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Results for “Integrin alpha2”

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PubMed1997

Molecular characterisation of integrin-procollagen C-propeptide interactions.

The carboxyl-terminal propeptide of type I procollagen (CPP-I) plays a key role in regulation of collagen fibrillogenesis, and may exert feedback control of collagen biosynthesis. We have previously shown that CPP-I is a ligand for the integrin alpha2beta1 [Weston, S. A., Hulmes, D. J. S., Mould, A. P., Watson, R. B. & Humphries, M. J. (1994) Identification of the integrin alpha2beta1 as a cell surface receptor for the C-propeptide of type I procollagen, J. Biol. Chem. 269, 20982-20986] suggesting that some of the phenotypic effects of C-propeptides may be mediated by adhesion receptors. Here we have extended this work to study the molecular basis of this interaction. We have broadened the ligand range by demonstrating that the C-terminal propeptide of type II procollagen supports alpha2beta1-mediated binding of NHS human fibroblasts in cell attachment assays. Also, we have used function-blocking antibodies in cell attachment and solid-phase binding assays with purified integrin to expand the CPP-I receptor family, showing that integrin alpha1beta1 is also a receptor for CPP-I. Integrin alpha-subunit A-domains are known to be major ligand-binding sites and recombinant alpha1 and alpha2 subunit A-domains were able to bind CPP-I. Finally we have shown that peptides corresponding to potential integrin-binding sequences in CPP-I do not mediate integrin-CPP-I adhesion. Taken together, these studies indicate that the interactions between C-propeptides and integrins are more numerous than previously reported, that C-propeptides are a new class of molecule which bind to A-domains, and that the integrin-C-propeptide interaction does not utilise established peptide motifs.

Amino Acid Sequence↗

PubMed1998

Laminin alpha2 muscular dystrophy: genotype/phenotype studies of 22 patients.

OBJECTIVE: To determine the number of primary laminin alpha2 gene mutations and to conduct genotype/phenotype correlation in a cohort of laminin alpha2-deficient congenital muscular dystrophy patients. BACKGROUND: Congenital muscular dystrophies (CMD) are a heterogeneous group of muscle disorders characterized by early onset muscular dystrophy and a variable involvement of the CNS. Laminin alpha2 deficiency has been reported in about 40 to 50% of cases of the occidental, classic type of CMD. Laminin alpha2 is a muscle specific isoform of laminin localized to the basal lamina of muscle fibers, where it is thought to interact with myofiber membrane receptor, such as integrins, and possibly dystrophin-associated glycoproteins. METHODS: Seventy-five CMD patients were tested for laminin alpha2 expression by immunofluorescence and immunoblot. The entire 10 kb laminin alpha2 coding sequence of 22 completely laminin alpha2-deficient patients was screened for causative mutations by reverse transcription (RT)-PCR/single strand conformational polymorphisms (SSCP) analysis and protein truncation test (PTT) analysis followed by automatic sequencing of patient cDNA. Clinical data from the laminin alpha2-deficient patients were collected. RESULTS: Thirty laminin alpha2-negative patients were identified (40% of CMD patients tested) and 22 of them were screened for laminin alpha2 mutations. Clinical features of laminin alpha2-deficient patients were similar, with severe floppiness at birth, delay in achievement of motor milestones, and MRI findings of white matter changes with normal intelligence. Loss-of-function mutations were identified in 95% (21/22) of the patients studied. SSCP analysis detected laminin alpha2 gene mutations in about 50% of the mutant chromosomes; PTT successfully identified 75% of the mutations. A two base pair deletion mutation at position 2,096-2,097 bp was present in 23% of the patients analyzed. CONCLUSIONS: Our data suggest that the large majority of laminin alpha2-deficient patients show laminin alpha2 gene mutations.

Base Sequence↗

PubMed2005

Detection of integrins in human cataract lens epithelial cells and two mammalian lens epithelial cell lines.

