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Results for “Integrin alpha2”

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PubMed1998

Metastatic dissemination of human ovarian epithelial carcinoma is promoted by alpha2beta1-integrin-mediated interaction with type I collagen.

Metastatic dissemination of epithelial ovarian carcinoma is thought to be mediated via tumor cell exfoliation into the peritoneal cavity, followed by adhesion to and invasion through the mesothelium which overlies the contents of the peritoneal cavity. In this study, we have utilized short-term primary cultures to analyze the effect of specific extracellular matrix proteins on properties of human ovarian epithelial carcinoma cells which contribute to the invasive phenotype. Analysis of cell:matrix adhesive profiles indicated that ovarian carcinoma cells adhere preferentially to type I collagen. Immunoprecipitation analyses demonstrated the presence of the collagen-binding alpha2beta1 integrin in biotin-labeled ovarian carcinoma cell membranes, and cellular adhesion was inhibited by blocking antibodies directed against the alpha2 and beta1 integrin subunits. The alpha2beta1-binding peptide Asp-Gly-Glu-Ala (DGEA) was also moderately effective at blocking adhesion to collagen relative to the control peptide Ala-Gly-Glu-Ala (AGEA). Analysis of cell motility on protein-coated colloidal gold coverslips demonstrated that ovarian carcinoma cells migrate preferentially on type I collagen coated surfaces. Type I collagen promoted migration in a concentration-dependent, saturable manner, with maximal migration observed at a collagen-coating concentration of 50 microg/ml. Migration on collagen was inhibited by antibodies directed against the alpha2 and beta1 integrin subunits and by DGEA peptide, providing evidence for the role of the alpha2beta1 integrin in ovarian carcinoma cell motility. Culturing ovarian carcinoma cells on type I collagen gels led to a significant increase in conversion of the matrix metalloproteinase 2 zymogen to the 66-kD form, suggesting that adhesion to collagen also influences matrix-degrading proteinases. These data suggest that alpha2beta1-integrin-mediated interaction of ovarian carcinoma cells with type I collagen, a protein prevalent both in the mesothelial extracellular matrix and in the peritoneal cavity of ovarian carcinoma patients, may function on multiple levels to promote metastatic dissemination of ovarian carcinoma cells.

Cell Adhesion↗

PubMed1997

Division of labor of Schwann cell integrins during migration on peripheral nerve extracellular matrix ligands.

Myelination of the peripheral nervous system (PNS) requires the migration of Schwann cells during both development and regeneration. We have characterized the expression pattern of Schwann cell integrins and analyzed their role in migration on different ECM substrates known to be present within the PNS. We found that Schwann cells in cell culture express four beta1 integrins, alpha1 beta1, alpha2 beta1, alpha6 beta1, and another unidentified beta1 integrin, as well as two alpha v integrins, alpha v beta3 and alpha v beta8. Using the Varani migration assay, we found that laminin-1, laminin-2 (merosin), and fibronectin increased Schwann cell migration, while vitronectin and collagen did not increase migration compared to an uncoated plastic substrate. Schwann cell migration on laminin-1 and laminin-2 (merosin) was blocked by antibodies against beta1 integrins, but not affected by RGD peptides or antibodies against beta3 integrins. In contrast, migration on fibronectin was unaffected by antibodies against beta1 and beta3 integrins but was blocked by RGD peptides. This in vitro study shows that there is a division of labor of Schwann cell integrins in the regulation of migration on peripheral nerve ECM components; beta1 integrins mediate migration on laminin-1 and laminin-2 (merosin), while alpha v integrins mediate migration on fibronectin. Taken together, these results suggest that multiple interactions between Schwann cell integrins and ECM within the PNS will contribute to Schwann cell migration during myelination of the PNS.

Animals↗

PubMed2005

The polymorphism of platelet membrane integrin alpha2beta1 (alpha2807TT) is associated with premature onset of fetal loss.

