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At least 811 records · Page 45Linked to original sources
PubMed1989

Immunolocalization of beta 3 subunit of integrins in osteoclast membrane.

Utilizing isolated and cultured osteoclasts it has been possible to establish that they adhere to the substrate through specialized close contact areas, the podosomes, that in fully spread osteoclasts in vitro or in vivo are located within the clear zone. The cytochemical organization of podosomes has further been investigated in order to elucidate their possible involvement in the control of substrate recognition, that precedes bone resorption. An immunofluorescence investigation, performed utilizing human osteoclasts, shows that the beta 2 integrin subunit that in human monocytes is expressed and located in podosomes is absent in human osteoclasts, while the beta 3 subunit of the vitronectin receptor is expressed by osteoclasts, but not by other monocyte-derived cells and colocalizes with vinculin around the actin core of the podosome. The beta 1 subunit of the fibronectin receptors is also found, but with a diffuse pattern, in the osteoclast membrane. These results indicate that podosomes, while present in different cell types, may have in the osteoclast an unique cytochemical organization related to the peculiar function of this cell.

Bone Resorption↗
PubMed1995

Beta 1 and beta 3 integrin upregulation in rapidly progressive glomerulonephritis.

The expression and distribution pattern of beta 1 (alpha 1-alpha 6) and alpha v beta 3 integrins and ICAM-1 and VCAM-1 counter receptors were evaluated by an immunohistochemical technique on eight renal samples from patients affected by rapidly progressive glomerulonephritis (RPGN) of different aetiologies. In all cases integrins and counterreceptors displayed similar patterns. On tubular cells of renal cortex, a marked upregulation of alpha 2 beta 1, alpha 3 beta 1, alpha 5 beta 1, alpha v beta 3 integrins and VCAM-1 was observed with as many as 60-90% of tubular cross-sections labelled, while a strong ICAM-1 reactivity was limited to the luminal surface. The same adhesion molecules were also uniformly expressed on crescentic cells. In glomeruli, integrin upregulation occurred only on apparently preserved capillary tufts, i.e. in an early stage of lesion, while collapsed and sclerotic tufts showed a reduced integrin expression. In addition a morphometric study of extracellular matrix (EM) proteins cellular fibronectin and tenascin showed a 9.56 +/- 1.9-fold and 3.35 +/- 0.6-fold increase respectively in these proteins, as compared to normal kidney (P < 0.001). The upregulation of alpha v beta 3 on podocytes might play a role in the adhesion of crescentic cells. An increased production of cytokines, in particular transforming growth factor-beta, might induce augmented deposition of EM proteins and upregulation of beta 1 and beta 3 integrins in RPGN.

Antigens, CD↗
PubMed1994

A mechanism for divalent cation regulation of beta 3-integrins.

Integrins alpha IIb beta 3 and alpha V beta 3 mediate numerous cell-matrix and cell-cell contacts. Both integrins contain multiple divalent cation-binding motifs that regulate ligand binding. Here, we elucidate a major difference in the regulation of alpha IIb beta 3 and alpha V beta 3 by divalent ions. Fibrinogen binding to alpha IIb beta 3 in Ca(2+)-containing buffer is rapid, with an apparent association rate constant (k1app) of 8.2 x 10(5) M-1 s-1, but Ca2+ does not support association between fibrinogen and alpha V beta 3. Interestingly, Mn2+ supports fibrinogen binding to both integrins, albeit with a relatively slow association rate (k1app = 10(4) M-1 s-1). This influence of divalent ions on ligand association rates accounts for the opposite divalent ion requirements for platelet aggregation and tumor cell adhesion to fibrinogen. Furthermore, the regulation of fibrinogen binding to alpha V beta 3 is complex when both Ca2+ and Mn2+ are present. Physiological concentrations of Ca2+ completely ablated adhesion. Kinetic analysis demonstrated that Ca2+ is a mixed-type inhibitor of Mn(2+)-supported fibrinogen binding to alpha V beta 3. Consequently, the data presented here suggest a mechanism in which two separate cation-binding sites regulate ligand binding to beta 3-integrins.