AIM: To compare the incidence of various integrin subunits in human cataract anterior lens epithelial cells (A-LEC) and in two mammalian LEC lines. METHODS: Circular sections of anterior capsules with attached LEC were obtained during cataract surgery. Integrin subunits were immunolocalised in these anterior LEC and in a human and rabbit LEC line, using four monoclonal antibodies specific for subunits alpha2, alpha3, and alpha5, and beta subunit 2. RESULTS: All of these subunits were found in at least a proportion A-LEC samples as follows: alpha2 71%, alpha3 92%, alpha5 62%, and beta2 24%. The human LEC line was immunoreactive for alpha2 and alpha3 only. The rabbit lens epithelial cell line was immunoreactive for alpha5 but there was no staining for alpha2, alpha3, or beta2. CONCLUSION: The A-LEC and mammalian LEC lines showed a similarity in their pattern of integrin expression. As these integrins are receptors for extracellular matrix (ECM) components, they are likely to be associated with the attachment and migration of LECs that precedes capsular opacification. Therefore these cell lines may be useful in the elucidation of mechanisms involved the pathogenesis of capsule opacification.

Animals↗

PubMed2005

Recombinant alpha2(IV)NC1 domain inhibits tumor cell-extracellular matrix interactions, induces cellular senescence, and inhibits tumor growth in vivo.

Cellular interaction with the extracellular matrix is thought to be a critical event in controlling angiogenesis and tumor growth. In our previous studies, genetically distinct noncollagenous (NC) domains of type-IV collagen were shown to interact with integrin receptors expressed on the surface of endothelial cells. Moreover, these NC1 domains were shown to inhibit angiogenesis in vivo. Here, we provide evidence that a recombinant form of the alpha2(IV)NC1 domain of type-IV collagen could bind integrins alpha1beta1 and alphavbeta3 expressed on melanoma cells and inhibit tumor cell adhesion in a ligand-specific manner. Systemic administration of recombinant alpha2(IV)NC1 domain potently inhibited M21 melanoma tumor growth within full thickness human skin and exhibited a dose-dependent inhibition of tumor growth in nude mice. Interestingly, alpha2(IV)NC1 domain enhanced cellular senescence in tumor cells in vitro and in vivo. Taken together, these results suggest that recombinant alpha2(IV)NC1 domain is not only a potent anti-angiogenic reagent, but it also directly impacts tumor cell behavior. Thus, alpha2(IV)NC1 domain represents a potent inhibitor of tumor growth by impacting both endothelial and tumor cell compartments.

Animals↗

PubMed2004

Cell growth inhibition and gene expression induced by the histone deacetylase inhibitor, trichostatin A, on human hepatoma cells.

OBJECTIVE: Histone deacetylase (HDAC) inhibitors have been reported to induce cell growth arrest, apoptosis and differentiation in tumor cells. The effect of the HDAC inhibitor, trichostatin A (TSA), on hepatoma cells, however, has not been well studied. In this study, we examined cell viability and gene expression profile in hepatoma cell lines treated with TSA. METHODS: To study cell growth inhibition and induction of apoptosis by TSA on human hepatoma cell lines including HuH7, Hep3B, HepG2, and PLC/PRF/5, cells were treated with TSA at various concentrations and analyzed by the 3-(4, 5-dimethyl-2-thiazolyl)-2H-tetrazolium bromide (MTT) and TUNEL assays, respectively. Changes in gene expression profile after exposure to TSA were assessed using a cDNA microarray consisting of 557 distinct cDNA of cancer-related genes. The levels of acetylated histones were examined by the chromatin immunoprecipitation (ChIP) assay using anti-acetylated histone H3 or H4 antibody. RESULTS: The MTT assay demonstrated that TSA showed cell growth inhibition not only in a concentration-dependent but also a time-dependent manner on all cell lines studied. The TUNEL assay also revealed the potential of TSA to induce apoptosis. The microarray analysis revealed that 8 genes including collagen type 1, alpha2 (COL1A2), insulin-like growth factor binding protein 2 (IGFBP2), integrin, alpha7 (ITGA7), basigin (BSG), quiescin Q6 (QSCN6), superoxide dismutase 3, extracellular (SOD3), nerve growth factor receptor (NGFR), and p53-induced protein (PIG11) exhibited substantial induction (ratio >2.0) after TSA treatment in multiple cell lines. ChIP assay, in general, showed a good correlation between the expression level of mRNA and levels of acetylated histones in these upregulated genes. CONCLUSIONS: This study showed cell growth inhibition and the gene expression profile in hepatoma cell lines exposed to TSA. The alteration in levels of acetylated histones was closely associated with expression of specific cancer-related genes in hepatoma cells.

