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At least 775 records · Page 43Linked to original sources
PubMed2006

Heparin-binding epidermal growth factor (HB-EGF) may improve embryonic development and implantation by increasing vitronectin receptor (integrin alphanubeta3) expression in peri-implantation mouse embryos.

PURPOSE: This study investigated the effects of HB-EGF on expression of integrin alphanubeta3 and implantation of embryos. METHODS: Two-cell embryos were recovered and cultured with or without 10 ng/mL HB-EGF for 96h. Expression of integrin alphanubeta3 in cultured embryos was examined by real time-RT-PCR and immunofluorescence analysis; embryos were cultured with or without HB-EGF, then transferred into the uteri of pseudo-pregnant female mice in order to analyze their implantation rate. RESULTS: HB-EGF improved embryonic hatching and outgrowth during extended culture, and up-regulated expression of integrin alphanubeta3 in both the preimplantation embryo and outgrowing blastocyst. Also, integrin alphanubeta3 subunits were localized at the pericellular borders and cell-cell contact areas. The number of successful implantation sites of transferred HB-EGF-treated embryos in the uterus was increased when compared to number of implantation sites with non-treated controls. CONCLUSIONS: HB-EGF may improve implantation by accelerating expression of integrin alphanubeta3 in peri-implantation mouse embryos.

Animals↗
PubMed2000

Identification and in vivo efficacy of small-molecule antagonists of integrin alphavbeta3 (the vitronectin receptor).

The integrin alphavbeta3 is thought to play a key role in the initiation and/or progression of several human diseases, including osteoporosis, restenosis following percutaneous transluminal coronary angioplasty (PTCA), rheumatoid arthritis, cancer and ocular diseases. Antagonism of integrin alphavbeta3 is therefore expected to provide an approach for the treatment and/or prevention of these diseases. A variety of potent, small-molecule alphavbeta3 antagonists have been identified, several of which are active in disease models, thereby demonstrating the therapeutic potential of alphavbeta3 antagonism. This review will focus on recent advances in the identification of small-molecule alphavbeta3 antagonists, with an emphasis on those studies where small-molecule alphavbeta3 antagonists have been used in proof-of-concept studies in vivo.

Journal Article↗
PubMedDate not supplied

Structure-activity relationships of 111In- and 99mTc-labeled quinolin-4-one peptidomimetics as ligands for the vitronectin receptor: potential tumor imaging agents.

The integrin receptor alpha(v)beta(3) is overexpressed on the endothelial cells of growing tumors and on some tumor cells themselves. Radiolabeled alpha(v)beta(3) antagonists have demonstrated potential application as tumor imaging agents and as radiotherapeutic agents. This report describes the total synthesis of eight new HYNIC and DOTA conjugates of receptor alpha(v)beta(3) antagonists belonging to the quinolin-4-one class of peptidomimetics, and their radiolabeling with (99m)Tc (for HYNIC) and (111)In (for DOTA). Tethering of the radionuclide-chelator complexes was achieved at two different sites on the quinolin-4-one molecule. All such derivatives maintained high affinity for receptor alpha(v)beta(3) and high selectivity versus receptors alpha(IIb)beta(3), alpha(v)beta(5), alpha(5)beta(1). Biodistribution of the radiolabeled compounds was evaluated in the c-neu Oncomouse mammary adenocarcinoma model. DOTA conjugate (111)In-TA138 presented the best biodistribution profile. Tumor uptake at 2 h postinjection was 9.39% of injected dose/g of tissue (%ID/g). Activity levels in selected organs was as follows: blood, 0.54% ID/g; liver, 1.94% ID/g; kidney, 2.33% ID/g; lung, 2.74% ID/g; bone, 1.56% ID/g. A complete biodistribution analysis of (111)In-TA138 and the other radiolabeled compounds of this study are presented and discussed. A scintigraphic imaging study with (111)In-TA138 showed a clear delineation of the tumors and rapid clearance of activity from nontarget tissues.