Calcium↗
PubMed1994

Transmembrane signal transduction by integrin cytoplasmic domains expressed in single-subunit chimeras.

Integrins are heterodimeric, transmembrane cell adhesion receptors that have recently been shown to function in transmembrane signal transduction. To examine the specific role of integrin intracellular domains in signal transduction, chimeric receptors containing various integrin intracellular domains coupled to a reporter consisting of the transmembrane and extracellular domains of the small, non-signaling subunit of the interleukin-2 receptor were expressed in cultured human fibroblasts and assayed for their ability to trigger tyrosine phosphorylation of the 125-kDa cytoplasmic tyrosine kinase, pp125FAK. Tyrosine phosphorylation of pp125FAK was induced in cultured fibroblasts that transiently expressed chimeric receptors containing either the beta 1, beta 3, or beta 5 integrin intracellular domain and were selected by magnetic bead sorting. However, expression of chimeric receptors containing either the alpha 5 or an alternatively spliced form of the beta 3 intracellular domain (beta 3B), as well as those lacking an intracellular domain, failed to induce tyrosine phosphorylation of pp125FAK. These results indicate that information contained in the beta 1, beta 3, or beta 5 integrin intracellular domain is sufficient to stimulate integrin-mediated tyrosine phosphorylation of specific intracellular proteins and that integrin extracellular and transmembrane domains are not required for inducing tyrosine phosphorylation. Our results also indicate that alternative splicing can regulate the ability of beta integrin intracellular domains to participate in signal transduction, and they further suggest that the carboxyl-terminal region of specific beta integrins may play a role in the signal transduction pathway involving extracellular matrix molecules.

Amino Acid Sequence↗
PubMed1994

Mutation of a ligand binding domain of beta 3 integrin. Integral role of oxygenated residues in alpha IIb beta 3 (GPIIb-IIIa) receptor function.

A single amino acid substitution in beta 3 (Asp119 --> Tyr) abrogates the ligand binding function of beta 3 integrins and alters the divalent cation conformation of the platelet integrin alpha IIb beta 3 (GPIIb-IIIa). This aspartic acid residue resides within a conserved cluster of oxygenated residues that may provide ligands for the coordination of divalent cations. To assign function to the other oxygenated residues in this group (Ser121, Ser123, Asp126, Asp127, and Ser130), each of these amino acids in beta 3 was individually substituted by alanine. None of these amino acid substitutions altered heterodimer formation or surface expression. However, the substitutions had differential effects on receptor function. Substitution at positions Asp119 or Ser121 produced a complete loss of receptor function. Cells expressing these mutants failed to adhere to fibrinogen, failed to bind activation-independent ligand-mimetic peptides, and did not bind the ligand-mimetic mAb PAC1 following activation of the receptor. Similarly, cells expressing beta 3 with a substitution at Ser123 also failed to adhere to fibrinogen and did not bind RGD peptide or mAb PAC1. These cells did retain the capacity to bind an alpha IIb beta 3-specific, high affinity peptidomimetic, but occupancy did not induce the conformational change from resting to activated state observed following occupancy of the wild type receptor. Substitution at positions Asp126, Asp127, or Ser130 had no effect on ligand binding function. These data indicate that Asp119, along with Ser121 and Ser123, plays an integral role in the ligand binding function of alpha IIb beta 3.

Amino Acid Sequence↗
PubMed1994

Vitronectin-driven human keratinocyte locomotion is mediated by the alpha v beta 5 integrin receptor.