Antineoplastic Agents↗

PubMed1996

Widespread expression of beta1 integrins in the developing chick retina: evidence for a role in migration of retinal ganglion cells.

During extension of axons, critical neuronal interactions with extracellular matrix (ECM) and other cells are thought to be mediated in part by heterodimeric beta1 integrin receptors. In this report, we examine the expression and function of beta1 integrins in the developing chick retina. Expression of the beta1 subunit, assayed by in situ hybridization and antibody staining of dissociated cells, was widespread in undifferentiated neuroepithelial cells, before the initiation of axons. Expression persisted in most retinal cell layers throughout embryonic development, during and after axon extension. The repertoire of beta1-associated alpha subunits was examined using reverse transcription-polymerase chain reaction. In addition to the alpha6 and alpha8 subunits previously reported, chick homologues of the alpha2 and alpha4 subunits were detected. Developmental Northern blots revealed varying patterns of integrin subunit expression and showed that expression of beta1 and the mRNAs of its associated alpha subunits are not always coregulated during retinal development. The timing and distribution of expression suggested that beta1 integrins may be involved in other developmental events in addition to axon extension. To address functions carried out by beta1 integrins in the early retina, explanted eye cups were incubated in the presence of function blocking anti-beta1 antibody and migration of newly born retinal ganglion cells (RGCs) was assessed. RGC migration from the ventricular zone to the vitreal border was significantly inhibited, suggesting that beta1 integrins play a role in neuroblast migration in the retina.

Amino Acid Sequence↗

PubMed1999

Expression of laminin alpha1, alpha2, alpha4, and alpha5 chains, fibronectin, and tenascin-C in skeletal muscle of dystrophic 129ReJ dy/dy mice.

The dy/dy mouse is an animal model for human merosin-negative congenital muscular dystrophy (CMD), which has been reported to have reduced or no expression of the basement membrane protein laminin alpha2. We here investigate various myogenic and nonmyogenic tissues of mature dy/dy and control 129ReJ mice histologically and for laminin alpha2 expression. In addition, expression patterns of laminin alpha1, alpha2, alpha4, and alpha5 chains, the interstitial proteins fibronectin and tenascin-C, and the adhesion molecules VCAM-1, ICAM-1, and alpha4 integrin were characterized in skeletal muscle of 1- and 7-day and mature (>6 weeks old) dy/dy and control 129ReJ mice. The laminin alpha2 chain remained detectable in myogenic tissues of dy/dy mice by immunofluorescence using two different monoclonal antibodies and by Northern blot analysis. However, laminin alpha2 expression was significantly reduced or not detectable in nonmyogenic tissues of dy/dy mice, including skin, lung, kidney, brain, thymus, and eye. Focal lesions were observed in mature skeletal muscle only, characterized by necrotic tissue, isolated VCAM-1- and ICAM-1-positive cells indicative of inflammatory processes, and regenerating muscle fibers surrounded by intense tenascin-C and fibronectin expression. In contrast to studies on human CMD muscle, laminin alpha1 was not detectable in either dy/dy or control skeletal muscle using immunofluorescence or Northern blot analysis. Immunofluorescence localized laminin alpha4 to basement membranes of blood vessels, the endoneurium of the intramuscular nerves, and the neuromuscular junction in skeletal muscle of 1- and 7-day-old dy/dy and control mice. In mature muscle, laminin alpha4 expression shifted to the perineurium of intramuscular nerves in both dy/dy and control mice. Furthermore, strong upregulation of laminin alpha4 in the basement membranes of blood vessels, the perineurium of intramuscular nerves, and of isolated regenerating muscle fibers in the dy/dy mice was apparent. Investigation of 1-day-old animals revealed expression of laminin alpha5 in skeletal muscle fiber basement membranes of dy/dy but not control animals. This difference between dy/dy and control animals was no longer apparent at 7 days after birth, indicating a temporary shift in expression pattern of laminin alpha5 in dy/dy animals. Analysis of the extracellular matrix components of 1- and 7-day-old dy/dy and control skeletal muscle revealed an early onset of the dystrophy, even before histopathological features of the disease were evident. Our data confirm the absence of laminin alpha1 chain in myogenic tissues of both dy/dy and control mice and suggest compensation for reduced laminin alpha2 in dy/dy skeletal muscle by laminin alpha4 and, in early development, also laminin alpha5. These results have significant ramifications in the diagnosis of human merosin-negative CMD.