Adenocarcinoma↗
PubMed2003

Upregulation of osteoclast alpha2beta1 integrin compensates for lack of alphavbeta3 vitronectin receptor in Iraqi-Jewish-type Glanzmann thrombasthenia.

Osteoclasts utilize alphavbeta3 integrin adhesion to bone matrix during bone resorption. We have generated osteoclasts from the peripheral blood of Iraqi-Jewish patients with Glanzmann thrombasthenia (GT) who are completely deficient in beta3 integrin and exhibit a haemorrhagic diathesis resulting from the absence of platelet alphaIIbbeta3. We show that, in contrast to osteoclasts generated from normal subjects or patients with alphaIIb integrin deficiency, GT osteoclasts lack alphavbeta3. These osteoclasts exhibited a two- to fourfold increase in alpha2 and beta1 integrin expression, whereas other alphav integrins, including alphavbeta5, were not significantly affected. An accompanying decrease in bone resorption was observed, with 44% and 59% declines in pit number and depth, respectively, and resorption lacunae showed abnormal morphology on scanning electron microscopy. However, osteoclasts from GT developed in similar numbers to controls and exhibited an otherwise 'normal' phenotype. We conclude that the observed rise in alpha2beta1 expression compensates for the chronic genetic deficiency of alphavbeta3 in osteoclasts from patients with GT and is sufficient to enable bone resorption to proceed, albeit to a submaximal extent. This explains why Iraqi-Jewish patients with GT do not have osteopetrosis.

Adolescent↗
PubMed2004

Apparent absolute oral bioavailability in excess of 100% for a vitronectin receptor antagonist (SB-265123) in rat. II. Studies implicating transporter-mediated intestinal secretion.

1. Transporters have been increasingly identified as a factor in limiting the oral bioavailability of certain drugs. Previously, the present authors investigated a compound (SB-265123) with an apparent absolute oral bioavailability (Fapp) consistently > 100%, and excluded likely artefactual causes for this observation, as well as standard considerations of non-stationary or non-linear pharmacokinetics. The data led the authors to believe that SB-265123 might be a transporter substrate in the rat, and it was hypothesized that transporter interactions might be responsible for the observed Fapp > 100%. 2. In the present study, a model was proposed incorporating rapid and complete absorption and elimination by a saturable intestinal secretory pathway. Intestinal secretion was demonstrated for SB-265123 using a rat single-pass intestinal perfusion technique. In addition, in a study employing both independent and simultaneous intravenous and oral administration of SB-265123, exposure to SB-265123 was greater than additive on joint intravenous and oral administration, lending further support to the hypothesis of a saturable transporter. Furthermore, in a study with co-administration of GF120918A, a transporter inhibitor, the observed Fapp for SB-265123 was only 84 +/- 17%, providing additional evidence for transporter involvement in the >100% Fapp phenomenon. 3. Experience with SB-265123 illustrates a counterintuitive impact of transporters on oral bioavailability and highlights the importance of considering transporter interactions in the systemic disposition of xenobiotics, even those not demonstrating low oral bioavailability.

Acetates↗
PubMed2000

Cloning and characterisation of ITGAV, the genomic sequence for human cell adhesion protein (vitronectin) receptor alpha subunit, CD51.

The integrin family of receptors serves as major receptors for extracellular matrix-mediated cell adhesion and migration, cytoskeletal organisation, cell proliferation, survival, and differentiation. The alpha-V integrins consist of a subset which share a common alpha-V subunit combined with one of five beta subunits (beta-1, 3, 5, 6, or 8). The alpha-V integrins have been implicated in a number of developmental processes, including vasculogenesis and angiogenesis, and are therapeutic targets for inhibition of angiogenesis and osteoporosis. The human cDNA for alpha-V integrin (ITGAV) consists of a 5,717-bp transcript with a coding sequence (CDS) of 3,146 bp encoding a 150-kDa mature peptide. Here we describe the gene structure of ITGAV.

