIa is associated with an increased risk for adverse events after coronary stent placement. BACKGROUND: Platelets play a central role in arterial thrombosis. The PlA polymorphism of GP IIIa, a constituent of the fibrinogen receptor, may influence the platelet function and, thereby, the early outcome of patients after coronary stent placement. METHODS: The study included 1,759 consecutive patients with stable or unstable angina and successful coronary stent placement. Platelet antigen genotypes were determined by allele-specific restriction enzyme analysis. The end point of the study was a composite of death, myocardial infarction and urgent revascularization during the first 30 days after stent placement. RESULTS: The PlA1 genotype of the patients included was: 70.2% were homozygous for platelet antigen 1 (PlA1), 2.6% homozygous for platelet antigen 2 (PlA1), and 27.2% were heterozygous (PlA1/A2). The incidence of the composite end point was 5.5% among PlA2 carriers and 5.4% in homozygous PlA1 subjects (p = 0.94). It was 5.4% in PlA1/A1 patients, 4.8% in PlA1/A2 patients and 13.0% in PlA2A2 patients (p = 0.06). The combined incidence of death or myocardial infarction was 4.3% in PlA1/A1 patients, 4.2% in PlA1/A2 patients and 13.0% in PlA2/A2 patients (p = 0.02). CONCLUSIONS: The isolated presence of the PlA2 allele in heterozygous patients is not associated with any detectable increase in the risk for an adverse 30-day outcome after coronary stenting. This study suggests also that an increased risk is likely to be present in homozygous carriers of the PlA2 allele, but this should be confirmed in a much larger series of patients.

Aged↗
PubMed2000

Genetic analysis of integrin function in man: LAD-1 and other syndromes.

The integrins are cell membrane receptors composed of alpha and beta subunits which orchestrate adhesive events in all tissues of the body (Hynes, R.O., 1992. Integrins: versatility, modulation, and signalling in cell adhesion. Cell 69, 11-25; and Hynes, R.O., 1999. Cell adhesion: old and new questions. Trends Cell Biol. 9, M33-37). At present 18 alpha subunits and 8 beta subunits have been identified which are loosely organised into families. There are three inherited autosomal recessive diseases in man which involve germline mutations in genes coding for integrins. Leukocyte adhesion deficiency-1 (LAD-1) is the result of mutations in the beta2 subunit of the CD11/CD18 integrins, LFA-1, Mac-1, p150,95 and alphadbeta2. The bleeding disorder Glanzmann thrombasthenia is caused by mutations in either the alpha or beta subunit of the platelet integrin, alphaIIbbeta3. Thirdly, it is now recognised than one of the variants of the usually lethal skin blistering disorder, epidermolysis bullosa (JEB-PA), is caused by mutation in either the alpha or beta subunit of the epithelial hemidesmosome integrin, alpha6beta4. Many of the mutations cause defective alphabeta heterodimer formation. The majority of the beta subunit mutations are in the conserved N-terminal region known as the betaI domain. It is suggested that this region participates in alphabeta heterodimer formation.

Animals↗
PubMed1997

Integrin cytoplasmic domains as connectors to the cell's signal transduction apparatus.

Integrins mediate the bidirectional transfer of signals across the plasma membrane. Integrin cytoplasmic domains provide one pathway linking integrin engagement with the cell's signal transduction apparatus. Recent structure-function studies have defined regions of beta cytoplasmic domains required for integrin function and have identified distinct roles for individual alpha cytoplasmic domains in regulating cell behavior. Newly identified proteins that bind to integrin alpha and beta cytoplasmic domains have provided new insights and new questions into the mechanisms involved in integrin signaling.

Amino Acid Sequence↗