Age of Onset↗

PubMed2000

New functions for non-collagenous domains of human collagen type IV. Novel integrin ligands inhibiting angiogenesis and tumor growth in vivo.

Collagen type IV is a major component of the basal lamina of blood vessels. Six genetically distinct collagen type IV chains have been identified and are distributed in a tissue-specific manner. Here we define a novel function for soluble non-collagenous (NC1) domains of the alpha2(IV), alpha3(IV), and alpha6(IV) chains of human collagen type IV in the regulation of angiogenesis and tumor growth. These NC1 domains were shown to regulate endothelial cell adhesion and migration by distinct alpha(v) and beta(1) integrin-dependent mechanisms. Systemic administration of recombinant alpha2(IV), alpha3(IV), and alpha6(IV) NC1 domains potently inhibit angiogenesis and tumor growth, whereas alpha1(IV), alpha4(IV), and alpha5(IV) showed little if any effect. These findings suggest that specific NC1 domains of collagen type IV may represent an important new class of angiogenesis inhibitors.

Amino Acid Sequence↗

PubMed1999

Integrin subunits responsible for adhesion of human osteoblast-like cells to biomimetic peptide surfaces.

We have identified the integrin subunits responsible for the initial adhesion of human osteoblast-like cells to peptide-modified surfaces. Biomimetic peptide surfaces containing homogenous RGD (Arg-Gly-Asp), homogenous FHRRIKA (Phe-His-Arg-Arg-Ile-Lys-Ala), and a mixed ratio of FHRRIKA:RGD (25:75) were used to assess integrin-mediated adhesion. The RGD and FHRRIKA peptides were selected from the cell-binding and putative heparin-binding domains of bone sialoprotein. A panel of monoclonal antibodies against human alpha1, alpha2, alpha3, alpha4, alpha5, beta1, alpha(v), and alpha(v)beta3 was used to identify the subunits most dominant in mediating short-term (10 or 30 minutes) and long-term (4 hours) cell adhesion to the peptide surfaces. Anti-alpha2, anti-beta1, and anti-alpha(v) significantly (p < 0.05) diminished cell attachment to homogenous RGD surfaces following 30 minutes of incubation. After 4 hours of incubation on RGD-grafted surfaces, immunostaining of these integrin subunits revealed discrete localization of the alpha(v) subunit at the periphery of the cell (similar to focal contact points), whereas the alpha2 and beta1 subunits stained very diffusely throughout the cell. A radial-flow apparatus was used to determine the effect of anti-integrin antibodies on strength of cell detachment following 10 minutes of incubation on peptide-grafted surfaces. The strength of detachment from surfaces containing RGD was significantly reduced (p < 0.05) in the presence of anti-alpha2, anti-alpha(v), or anti-beta1 compared with controls (presence of preimmune mouse IgG). None of the antibodies significantly influenced cell attachment to homogenous FHRRIKA-grafted surfaces. These results demonstrate that initial (30 minutes) attachment of human osteoblast-like cells to homogenous RGD surfaces was mediated by the collagen receptor alpha2beta1 and the vitronectin receptor alpha(v)beta3, whereas only the vitronectin receptor governed longer term (longer than 30 minutes) adhesion (localization to focal contacts). The importance of distinct integrins in mediating the attachment of bone cells to RGD-immobilized surfaces indicates a strategy for engineering orthopaedic implants with a built-in surface specificity for cell adhesion.

Amino Acid Sequence↗

PubMed2000

Beta1 integrins play an essential role in adhesion and invasion of pancreatic carcinoma cells.