Antigens, CD↗
PubMed2002

Vitronectin receptor alpha(V)beta(3) integrin antagonists: chemical and structural requirements for activity and selectivity.

Alpha(V)beta(3) integrin, a cell surface protein, has been targeted by a variety of natural and synthetic antagonists in the search for potential cancer and osteoporosis drug candidates. This review discusses chemical and structural requirements for activity and selectivity deduced from SAR studies and draws a tentative picture of the pharmacophore.

Benzodiazepines↗
PubMed2002

Vitronectin receptors in vascular disorders.

Various integrin antagonist candidates, including antibodies, cyclic peptides, peptidomimetics and non-peptides, have been clinically evaluated and have been shown to successfully modulate certain disease processes. The most advanced integrin antagonists in clinical development include intravenous platelet alphaIIb/beta3 integrin antagonists, leukocyte alpha4/beta1 integrin antagonists and vascular alpha v/beta3 antagonists. This review will focus on the key role of the alpha v integrin (alpha v/beta3 and alpha v/beta5) in vascular disorders, such as angiogenesis-mediated disorders and vascular restenosis.

Animals↗
PubMed2000

Substrate specificity of alpha(v)beta(3) integrin-mediated cell migration and phosphatidylinositol 3-kinase/AKT pathway activation.

The alpha(v)beta(3) integrin has been shown to bind several ligands, including osteopontin and vitronectin. Its role in modulating cell migration and downstream signaling pathways in response to specific extracellular matrix ligands has been investigated in this study. Highly invasive prostate cancer PC3 cells that constitutively express alpha(v)beta(3) adhere and migrate on osteopontin and vitronectin in an alpha(v)beta(3)-dependent manner. However, exogenous expression of alpha(v)beta(3) in noninvasive prostate cancer LNCaP (beta(3)-LNCaP) cells mediates adhesion and migration on vitronectin but not on osteopontin. Activation of alpha(v)beta(3) by epidermal growth factor stimulation is required to mediate adhesion to osteopontin but is not sufficient to support migration on this substrate. We show that alpha(v)beta(3)-mediated cell migration requires activation of the phosphatidylinositol 3-kinase (PI 3-kinase)/protein kinase B (PKB/AKT) pathway since wortmannin, a PI 3-kinase inhibitor, prevents PC3 cell migration on both osteopontin and vitronectin; furthermore, alpha(v)beta(3) engagement by osteopontin and vitronectin activates the PI 3-kinase/AKT pathway. Migration of beta(3)-LNCaP cells on vitronectin also occurs through activation of the PI 3-kinase pathway; however, AKT phosphorylation is not increased upon engagement by osteopontin. Furthermore, phosphorylation of focal adhesion kinase (FAK), known to support cell migration in beta(3)-LNCaP cells, is detected on both substrates. Thus, in PC3 cells, alpha(v)beta(3) mediates cell migration and PI 3-kinase/AKT pathway activation on vitronectin and osteopontin; in beta(3)-LNCaP cells, alpha(v)beta(3) mediates cell migration and PI 3-kinase/AKT pathway activation on vitronectin, whereas adhesion to osteopontin does not support alpha(v)beta(3)-mediated cell migration and PI 3-kinase/AKT pathway activation. We conclude therefore that alpha(v)beta(3) exists in multiple functional states that can bind either selectively vitronectin or both vitronectin and osteopontin and that can differentially activate cell migration and intracellular signaling pathways in a ligand-specific manner.

Androstadienes↗
PubMed2003

Adhesion and migration of extracellular matrix-stimulated breast cancer.