Vitronectin is a soluble serum factor that is known to promote epiboly of keratinocytes in explant cultures and enhance cell spreading and attachment to matrix. Recently, vitronectin was demonstrated to promote human keratinocyte locomotion. The mechanism(s) by which vitronectin enhances keratinocyte migration is unknown. In this study, we quantitated the vitronectin-driven migration of human keratinocytes in the presence of antibodies to vitronectin receptors. We found that vitronectin's effect of promoting human keratinocyte migration was inhibited by antibody-directed against the alpha v beta 5 receptor. In addition, we surface-labeled human keratinocytes, chromatographed extracts of the cell membranes on a vitronectin column, and then immunoprecipitated the bound and eluted proteins with antibodies to specific vitronectin receptors. We identified the vitronectin receptors on human keratinocytes as bands of 150,000 and 100,000 daltons without reduction and as 125,000 and 110,000 daltons under reducing conditions. Immunoprecipitation with specific antibodies identified the major receptor to be the alpha v beta 5 integrin. In addition, we quantitated vitronectin-driven migration of human keratinocytes in the presence of Arg-Gly-Asp (RGD) and control peptides. We found that the presence of RGD, but not control peptide, inhibited vitronectin-driven migration of human keratinocytes. These studies demonstrate that human keratinocytes express vitronectin receptors and use the alpha v beta 5 receptor for cellular locomotion.

Antibodies↗
PubMedDate not supplied

Differential expression of transforming growth factor alpha, adhesions molecules and integrins in primary, metastatic liver tumors and in liver cirrhosis.

Changes in cytokines, intercellular cell-matrix adhesion molecules and integrins may influenced tumor cell invasion and metastases. This study described the distribution, pattern and intensity of cytokine TGFa, adhesion molecules CD 34 and CD 44 and integrins a2, a3, CD 29 (beta 1 chain) and CD 61 (beta 3 chain) in hepatocellular carcinoma (HCC), metastatic liver tumors and hepatic cirrhosis. Fresh snap-frozen tissue from 20 cases of HCC, 5 metastatic adenocarcinomas and 10 cirrhotic livers was studied immunohistochemically using available antibodies. The most intense staining of TGFa was found in metastatic adenocarcinoma, following by regenerating hepatocytes in cirrhotic liver and well differentiated HCC. Insignificant differences in activity of CD 34 in various pathologies, up-regulation of CD 44 in poorly differentiated HCC and down-regulation in metastatic tumors were found. All integrins studied showed down-regulation in poorly differentiated HCC, relatively high activity of a2, a3 and beta 1 in metastatic tumors and the presence of all integrins in cirrhotic liver.

Adenocarcinoma↗
PubMed1995

Human mast cells derived from fetal liver cells cultured with stem cell factor express a functional CD51/CD61 (alpha v beta 3) integrin.

Human fetal livers contain progenitor cells that become mast cells after 4 weeks of culture with recombinant human stem cell factor. Expression of cell surface CD29 (beta 1), CD18 (beta 2), CD61 (beta 3), and beta 5 integrins was investigated on such cells by flow cytometry and adhesion measurements. High surface expression of CD49e, CD51, and CD61 along with kit was apparent by 4 weeks of culture, whereas expression of each at day 0 was low to undetectable. CD29 and CD49d were detected on cells from day 0 to 4 weeks of culture; CD49b, CD49c, CD49f, CD18, and CD54 expression was negligible. The fetal liver-derived mast cells spontaneously adhered to vitronectin. No evidence for degranulation was found during vitronectin-dependent adhesion. Adhesion occurred in part through the CD61/CD51 receptor. No evidence for adhesion to vitronectin through CD29 and beta 5 integrins was obtained. Almost all of the vitronectin-adherent cells expressed CD51, CD61, kit, and tryptase, and exhibited metachromasia with toluidine blue. Thus, among the fetal liver-derived cells, developing mast cells were selectively adherent to vitronectin. These mast cells and the other cell types present also adhere spontaneously to fibronectin and to laminin, this adhesion being partially inhibited by antibodies against CD61 and CD29 integrins. In conclusion, human mast cells acquire functional vitronectin receptors as they develop from fetal liver progenitors under the influence of rhSCF. This may be important for the recruitment, localization, and retention of developing mast cells.

Amino Acid Sequence↗
PubMed1995

Beta 3 integrin-mediated fibrin clot retraction by nucleated cells: differing behavior of alpha IIb beta 3 and alpha v beta 3.