Inherited thrombophilia could increase susceptibility to adverse pregnancy outcomes such as fetal loss. We determined the G1691A mutation of the factorV gene (FVL), the G20210A mutation of the prothrombin gene, the C677T polymorphism of the methylenetetrahydrofolate-reductase (MTHFR) gene, the HPA-1 polymorphism of the beta3 subunit of the platelet integrin alphaIIbbeta3 and the C807T polymorphism of the alpha2 subunit of integrin alpha2beta1 in 104 women with fetal loss and 277 normal women. In a subgroup analysis of women with recurrent early fetal loss (n=34), the prevalence of the genetic markers did not differ significantly between the women with early fetal loss and the normal women. However, in this subgroup of patients the onset of fetal loss was significantly earlier in women with the alpha2807TT genotype (7.1 +/- 1.9 vs. 8.8 +/- 1.5 weeks, p=0.001). No such significant difference was observed in carriers of the other genetic markers. In the subgroup analysis of women with late fetal loss (n=70), only the prevalence of heterozygous FVL was significantly associated with late fetal loss (odds ratio 3.2, p=0.002). There was no significant association of any genetic risk factor with premature fetal loss in the subgroup analysis of women with at least one late miscarriage. This study demonstrates a significant association of the alpha2807TT genotype of the platelet membrane integrin alpha2beta1 with premature onset of early fetal loss. It appears that this risk factor does not induce the pathomechanism, but modulates the course of fetal loss. Furthermore, our study confirms the association of FVL with late fetal loss.

Abortion, Spontaneous↗

PubMed2003

Alpha2beta1 integrin and development of atherosclerosis in a mouse model: assessment of risk.

OBJECTIVE: The alpha2beta1 integrin serves as a collagen or collagen/laminin receptor on many cell types, including endothelial cells and platelets. Many studies indicate that the alpha2beta1 integrin is a critical mediator of platelet adhesion to collagen. Epidemiologic studies suggest a direct correlation between the genetically determined platelet surface density of the alpha2beta1 integrin and the risk of thrombotic diseases, such as myocardial infarction and stroke, in the young, which are well-established complications of atherosclerosis. We have now used the alpha2beta1 integrin-deficient mouse to evaluate the contributions of the alpha2beta1 integrin to the development of atherosclerosis. METHODS AND RESULTS: We generated wild-type (alpha2+/+) or alpha2beta1 integrin-deficient (alpha2-/-) mice that were also deficient in the apolipoprotein E (ApoE) gene (ApoE-/-) and compared atherosclerotic lesion development in alpha2+/+ ApoE-/- and alpha2-/- ApoE-/- mice that were fed a high-fat, cholesterol-containing diet for 6 or 15 weeks. Total lesional area did not differ significantly between the alpha2-null animals and the wild-type animals at either 6 or 15 weeks. CONCLUSIONS: Our results suggest that risk for arterial thrombotic disease associated with high-level alpha2beta1 integrin expression is not attributable to enhanced development of atherosclerosis per se but may rather be a consequence of thrombotic complications at the plaques.

Animals↗

PubMed1997

Concomitant down-regulation of expression of integrin subunits by N-myc in human neuroblastoma cells: differential regulation of alpha2, alpha3 and beta1.

Amplification and over-expression of the N-myc oncogene is associated with the progression of neuroblastoma in children and in a nude mouse model system. Neuroblastoma cell lines with widely different levels of N-myc illustrate an inverse relationship between N-myc over-expression and reduced expression of several integrin extracellular matrix receptors. Transfection and over-expression of N-myc in a neuroblastoma cell line not normally expressing the protein resulted in cells that grew loosely associated with tissue culture plates; this correlated with reduced levels of beta1 integrin subunit. Evidence is now presented that alpha2 and alpha3 integrin subunit levels are also reduced in cells that over-express N-myc, with virtually no association of alpha2 or alpha3 subunits with beta1. Consequently, maturation of the beta1 subunit and cell surface expression of the integrins are greatly reduced in N-myc-transfected cells. A small amount of beta1 protein does get to the cell surface, however, suggesting that an as yet unidentified alpha subunit is produced by the N-myc-expressing cells. Finally, the observed reductions in integrin protein levels are reflections of greatly reduced levels of integrin alpha2 and alpha3 mRNAs, as well as a smaller reduction in beta1 mRNA (80%, 94% and 52%, respectively). Post-transcriptional mechanisms modulating beta1 integrin levels are also operative. These results indicate that over-expression of N-myc from a transfected gene in a neuroblastoma cell line that does not normally produce the protein generates cell lines with many of the characteristics of naturally metastatic cells with amplified N-myc genes. Modulation of N-myc and integrin expressions may play a significant role in progression of human neuroblastoma.