BACKGROUND: Extracellular matrix (ECM) components, such as vitronectin and fibronectin, have been shown to enhance the metastatic potential of breast cancer cells. We hypothesized that ECM binding to integrin receptors on breast cancer cells influenced cellular adhesion and migration. MATERIALS AND METHODS: Adhesion assays were performed using breast cancer cell lines MDA-MB-435 and MDA-MB-231 and various concentrations of vitronectin or fibronectin. Migration assays were performed using the same cell lines and invasion chambers with 8 microm pore polycarbonate membranes. Blocking antibodies and specific peptidomimetic inhibitors to integrin receptors were used to identify the integrin subunits reacting with vitronectin and fibronectin. RESULTS: While both breast cancer cell lines adhered to and migrated toward vitronectin and fibronectin, MDA-MB-435 had a higher maximum binding to vitronectin and MDA-MB-231 had a higher maximum binding to fibronectin. Anti-beta1 antibody inhibited the adhesion and migration of MDA-MB-231 to fibronectin and the adhesion of MDA-MB-231 to vitronectin but had no effect on vitronectin-induced adhesion or migration of MDA-MB-435. The alpha(v)beta3/alpha(v)beta5 antagonist, SB 265123, inhibited MDA-MB-231 and MDA-MB-435 adhesion and migration to vitronectin but had no effect on migration to fibronectin in either cell line. CONCLUSIONS: We conclude that the integrin subunits beta1, alpha(v)beta3, and alpha(v)beta5 can be involved in breast cancer cell adhesion and migration to vitronectin and fibronectin. Because more than one integrin inhibitor was required to block adhesion or migration in the cell lines studied, breast cancer therapy based on integrin antagonists would most likely require concomitant use of multiple agents.

Acetates↗
PubMed2000

New insights into the size and stoichiometry of the plasminogen activator inhibitor type-1.vitronectin complex.

Plasminogen activator inhibitor-type 1 (PAI-1) is the primary inhibitor of endogenous plasminogen activators that generate plasmin in the vicinity of a thrombus to initiate thrombolysis, or in the pericellular region of cells to facilitate migration and/or tissue remodeling. It has been shown that the physiologically relevant form of PAI-1 is in a complex with the abundant plasma glycoprotein, vitronectin. The interaction between vitronectin and PAI-1 is important for stabilizing the inhibitor in a reactive conformation. Although the complex is clearly significant, information is vague regarding the composition of the complex and consequences of its formation on the distribution and activity of vitronectin in vivo. Most studies have assumed a 1:1 interaction between the two proteins, but this has not been demonstrated experimentally and is a matter of some controversy since more than one PAI-1-binding site has been proposed within the sequence of vitronectin. To address this issue, competition studies using monoclonal antibodies specific for separate epitopes confirmed that the two distinct PAI-1-binding sites present on vitronectin can be occupied simultaneously. Analytical ultracentrifugation was used also for a rigorous analysis of the composition and sizes of complexes formed from purified vitronectin and PAI-1. The predominant associating species observed was high in molecular weight (M(r) approximately 320,000), demonstrating that self-association of vitronectin occurs upon interaction with PAI-1. Moreover, the size of this higher order complex indicates that two molecules of PAI-1 bind per vitronectin molecule. Binding of PAI-1 to vitronectin and association into higher order complexes is proposed to facilitate interaction with macromolecules on surfaces.

Antibodies, Monoclonal↗
PubMed1998

Opposing effects of low and high molecular weight kininogens on cell adhesion.