Fibrin clot retraction may be important in resolution of thrombi and, in platelets, is mediated by integrin alpha IIb beta 3 (GPIIb-IIIa). Nucleated cells that lack alpha IIb beta 3 can retract fibrin clots, and we now report that integrin alpha v beta 3 can support this process. In addition, we compared the capacities of recombinant beta 3 integrins to mediate clot retraction in Chinese hamster ovary and M21 melanoma cells. We found that alpha v beta 3, but not alpha IIb beta 3, could spontaneously support retraction. Transferring the cytoplasmic domain of alpha v to alpha IIb enabled the resulting chimeric alpha IIb beta 3 to support clot retraction. The capacity of the alpha v cytoplasmic domain to support clot retraction was not caused by activation of the ligand binding function of alpha IIb beta 3 or by enhancement of alpha IIb beta 3's capacity to stimulate the formation of focal adhesions or the tyrosine phosphorylation of pp125FAK. These experiments define requirements for alpha IIb beta 3-mediating clot retraction, establish the capacity of alpha v beta 3 to mediate this process, and suggest differing functional roles of the alpha v and alpha IIb cytoplasmic domains.

Animals↗
PubMed1995

Development of skeletal metastases.

Skeletal metastases result from a series of complex steps including activation of osteoclasts and interaction between adhesion molecules on cancer cells and bone matrices. Researchers of this study used pathologic specimens of breast cancer cells from primary and metastatic sites obtained at surgery or autopsy to demonstrate the expression of parathyroid hormone-related protein by immunohistochemistry and beta 3 integrin by in situ hybridization to clarify the role of tumor-derived osteoclast activating factors and adhesion molecules in the development of skeletal metastases. The results of this retrospective study showed a significant difference of parathyroid hormone-related protein and beta 3 integrin expression in cases with and without skeletal metastases. These expressions were enhanced or clonally selected or both in skeletal metastatic sites. Because activation of osteoclastic bone resorption by parathyroid hormone-related protein could facilitate tumor cells to attach to the eroded bone surface through cell adhesion molecules, these 2 factors could make it easier for tumor cells to grow in bone.

Adult↗
PubMed1993

Amino acid 489 is encoded by a mutational "hot spot" on the beta 3 integrin chain: the CA/TU human platelet alloantigen system.

A new platelet alloantigen, termed CA, has recently been implicated in a case of neonatal alloimmune thrombocytopenia (NATP) in a Filipino family in Canada. Maternal anti-CA serum reacted with glycoprotein (GP) IIIa and maintained its reactivity after removal of high mannose carbohydrate residues from GPIIIa. The monoclonal antibody (MoAb) AP3 partially blocked binding of anti-CA to GPIIIa, suggesting that the CA polymorphism is proximal to the AP3 epitope. Platelet RNA polymerase chain reaction (PCR) was used to amplify the region of GPIIIa cDNA that encodes this region of the protein. DNA sequence analysis showed a G<==>A nucleotide substitution at base 1564 that results in an arginine (Arg) (CGG)<==>glutamine (Gln) (CAG) polymorphism in amino acid (AA) 489. Further analysis of PCR-amplified genomic DNA from 27 normal individuals showed that AA 489 is encoded by a mutational "hot spot" of the GPIIIa gene, as three different codons for the wild-type Arg489 of GPIIIa were also found. The codon usage for Arg489 was found to be: CGG (63%), CGA (37%), and CGC (< 1%). These frequency data were valuable in determining the relationship of the CA alloantigen to the serologically defined TU GPIIIa polymorphism that is present in low frequency in the Finish population. Analyses of PCR-amplified genomic DNA showed the CA and TU alloantigens to be identical at the molecular level. Definition of these new molecular variants of the beta 3 integrin chain should prove valuable in the diagnosis of NATP in these two geographically disparate populations, and it may also provide useful genetic markers for examining other pathologic variations of the GPIIb-IIIa complex.

Base Sequence↗
PubMed1995

Integrins as markers of uterine receptivity in women with primary unexplained infertility.