Antigens, CD↗

PubMed1997

Ascorbic acid alters collagen integrins in bone culture.

The effects of ascorbic acid on collagen synthesis, mineralization, and integrins were investigated in a mineralizing organ culture system derived from 20-day fetal rat parietal bones. A significant dose-dependent decrease in calcification at 96 h was demonstrated with decreasing concentrations of ascorbic acid (100-0 microg/ml). No effect on DNA content, [3H]thymidine incorporation, or dry weight was found in control (100 microg/ml ascorbic acid) bones compared with bones treated with decreased ascorbic acid concentrations (10, 1, and 0 microg/ml). Collagen synthesis, measured by [3H]proline incorporation, and alpha1(I) procollagen messenger RNA levels were also unaffected. However, ascorbic acid produced a dose-dependent decrease in the hydroxyproline content, with a maximal 76.8% decrease in bones without ascorbic acid compared with the control bones with 100 microg/ml ascorbic acid. Light microscopy of the ascorbic acid-deficient bones revealed a disruption of the osteoblast layer with misshapen osteoblasts and a decrease in the osteoid seam. The loss of osteoblast organization was also confirmed by analyzing the integrins for collagen by Northern and Western blot and immunofluorescence microscopy. A dose-dependent decrease in alpha2 and beta1 integrin messenger RNA levels and in alpha1, alpha2, and beta1 protein were found in 96-h bone cultures deficient in ascorbic acid. These integrin subunits mediate the binding of osteoblasts to collagen. Immunofluorescence microscopy also demonstrated a dose-dependent decrease in alpha2 and beta1 staining of the osteoblast layer. However, the protein levels of alpha3 and alpha5 subunits were not affected. No beta5 was detected, whereas only bones cultured without ascorbic acid demonstrated a small decrease in alpha(v) and beta3 protein levels. The alpha3, alpha5, alpha(v), and beta3 subunits are involved in cell binding to extracellular matrix proteins other than collagen. Thus, the integrins for collagen are down-regulated, probably in response to the underhydroxylated collagen fibrils, which causes a disruption of osteoblast organization leading to a decrease in mineralization of bone. Integrin assays for specific extracellular proteins may be useful tools in detecting matrix defects in various metabolic bone diseases.

Animals↗

PubMed2002

VLA-2 (alpha2beta1) integrin promotes rotavirus entry into cells but is not necessary for rotavirus attachment.

In an attempt to identify the rotavirus receptor, we tested 46 cell lines of different species and tissue origins for susceptibility to infection by three N-acetyl-neuraminic (sialic) acid (SA)-dependent and five SA-independent rotavirus strains. Susceptibility to SA-dependent or SA-independent rotavirus infection varied depending on the cell line tested and the multiplicity of infection (MOI) used. Cells of renal or intestinal origin and transformed cell lines derived from breast, stomach, bone, or lung were all susceptible to rotavirus infection, indicating a wider host tissue range than previously appreciated. Chinese hamster ovary (CHO), baby hamster kidney (BHK-21), guinea pig colon (GPC-16), rat small intestine (Rie1), and mouse duodenum (MODE-K) cells were found to support only limited rotavirus replication even at MOIs of 100 or 500, but delivery of rotavirus particles into the cytoplasm by lipofection resulted in efficient rotavirus replication. The rotavirus cell attachment protein, the outer capsid spike protein VP4, contains the sequence GDE(A) recognized by the VLA-2 (alpha2beta1) integrin, and to test if VLA-2 is involved in rotavirus attachment and entry, we measured infection in CHO cells that lack VLA-2 and CHO cells transfected with the human alpha2 subunit (CHOalpha2) or with both the human alpha2 and beta1 subunits (CHOalpha2beta1) of VLA-2. Infection by SA-dependent or SA-independent rotavirus strains was 2- to 10-fold more productive in VLA-2-expressing CHO cells than in parental CHO cells, and the increased susceptibility to infection was blocked with anti-VLA-2 antibody. However, the levels of binding of rotavirus to CHO, CHOalpha2, and CHOalpha2beta1 cells were equivalent and were not increased over binding to susceptible monkey kidney (MA104) cells or human colonic adenocarcinoma (Caco-2, HT-29, and T-84) cells, and binding was not blocked by antibody to the human alpha2 subunit. Although the VLA-2 integrin promotes rotavirus infection in CHO cells, it is clear that the VLA-2 integrin alone is not responsible for rotavirus cell attachment and entry. Therefore, VLA-2 is not involved in the initial attachment of rotavirus to cells but may play a role at a postattachment level.