To investigate the role of beta1 integrins in pancreatic carcinoma invasion, we analyzed the relationship between the activity of beta1 integrins and the invasive ability of human pancreatic carcinoma cell lines. AsPC1, BxPC3, PANC1, SU8686, KP1NL, KP2, and H48N cells had high expression of beta1 and alpha6 subunits, and various levels of alpha2, alpha3, and alpha5 expression as determined by flow cytometry. Cell adhesion assay revealed that alpha2beta1, alpha5beta1, and alpha6beta1 integrins were the predominant adhesion receptors for collagen, fibronectin, and laminin, respectively. Beta1 integrins on different cell types showed a wide range of constitutive activity. Anti-beta1 monoclonal antibody (MAB) TS2/16 rapidly activated beta1 integrins, and thus TS2/16 requirement in cell adhesion represented the levels of constitutive activity of beta1 integrins. Notably, as the result of in vitro chemoinvasion assay, the levels of constitutive activity of beta1 integrins correlated with the invasive ability of pancreatic carcinoma cells. The inhibitory anti-beta1 MAB 13 completely blocked the invasion of these cell lines. Alternatively, the stimulatory anti-beta1 MAB TS2/16 strongly inhibited the invasion. These results show an essential role of beta1 integrins in invasion of pancreatic carcinoma cells and also suggest subtle regulatory mechanisms of cell invasion.

Antibodies, Monoclonal↗

PubMed1999

Expression of integrins of the beta1 family in thyroid cells from patients with Graves' disease in vivo and in vitro.

The expression of the beta1 family of integrins was determined in thyroid follicular cells from patients with Graves' disease (GD). Integrin expression was quantitated by flow fluorocytometry of single cell suspensions with antibodies against the common beta1 chain and the alpha1-alpha6 subunits. Results indicated that also in thyroid glands of GD, as previously observed in nodular goiters, two follicular cell populations with different patterns of beta1 integrin expression coexist (VLAalpha3beta1 and VLAalpha1,3,5,6beta1). The VLAalpha1,3,5,6beta1 thyrocyte population in GD was more abundant than in nodular goiters, ranging from 40 to 70% of the total follicular cells and the overall expression of the beta1 integrins was a two-fold higher. In thyrocytes from patients with GD cultured in vitro, alpha3 and alpha2 expression was regulated by cell-to-cell contact as previously described in normal thyroid cells, while the expression of alpha1, alpha5 and alpha6 was quickly lost during the culture. Our data suggest that the integrin profile of the VLAalpha1,3,5,6beta1 thyrocyte population in GD is induced by micro-environmental conditions rather than being the expression of a constitutive phenotype.

Cells, Cultured↗

PubMed1999

Mutation of a basic sequence in the laminin alpha2LG3 module leads to a lack of proteolytic processing and has different effects on beta1 integrin-mediated cell adhesion and alpha-dystroglycan binding.

A RRKRRQ sequence unique to the LG3 module of the laminin alpha2 chain was previously shown to be sensitive to endogenous proteolysis during the recombinant production of the tandem array alpha2LG1-3. Mutation of RQ surrounding the cleaved peptide bond did not prevent this processing and intracellular degradation. Alanine mutagenesis of three alternate basic residues, however, was shown to prevent the cleavage in alpha2LG1-3, allowing for the alpha2LG3 module to be obtained as a folded, globular fragment. The mutation did not change heparin and sulfatide binding or cell adhesion of alpha2LG1-3 which can be mediated by alpha3beta1 and alpha6beta1 integrins. It did, however, cause a 10-fold reduction in alpha-dystroglycan binding. The data favor the interpretation that binding epitopes for heparin/sulfatides, beta1 integrins and alpha-dystroglycan occupy different parts of the alpha2LG1-3 structure.

Animals↗

PubMed2002

Initial interaction of U2OS cells with noncoated and calcium phosphate coated titanium substrates.