OBJECTIVE: To assess uterine receptivity in women with unexplained infertility using integrin cell adhesion molecules as markers. DESIGN: Prospective, controlled study design. PATIENTS: Eighty-seven nulliparous women with unexplained infertility and 32 fertile and infertile parous controls. MAIN OUTCOME MEASURE: Immunohistochemical staining for alpha 1, alpha 4, and beta 3 integrin subunits in endometrial biopsies obtained during the window of implantation (days 20 to 24), using the semiquantitative HSCORE by two observers in a blinded fashion. RESULTS: All endometrial biopsies from parous controls contained positive immunostaining for the alpha 1, and beta 3 integrin subunits in glandular epithelium. Some samples from parous controls were missing the alpha 4 subunit. In contrast, compared with parous controls, biopsies from women with unexplained infertility had reduced significantly beta 3 expression, with similar expression of alpha 1 and alpha 4. Two distinct defects in integrin expression were identified: "out-of-phase" samples that lacked beta 3 because of histologic lag (type I defects) and "in-phase" endometrium that still failed to express this integrin (type II defects). These subclassifications accounted for 26% and 39% of the total unexplained infertility group, respectively. CONCLUSIONS: Abnormal endometrial integrin expression was a frequent finding in women with unexplained infertility. These data suggest that defective uterine receptivity may be an unrecognized cause of infertility in this population of women.

Adult↗
PubMed1994

A point mutation in the integrin beta 3 cytoplasmic domain (S752-->P) impairs bidirectional signaling through alpha IIb beta 3 (platelet glycoprotein IIb-IIIa).

Agonist-induced inside-out signaling results in an increased affinity of integrin alpha IIb beta 3 (platelet glycoprotein IIb-IIIa) for soluble ligands (fibrinogen [Fg] and PAC1). Ligand binding to integrins initiates outside-in signaling that leads to cellular responses such as cell spreading and focal adhesion formation. A point mutation in the beta 3 cytoplasmic domain (S752-->P) is associated with blocked inside-out alpha IIb beta 3 signaling in a variant Glanzmann's thrombasthenia. This mutation was introduced into beta 3 and cotransfected into Chinese hamster ovary cells with a chimeric alpha subunit consisting of the alpha IIb extracellular and transmembrane domains and the alpha 6B cytoplasmic domain. The substitution of the alpha IIb cytoplasmic domain with that of alpha 6 led to activation of alpha IIb beta 3 to bind PAC1, mimicking inside-out signaling. This effect was reversed by the S752-->P mutation, indicating a disruption of inside-out signaling by the mutation. In addition, transfectants expressing this beta 3 variant showed reduced alpha IIb beta 3-mediated cell spreading on immobilized Fg, focal adhesion, and fibrin clot retraction, suggesting an impairment in outside-in alpha IIb beta 3 signaling. Therefore, a single point mutation in the beta 3 cytoplasmic domain impaired bidirectional signaling through alpha IIb beta 3.

Animals↗
PubMed1993

Cloning of the promoter for the avian integrin beta 3 subunit gene and its regulation by 1,25-dihydroxyvitamin D3.

We have cloned the promoter of the avian beta 3 integrin gene. Using a probe comprising the 5'-untranslated region of an avian macrophage beta 3 cDNA, characterized by 5' rapid amplification of cDNA ends, several clones were isolated from an avian genomic library. One major and one minor transcriptional start site were identified at +1 and -47 base pairs, respectively, with the latter coinciding with a consensus sequence of an initiator. DNA sequence analysis of 800 base pairs 5' of the transcriptional start site fails to reveal either a TATA or CAAT box. In addition to an initiator, the first 200 base pairs contain consensus sequences for the binding of AP-1 and SP-1. A 3.5-kilobase fragment located immediately upstream of the transcriptional start site exhibits functional promoter activity, and deletion analysis reveals both suppressor and enhancer elements. In light of our observation that 1,25-dihydroxyvitamin D3 (D3) accelerates beta 3 transcription, we determined whether the avian beta 3 promoter contains a vitamin D response element (VDRE). Transfected reporter constructs containing the first 1.5 kilobases upstream of the major beta 3 transcriptional start site respond to D3 with enhanced luciferase activity. Analysis of this region reveals a classical VDRE consensus sequence, located at -756 to -770. The following observations support the hypothesis that this sequence represents a functional VDRE: 1) a 600-base pair genomic fragment or a 29-base pair oligomer, each containing the putative VDRE, respond to D3 when transfected into HD11 cells; 2) a 67-base pair DNA fragment derived from genomic DNA and containing the candidate beta 3 VDRE specifically binds the vitamin D receptor-retinoid X receptor beta complex; and 3) avian osteoclast precursor-derived nuclear extracts bind to a synthetic oligomer containing the beta 3 VDRE-like sequence and, in turn, are specifically displaced by unlabeled beta 3 VDRE and anti-vitamin D receptor antibody.