Animals↗

PubMed1999

The compliance of collagen gels regulates transforming growth factor-beta induction of alpha-smooth muscle actin in fibroblasts.

Wound contraction is mediated by myofibroblasts, specialized fibroblasts that appear in large numbers as the wound matures and when resistance to contractile forces increases. We considered that the regulation of myofibroblast differentiation by wound-healing cytokines may be dependent on the resistance of the connective tissue matrix to deformation. We examined transforming growth factor-beta1 (TGF-beta1) induction of the putative fibroblast contractile marker, alpha-smooth muscle actin (alpha-SMA), and the regulation of this process by the compliance of collagen substrates. Cells were cultured in three different types of collagen gels with wide variations of mechanical compliance as assessed by deformation testing. The resistance to collagen gel deformation determined the levels of intracellular tension as shown by staining for actin stress fibers. For cells plated on thin films of collagen-coated plastic (ie, minimal compliance and maximal intracellular tension), TGF-beta1 (10 ng/ml; 6 days) increased alpha-SMA protein content by ninefold as detected by Western blots but did not affect beta-actin content. Western blots of cells in anchored collagen gels (moderate compliance and tension) also showed a TGF-beta1-induced increase of alpha-SMA content, but the effect was greatly reduced compared with collagen-coated plastic (<3-fold increase). In floating collagen gels (high compliance and low tension), there were only minimal differences of alpha-SMA protein. Northern analyses for alpha-SMA and beta-actin indicated that TGF-beta1 selectively increased mRNA for alpha-SMA similar to the reported protein levels. In pulse-chase experiments, [35S]methionine-labeled intracellular alpha-SMA decayed most rapidly in floating gels, less rapidly in anchored gels, and not at all in collagen plates after TGF-beta1 treatment. TGF-beta1 increased alpha2 and beta1 integrin content by 50% in cells on collagen plates, but the increase was less marked on anchored gels and was undetectable in floating gels. When intracellular tension on collagen substrates was reduced by preincubating cells with blocking antibodies to the alpha2 and beta1 integrin subunits, TGF-beta1 failed to increase alpha-SMA protein content in all three types of collagen matrices. These data indicate that TGF-beta1-induced increases of alpha-SMA content are dependent on the resistance of the substrate to deformation and that the generation of intracellular tension is a central determinant of contractile cytoskeletal gene expression.

Actins↗

PubMedDate not supplied

Expression of cell surface glycoprotein CD44 and integrins in breast cancers among Indian women.

Parsis, the sole surviving group of followers of Zoroaster who are settled in Bombay, have a fourfold higher incidence of breast cancer than the general population of Greater Bombay. CD44 expression was studied by immunohistochemistry in breast cancers of 50 non-Parsi and 35 Parsi women, 10 normal breast tissues, 10 proliferative lesions and 49 tissues adjoining a tumor mass. Alpha2 and beta1 integrins could be studied in only 42 malignant cases and five normal tissues. The immunohistochemistry results were correlated with other parameters including tumor grade and size, estrogen and progesterone receptor status, lymph node involvement and mitotic index. CD44 was not expressed in normal areas. Benign areas and tissues adjacent to tumor masses showed increased staining. Both Parsi and non-Parsi women showed significantly high CD44 expression. All Parsi ILCs were strongly positive for CD44. In both groups ER negativity was associated with strong CD44 positivity, while mitotic counts correlated with decreased CD44 expression in Parsis but not in non-Parsis. Alpha2 and beta1 integrins were strongly expressed on the basolateral surface of normal epithelium. However, they were downregulated in tumors. In general breast tumor tissues from Parsi and non-Parsi patients did not differ significantly with respect to most parameters. However, among Parsis lymph node involvement and CD44 correlated weakly whereas the mitotic index was inversely correlated with CD44. The reverse was true for non-Parsis. The deviation from the general pattern needs further study based on a large number of samples and appropriate use of splice variants.

Breast↗

PubMed1998

Integrins in thyroid tissue: upregulation of alpha2beta1 in anaplastic thyroid carcinoma.