From previous studies, we know that calcium phosphate (CaP) coated implants stimulate bone formation compared to uncoated implants. Nevertheless, the mechanism by which substrate surface characteristics affect cell function is unclear. In this study, we examined the initial interaction (30 min to 24 h) of U2OS cells with titanium substrates with or without a CaP coating. The effect of substrate roughness was also studied. When cell attachment was studied, we found that cells attached more readily to rough than to smooth surfaces. Also, more cells attached to the uncoated than to the CaP coated surface. After 24 h, cell numbers were similar for all substrate surfaces. Further, cells spread to a larger area on noncoated titanium than on the CaP coated substrates. At 24 h, the sequence of cell size was smooth titanium > rough titanium > CaP coated titanium. Shape measurements showed differences in cell shape between the cells on the different materials only at 7 h, not at different culture times. Cells expressed alpha2, alpha3, alpha5, alpha6, alphav, and beta1 subunits. Expression of alpha1, alpha4, alphavbeta3, beta3, beta4, and beta7 was extremely low or was not found. The beta1 integrin expression was higher on the coated than on the noncoated titanium at 3 h, but not on the other studied times. Expression of alpha2, alpha5, alpha6, and alphav expression was found to be upregulated at 24 h compared to earlier culture times on coated titanium, but not on uncoated titanium substrates. From this we conclude that the surface characteristics of a material (roughness and composition) can affect the initial interaction of cells with the material.

Calcium Phosphates↗

PubMed1996

Active peptides from the carboxyl-terminal globular domain of laminin alpha2 and Drosophila alpha chains.

The laminin alpha1 chain carboxyl-terminal globular domain (G domain) contains multiple biological activities. Recently, we identified five cell binding sequences from the G domain by screening with overlapping 12-mer peptides encompassing the entire domain. The structures of these five sequences in the alpha1 chain are conserved in the corresponding regions of the different laminin alpha chains. Here we characterize the adhesion activities of the corresponding peptide segments from both the mouse laminin alpha2 chain and Drosophila laminin alpha chain using peptide-coated plastic plates and peptide-conjugated Sepharose beads. Using several cell lines, the laminin alpha2 chain peptides showed cell attachment and/or spreading activities with cell type specificities. Cell spreading on MG-10 was inhibited by integrin antibodies. Four of the Drosophila laminin peptides showed cell attachment activities. These results suggest that biologically active regions in the G domain are conserved in the laminin alpha1 and alpha2 chains, and that these regions in laminin play an important role in cell surface receptor interactions.

Amino Acid Sequence↗

PubMed2004

Anti-glycoprotein VI treatment severely compromises hemostasis in mice with reduced alpha2beta1 levels or concomitant aspirin therapy.

BACKGROUND: Platelet inhibition is a major strategy to prevent arterial thrombosis, but it is frequently associated with increased bleeding because of impaired primary hemostasis. The activating platelet collagen receptor, glycoprotein VI (GP VI), may serve as a powerful antithrombotic target because its inhibition or absence results in profound protection against arterial thrombosis but no major bleeding in mice. METHODS AND RESULTS: Mice lacking (-/-) or expressing half-levels (+/-) of the other major platelet collagen receptor, integrin alpha2beta1, were injected with the anti-GP VI antibody JAQ1 and analyzed on day 5. Anti-GP VI treatment resulted in a marked hemostatic defect in alpha2-/- or alpha2+/- mice, as shown by dramatically prolonged tail bleeding times. Platelet adhesion to collagen was studied in an ex vivo whole-blood perfusion system under high shear conditions. Weak integrin activation by thromboxane A2 (TxA2) receptor stimulation restored defective adhesion of anti-GP VI-treated wild-type but not alpha2-/- or alpha2+/- platelets to collagen. This process required the simultaneous activation of the G(q) and G13 signaling pathways, as demonstrated by use of the respective knockout strains. Conversely, inhibition of TxA2 production by aspirin severely compromised hemostasis in anti-GP VI-treated or GP VI/Fc receptor gamma-chain-deficient but not control mice. CONCLUSIONS: Anti-GP VI therapy may result in defective hemostasis in patients with reduced alpha2beta1 levels or concomitant aspirin therapy. These observations may have important implications for a potential use of anti-GP VI-based therapeutics in the prevention of cardiovascular disease.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2003

Regulation of the intestinal epithelial response to cyclic strain by extracellular matrix proteins.