High molecular weight kininogen (HK) blocks cell spreading but not cell attachment to surfaces coated with vitronectin and other ligands of beta3 integrins. We sought to learn the structural basis of this phenomenon. Monoclonal antibodies against the histidine-rich D5 domain in the light chain of 2-chain HK abolished the inhibitory effect of 2-chain HK on spreading of MG-63 osteosarcoma cells on vitronectin-coated tissue-culture plastic. The antibodies were effective only if incubated with 2-chain HK in solution and did not abolish the anti-cell-spreading effect of 2-chain HK that was pre-adsorbed to tissue-culture plastic. Exposure of an epitope in the histidine-rich domain was less when HK was adsorbed to tissue-culture plastic (oxidized polystyrene) than when it was adsorbed to ELISA plastic (untreated polystyrene). Loss of the epitope correlated with increased anti-cell-spreading activity of HK on tissue-culture plastic. The light chain of 2-chain HK containing D5 and that containing recombinant D5 both had anti-cell-spreading activity, but only when present in solution during adhesion assays. Pre-adsorption of recombinant D5 to tissue-culture plastic resulted in a surface on which adsorbed 2-chain HK had little anti-cell-spreading activity. Binding study revealed that HKa bound to immobilized vitronectin. The histidine-rich D5 domain of light chain of HK was identified as one of the binding sites of vitronectin, suggesting that the masking of the RGD cell-binding site of immobilized vitronectin is the molecular mechanism of anti-cell-spreading effect of HKa. In contrast, low molecular weight kininogen (LK), which lacks D5, augmented cell spreading on vitronectin-coated tissue-culture plastic. Thus, HK and LK have opposing effects on VN-dependent cell adhesion. The augmenting effect of LK was greater if LK was preincubated with cells or adsorbed to the surface at pH>7.0. Analysis of fragments of LK and antibody inhibition studies localized the cell-adhesion activity to the D3 domain that is common to LK and HK. These findings indicate that the D5 domain mediates the adsorption of HK or 2-chain HK to vitronectin substratum in anti-adhesive conformations, i.e., masking of the RGD cell-binding site of vitronectin. Such conformers inhibit cell spreading on vitronectin even though a cell-adhesion site is present in D3.

Antibodies, Monoclonal↗
PubMed1989

The distribution of distinct integrins in focal contacts is determined by the substratum composition.

The distribution of two integrins, the fibronectin receptor and the vitronectin receptor, has been explored in an endothelium-derived cell line plated onto various substrata. On a fibronectin substratum, in the presence of serum, these cells develop focal contacts that contain the fibronectin receptor, whereas the vitronectin receptor is diffusely distributed over the cell surface. Conversely, cells plated onto vitronectin-coated coverslips concentrate only the vitronectin receptor within focal contacts. The accumulation of the vitronectin receptor within focal contacts also occurs when the cells are plated on uncoated coverslips but in the presence of serum. Therefore, we conclude that under normal culture conditions (i.e. in serum-containing media), the vitronectin receptor is the predominant form of integrin involved in substratum adhesion. This conclusion is supported by experiments in which cells were cultured on fibronectin-coated coverslips in the presence of serum. Initially these cells developed focal contacts containing only the fibronectin receptor. Within several hours, however, there was a progressive replacement of focal contacts containing the fibronectin receptor by focal contacts expressing the vitronectin receptor. After approximately 12 h in culture, most cells contained focal contacts expressing only the vitronectin receptor. Focal contacts containing either the fibronectin or vitronectin receptor were both associated with the termini of stress fibres and contained the proteins talin and vinculin. These observations lead us to propose that the cell does not discriminate between these different integrins when assembling the cytoskeletal components at the cytoplasmic face of focal contacts.

Cell Adhesion↗
PubMed1993

Regulation of integrin-mediated adhesion at focal contacts by cyclic AMP.

Cyclic AMP (cAMP) elevation causes diverse types of cultured cells to round partially and develop arborized cell processes. Renal glomerular mesangial cells are smooth, muscle-like cells and in culture contain abundant actin microfilament cables that insert into substratum focal contacts. cAMP elevation causes adhesion loss, microfilament cable fragmentation, and shape change in cultured mesangial cells. We investigated the roles of the classical vitronectin (alpha V beta 3 integrin) and fibronectin (alpha 5 beta 1 integrin) receptors in these changes. Mesangial cells on vitronectin-rich substrata contained microfilament cables that terminated in focal contacts that stained with antibodies to vitronectin receptor. cAMP elevation caused loss of focal contact and associated vitronectin receptor. Both fibronectin and its receptor stained in a fibrillary pattern at the cell surface under control conditions but appeared aggregated along the cell processes after cAMP elevation. This suggested that cAMP elevation caused loss of adhesion mediated by vitronectin receptor but not by fibronectin receptor. We plated cells onto fibronectin-coated slides to test the effect of ligand immobilization on the cellular response to cAMP. On fibronectin-coated slides fibronectin receptor was observed in peripheral focal contacts where actin filaments terminated, as seen with vitronectin receptor on vitronectin-coated substrata, and in abundant linear arrays distributed along microfilaments as well. Substratum contacts mediated by fibronectin receptor along the length of actin filaments have been termed fibronexus contacts. After cAMP elevation, microfilaments fragmented and fibronectin receptor disappeared from peripheral focal contacts, but the more central contacts along residual microfilament fragments appeared intact. Also, substratum adhesion was maintained after cAMP elevation on fibronectin--but not on vitronectin-coated surfaces. Although other types of extracellular matrix receptors may also be involved, our observations suggest that cAMP regulates adhesion at focal contacts but not at fibronexus-type extracellular matrix contacts.