OBJECTIVE: To evaluate the integrin pattern in the normal thyroid gland and in different pathological disorders including malignant tumors, because the aggressiveness of several malignant tumors correlates with alterations in the expression of one or more integrins. DESIGN: We examined the expression of integrins and E-cadherin immunohistochemically in a large and well-defined sample of normal and pathological human thyroid tissue. METHODS: Cryosections of 58 thyroid tissue specimens from normal tissue, thyrotoxicosis, nodular goiter, oxyphilic adenoma, follicular adenoma, follicular carcinoma, papillary carcinoma and anaplastic carcinoma, and three lymph node metastases were investigated immunohistochemically using monoclonal antibodies specifically recognizing the integrin beta1-, beta4-, alpha1-, alpha2-, alpha3-, alpha5- and alpha6-subunits, or E-cadherin. RESULTS: All thyroid epithelial cells expressed integrin beta1- and alpha3-subunits. Immunostaining of the beta4-subunit and the alpha6-subunits was found only in tumors. The staining pattern in the three lymph node metastases from papillary carcinomas did not differ from that in their primaries. Anaplastic carcinomas demonstrated neoexpression of the integrin alpha2-subunit. E-cadherin was detected in all tissues except anaplastic carcinomas. CONCLUSIONS: Neoexpression of alpha6beta4 was seen in most malignant tumors, whereas alpha2 was exclusively found in anaplastic carcinomas. In the latter, a loss of E-cadherin expression was also seen. These changes in cell adhesion molecule expression strongly suggest an association with the acquisition of proliferative and invasive properties.

Cadherins↗

PubMedDate not supplied

A mandibular propulsive appliance modulates collagen-binding integrins distribution in the young rat condylar cartilage.

We have previously shown that a mandibular propulsive appliance (MPA) stimulates cell proliferation and the synthesis of growth factors in the rat condylar cartilage. The aim of this study was to evaluate the effects of a MPA in the distribution of the integrin subunits alpha1 and alpha2 in this cartilage. Twenty eight days-old male Wistar rats were divided into treated (T) and age-matched control groups (C). Treated rats wore the appliance during 3, 5, 7, 9, 11, 15, 20, 30 and 35 days. The condyles were fixed, decalcified and paraffin-embedded. The distribution of alpha1 and alpha2 was studied by immunohistochemistry. Alpha1 distribution was uniform along the cartilage, increasing in 48 days-old rats (C20). Treated animals anticipated this increase to the age of 36 days (T9). The number of alpha2-positive cells was increased in C9 in the anterior condylar region, in C9 and C20 in the middle region and showed no differences in the posterior region. The MPA apparently abolished all variations, leading to a single increase at T30 in all regions. These results suggest that integrins containing the alpha1 and alpha2 subunits are modulated by forces promoted by the MPA, participating of the biological response to this therapy.

Animals↗

PubMed1997

The laminin alpha2-chain short arm mediates cell adhesion through both the alpha1beta1 and alpha2beta1 integrins.

Laminin-2, a heterotrimer composed of alpha2, beta1, and gamma1 subunits, is the primary laminin isoform found in muscle and peripheral nerve and is essential for the development and stability of basement membranes in these tissues. Expression of a domain VI-truncated laminin alpha2-chain results in muscle degeneration and peripheral nerve dysmyelination in the dy2J dystrophic mouse. We have expressed amino-terminal domains VI through IVb of the laminin alpha2-chain, as well as its laminin-1 alpha1-chain counterpart, to identify candidate cell-interactive functions of this critical region. Using integrin-specific antibodies, recognition sites for the alpha1beta1 and alpha2beta1 integrins were identified in the short arms of both laminin alpha1- and alpha2-chain isoforms. Comparisons with a beta-alpha chimeric short arm protein possessing beta1-chain domain VI further localized these activities to alpha-chain domain VI. In addition, we found that the laminin alpha2-chain short arm supported neurite outgrowth independent of other laminin-2 subunits. A heparin/heparan sulfate binding activity was also localized to this region of the laminin alpha2 subunit. These data provide the first evidence that domain VI of the laminin alpha2-chain mediates interactions with cell surface receptors and suggest that these integrin and heparin binding sites, alone or in concert, may play an important role in muscle and peripheral nerve function.

Animals↗

PubMed2001

Integrin expression, enterocyte maturation, and bacterial internalization.