Repetitive mechanical deformation may stimulate intestinal epithelial proliferation. Because the extracellular matrix modulates static intestinal epithelial biology, we examined whether matrix proteins influence intestinal epithelial responses to deformation. Human Caco-2BBE cells and nontransformed human enterocytes (HIPEC) were subjected to 10% average cyclic strain at 10 cycles/min on flexible membranes precoated with matrix proteins without or with plasma fibronectin or functional anti-integrin antibodies in the medium. Strain stimulated proliferation, focal adhesion kinase, extracellular signal-regulated protein kinase (ERK), p38, and Jun N-terminal kinase similarly on collagen I or IV, and more weakly on laminin, but had no effect on fibronectin. MEK blockade (PD98059) prevented strain-stimulated proliferation on collagen but did not affect proliferation on fibronectin. Adding tissue fibronectin to a collagen substrate or plasma fibronectin to the media suppressed strain s mitogenic and signal effects, but not those of epidermal growth factor. Functional antibodies to the alpha5 or alpha(v) integrin subunit blocked strain's effects on Caco-2 proliferation and ERK activation, although ligation of the alpha2 or alpha6 subunit did not. Repetitive strain also stimulated, and fibronectin inhibited, human intestinal primary epithelial cell proliferation. Repetitive deformation stimulates transformed and nontransformed human intestinal epithelial proliferation in a matrix-dependent manner. Tissue or plasma fibronectin may regulate the intestinal epithelial response to strain via integrins containing alpha5 or alpha(v).

Caco-2 Cells↗

PubMed2006

Altered expression of beta1 integrins in renal carcinoma cell lines exposed to the differentiation inducer valproic acid.

Renal cell carcinoma (RCC) is the most common malignant tumor of the kidney. Adhesion receptors of the beta1 integrin family are assumed to be involved in carcinogenesis, but it is not clear how they contribute to RCC progression. In an in vitro model, we evaluated growth and adhesion capacity of Caki-I and KTC-26 kidney carcinoma cell lines compared to normal renal proximal tubular epithelial cells (PTC). alpha1-alpha6beta1 integrin subunits in malignant and non-malignant cells were evaluated by Western blotting and RT-PCR, integrin surface expression was measured by flow cytometry and confocal microscopy. Additionally, tumor cells were allowed to re-differentiate in the presence of valproic acid (VPA) and dynamic alterations of the integrin profile were analyzed. Caki-I and KTC-26 were characterized by accelerated proliferation and adhesion to an endothelial cell monolayer, compared to PTC cells. The integrin beta1 repertoire in RCC cell lines was significantly different from that detected in PTC, and included down-regulated alpha2 and alpha6, but up-regulated alpha1, alpha3 and alpha5 proteins. VPA application reduced tumor malignancy which was evidenced by reduced cell growth and adhesion capacity. The reduction in tumor malignancy was paralleled by the integrin expression profile of renal tumor cells 'matching' the pattern seen in PTC. We assume that a sensitive integrin balance exists in normal renal epithelial cells, and that dysregulation of the 'physiological' receptor equipment drives these cells towards malignancy. VPA acted on all investigated integrin subtypes and restored the receptor pattern typical for non-malignant cells. Therefore, VPA may represent a novel therapeutic option in RCC treatment.

Carcinoma, Renal Cell↗

PubMed1998

Integrins of the beta1 family influence keratinocyte-lymphocyte interaction.

Data from the literature indicate that ICAM-1 molecules play an important role in keratinocyte interactions with lymphocytes via the lymphocyte function-associated-1 lymphocyte-adhesion molecule. We examined the role of beta1 integrins in keratinocyte-lymphocyte adhesion under different activation conditions. Among the beta1 integrins expressed on keratinocytes and lymphocytes detected by indirect immunofluorescence microscopy and flow cytofluorometry, primarily the alpha2 and the alpha3 subunits on both cell types were involved in keratinocyte-lymphocyte adhesion. Moreover, the highest adhesion level was observed when both cell types were activated by IFN-gamma for keratinocytes and phorbol 12-myristate 13-acetate for lymphocytes, suggesting that the former involved the protein kinase C pathway. Keratinocyte activation, characterized by the expression of ICAM-1, a decrease of beta1 integrins, and the absence of alpha5beta1 integrin, was required for optimal lymphocyte adhesion. Thus, beta1 integrins remaining at the surface of IFN-gamma-treated keratinocytes could be activated by this cytokine, and could synergize with ICAM-1 and lymphocyte function-associated-1 molecules to consolidate keratinocyte-lymphocyte adhesion.

Cell Adhesion↗