Actin Cytoskeleton↗
PubMed2004

Increased expression levels of integrin alphavbeta5 on scleroderma fibroblasts.

Integrin alphavbeta5 is a receptor for vitronectin, a plasma glycoprotein that is also distributed in extracellular matrix of various tissues. Matrix-bound vitronectin has the potential to stabilize the active form of plasminogen activator inhibitor-1, resulting in the inhibition of the plasmin-mediated pericellular proteolytic cascade. In this study, we compared the levels of alphavbeta5 and matrix-bound vitronectin between normal and scleroderma fibroblasts and investigated the association with fibrosis. We demonstrated that alphavbeta5 was up-regulated on scleroderma fibroblasts. The up-regulated alphavbeta5 contributed to the increase in vitronectin-binding ability in scleroderma fibroblasts, which led to the vitronectin-dependent activation of plasminogen activator inhibitor-1. In immunohistochemistry, the alphav and beta5 subunits were stained strongly on scleroderma fibroblasts and the amount of vitronectin was increased in the pericellular matrix of those cells. The transient overexpression of alphavbeta5 on normal fibroblasts enhanced the human alpha2(I) collagen promoter activity through Sp-1 and Smad3 as well as the vitronectin-dependent plasminogen activator inhibitor-1 activity. This effect on the promoter activity was also observed in the absence of vitronectin and completely disappeared in the presence of anti-alphavbeta5 antibody. These results indicate that the up-regulated alphavbeta5 may contribute to the phenotypical alteration of scleroderma fibroblasts, while at the same time suppressing the plasmin-mediated pericellular proteolytic cascade.

Blotting, Northern↗
PubMed1991

Differences in adhesion to tissue culture plastic of clonally related transformed and control sublines from an epithelial cell strain.

Clonally related sublines of the NAL1A lung epithelial cell strain were used in a comparison of the mechanism of attachment and the morphology of control and transformed epithelial cells. The initial attachment and spreading of the control cells on tissue culture plastic was shown to be dependent upon adsorption of serum vitronectin to the substratum. The alpha v subunit of the vitronectin receptor was detected in both the control and transformed cells by immunoprecipitation and immunoblot methods. The spontaneously transformed cells differed from the control cells in that, whereas attachment to tissue culture plastic could occur by binding to adsorbed vitronectin, the transformed cells could also become attached, with time, by a vitronectin-independent mechanism. Attachment by this vitronectin-independent reaction was inhibited by the protein synthesis inhibitor cycloheximide and also by the microtubule-disrupting drugs demicolcemid and nocodazole. The morphologies of attached control and transformed cells cultured on tissue culture plastic were disrupted by treatment with cytochalasin B, demicolcemid or nocodazole, indicating that the shape of these cultured epithelial cells is dependent upon the microtubule system as well as the actin filaments. These results show one important difference between the control and transformed cells, in that the transformed cells can attach to tissue culture plastic by a vitronectin-independent mechanism that involves new protein synthesis by the cell. Another interesting difference is that this vitronectin-independent attachment of the transformed cells was sensitive to inhibition by microtubule-disrupting agents. On the other hand, the attachment of either transformed or control cells to fibronectin- or vitronectin-coated surfaces was not affected by microtubule-disrupting agents.

Cell Adhesion↗