BACKGROUND: Little is known about the molecular mechanisms involved in the translocation of enteric bacteria. Adhesion molecules mediate interactions between some enteric pathogens and mammalian cells, but no such interactions have been identified for enterocytes and normal enteric bacteria. Using enteric pathogens, adhesion molecule expression has been linked to bacterial internalization and to enterocyte differentiation. Therefore, experiments were designed to study enterocyte integrin expression and differentiation, as well as enterocyte internalization of Salmonella typhimurium, Proteus mirabilis, and Escherichia coli. MATERIALS AND METHODS: Relative expression of the alpha2, alpha3, and beta1 integrin subunits on Caco-2 and HT-29 enterocytes (mature and immature) was measured by ELISA. Bacteria-enterocyte surface interactions were observed by light and scanning electron microscopy. Bacterial internalization by enterocytes was quantified using the gentamicin protection assay. RESULTS: Expression of the alpha2, alpha3, and beta1 integrin subunits was consistently increased in immature compared to mature Caco-2 enterocytes; however, compared to mature enterocytes, immature HT-29 enterocytes had similar expression of alpha3 and beta1 but decreased alpha2. Compared to untreated mature enterocytes, bacterial internalization was increased in immature enterocytes as well as mature enterocytes with lateral membranes artifactually exposed. However, there was no difference in bacterial internalization between immature enterocytes and mature enterocytes treated to expose the lateral membrane. CONCLUSIONS: Bacterial internalization by enterocytes appeared to be due to factors other than integrin expression or enterocyte differentiation. Exposure of the lateral enterocyte membrane may play an important role in facilitating bacterial internalization by enterocytes.

Antigens, CD↗

PubMed2004

Differential expression of integrin subunits in DU-145/AR prostate cancer cells.

We have established a clonal DU-145 prostate cancer cell line (DU-145/AR) stably transfected with androgen receptor cDNA. We investigated the expression of integrin subunits, adhesion to extracellular matrices, the invasion of DU-145/AR prostate cancer cells. The expression of various integrin subunits and adhesion to various extracellular matrices in DU-145, DU-145/Neo and DU-145/AR cells were examined. The haptoinvasion and the haptotactic migration of these cells were investigated using a Transwell cell culture chamber assay. DU-145/AR cells exhibited lower expression of alpha6 and beta4 integrin subunits and higher expression of alpha2 and alpha5 than DU-145 cells. DU-145/AR cells showed significantly lower adhesion to fibronectin, laminin-1 and laminin-5 than DU-145/ Neo cells, whereas DU-145/AR cells showed higher adhesion to type I and type IV collagen. Haptoinvasion of DU-145/AR cells into Matrigel/fibronectin-coated filter was significantly reduced as compared with DU-145/Neo or DU-145 cells, but there was no significant difference between DU-145/AR and control cells in the haptotactic migration to fibronectin. Dihydrotestosterone (DHT) inhibited the invasive ability of DU-145/AR cells. These results indicate that androgen receptor may play a role in the regulation of adhesion to the extracellular matrices and invasion of prostate cancer cells through influencing the expression of specific integrin subunits.

Androgens↗

PubMed2002

The expression patterns of integrin subunits on human breast tissues obtained during pregnancy.

Integrins have been shown to exert regulatory influences on mammary differentiation and morphogenesis in rodent experimental systems. We have, therefore, examined the expression patterns of integrin subunits on human breast tissues obtained at the 12th, 15th and 18th weeks of pregnancy. Myoepithelial cells were positive for all the integrin subunits examined. alpha2, alpha6 and beta4 showed increased and more defined labelling during pregnancy, indicating that myoepithelial cells and extracellular matrix strengthen their support for the expanding alveoli during pregnancy. Sub-populations of stromal cells were positive for alpha1, alpha3, alpha6, beta1 and beta4. On luminal epithelial cells, alpha1, alpha2, alpha3, alpha6 and beta1 were detectable. alpha2 showed a focal decrease, but the expression patterns of other integrins in luminal cells did not change during pregnancy. Therefore, the expression patterns of most integrins existing prior to pregnancy seem sufficient in this cell type to support the morphological and functional development during early pregnancy.

Adult↗

PubMed2006

Laminin alpha1 chain mediated reduction of laminin alpha2 chain deficient muscular dystrophy involves integrin alpha7beta1 and dystroglycan.

Transgenically introduced laminin (LN) alpha1 chain prevents muscular dystrophy in LNalpha2 chain deficient mice. We now report increased integrin alpha7Bbeta1D synthesis in dystrophic LNalpha2 chain deficient muscle. Yet, immunofluorescence demonstrated a reduced expression of integrin alpha7B subunit at the sarcolemma. Transgenic expression of LNalpha1 chain reconstituted integrin alpha7B at the sarcolemma. Expression of alpha- and beta-dystroglycan is enhanced in LNalpha2 chain deficient muscle and normalized by transgenic expression of LNalpha1 chain. We suggest that LNalpha1 chain in part ameliorates the development of LNalpha2 chain deficient muscular dystrophy by retaining the binding sites for integrin alpha7Bbeta1D and alpha-dystroglycan, respectively.

Animals↗

PubMed2001

Effects of leptin, interleukin-1alpha, interleukin-6, and transforming growth factor-beta on markers of trophoblast invasive phenotype: integrins and metalloproteinases.

Phenotypic changes of integrin and metalloproteinase secretion of the invasive human cytotrophoblast are regulated by cytokines and growth factors, but how this occurs is not completely understood. We used 24-h cytotrophoblast cultures from first trimester pregnancies to investigate the effects of leptin and cytokines on the expression of the alpha2, alpha5, and alpha6 integrin subunits and on the activity of metalloproteinase-2 (gelatinase A) and metalloproteinase-9 (gelatinase B). The alpha2 subunit was marginally upregulated by leptin and interleukin-1alpha (IL-1alpha). All compounds tested upregulated, in some degree, the alpha5 expression. The a6 integrin subunit was massively upregulated, by leptin, interleukins, and transforming growth factor-beta. None of the factors tested affected metalloproteinase-2 activity, but the activity of metalloproteinase-9 was upregulated by leptin and IL-1alpha. In conclusion, leptin and IL-1alpha actively induce some of the changes that cytotrophoblasts undergo to achieve a more invasive phenotype. A novel role for leptin is proposed during early pregnancy: leptin might be an autocrine/paracrine regulator of cytotrophoblast invasiveness during implantation and placentation.

Antigens, CD↗

PubMed2000

Distinct structural forms of type I collagen modulate cell cycle regulatory proteins in mesangial cells.

BACKGROUND: Extracellular matrix molecules profoundly regulate cell behavior, including proliferation. In glomerulonephritis, type I collagen accumulates in the mesangium and is constantly structurally modified and degraded during the course of the disease. METHODS: We studied how two structurally distinct forms of type I collagen, monomer versus polymerized fibrils, affect cell proliferation, mitogen-activated protein kinase (MAPK) activation, and expression of G1-phase regulatory proteins in cultured rat mesangial cells (MCs). To analyze the possible involvement of collagen-binding integrins in type I collagen-derived growth signals further, distribution patterns of integrin chains were examined by immunocytochemistry. RESULTS: Polymerized type I collagen completely prevented the increase of DNA synthesis and cell replication induced by 5% fetal calf serum (FCS) or 25 ng/mL platelet-derived growth factor (PDGF) in MCs on monomer type I collagen. Protein expression of cyclins D1 and E was markedly down-regulated in MCs plated on polymerized type I collagen for eight hours in 5% FCS, as compared with MCs on monomer type I collagen. Incubation with 5% FCS reduced expression of the cdk-inhibitor protein p27Kip1 on monomer but not on polymerized type I collagen. Moreover, polymerized type I collagen markedly reduced cyclin E-associated kinase activity in the presence of 5% FCS. Polymerized type I collagen diminished the PDGF-induced phosphorylation and nuclear translocation of p42/p44 MAPK, but did not affect phosphorylation of PDGF beta-receptors. In MCs plated on monomer type I collagen, alpha1, alpha2, and beta1 integrin chains were recruited into focal contacts. However, on polymerized type I collagen, alpha2 and beta1, but not alpha1, integrin chains were condensed into focal contacts. CONCLUSIONS: The growth-inhibitory effect of polymerized type I collagen is characterized by rapid changes of expression and/or activation of MAPK and G1-phase regulators and could result from the lack of alpha1beta1 integrin signaling in MCs on polymerized type I collagen. Conceivably, deposition of polymerized type I collagen might reflect a reparative response to control MC replication in glomerular inflammation.

Animals↗