Amino Acid Sequence↗
PubMed1993

Distribution of integrin subunits on rat metaphyseal osteoclasts and osteoblasts.

A key event in bone resorption is the attachment of osteoclasts to the bone matrix. The process apparently involves integrin plasma membrane receptors for extracellular matrix proteins. In the present study the distribution of some integrin subunits among different osteoclastic and osteoblastic domains was determined using immunocytochemistry on rat metaphyseal bone. Ultrathin cryosections were incubated with polyclonal antibodies against the alpha v beta 3 integrin and against the individual integrin subunits, alpha v, beta 1, beta 3, and beta 5. Bound antibodies were detected with 10-nm colloidal gold coated with protein A. The results show that alpha v- and beta 3-subunits are enriched at the osteoclast plasma membrane facing the bone matrix, i.e., the clear zone. Furthermore, beta 1- and beta 5-subunits were somewhat enriched at the osteoblast plasma membrane facing the bone surface. The present observations corroborate and extend our previous data indicating that the alpha v beta 3 integrin mediates tight attachment of the osteoclast to the bone matrix. Moreover, a role for integrins in the attachment and interactions of the osteoblast is suggested.

Animals↗
PubMed1994

Isolation and characterization of a TATA-less promoter for the human beta 3 integrin gene.

Proper expression of the human platelet fibrinogen receptor is necessary for the maintenance of normal hemostasis. This receptor is formed by the heterodimer alpha IIb beta 3, a prototypic member of the integrin family of adhesive molecules. beta 3 is also expressed in other tissues with alpha v as the vitronectin receptor. It was not possible to study the basis for tissue-specific expression of this gene, because the beta 3 gene promoter had not been isolated previously. We have now isolated a 6.0-kb human genomic DNA fragment containing 2.0 kb of sequence 5' to the beta 3 ATG start codon. This clone also contains sequence encoding the signal peptide of the immature beta 3 protein and 3.0 kb of 3' intronic sequence. Primer extension and RNase protection studies of poly A+ RNA from a human erythroleukemia (HEL) cell line indicated a major transcription start site 30 bp upstream of the ATG start codon. In an orientation-dependent manner, a 584-bp fragment 5' to the start codon promotes expression of the chloramphenicol acetyl transferase (CAT) reporter gene in K562 cells. CAT expression from this beta 3 promoter is fivefold above expression from a "promoter-less" control CAT construct. This beta 3 promoter lacks TATA and CAAT cis-acting elements, but there are two Sp1 sites flanking the transcription start site. Other potential transcription factor binding sites are also identified. Phorbol esters (TPA), which increase beta 3 transcription in K562 cells, stimulated transcription from the 584-bp 5' beta 3 region. The isolation of this beta 3 promoter region should permit a more detailed analysis of its transcriptional regulation.

Amino Acid Sequence↗
PubMed1993

Peptides derived from a sequence within beta 3 integrin bind to platelet alpha IIb beta 3 (GPIIb-IIIa) and inhibit ligand binding.

Peptides derived from a sequence within the loop structure of human platelet glycoprotein (GP) IIIa (integrin beta 3) were previously shown to inhibit fibrinogen binding to purified GPIIb-IIIa. In this study a series of peptides based on the GPIIIa sequence 211-221 (SVSRNRDAPEG) was synthesized. The most active peptide was determined to be RNRDA, and its inhibitory potency was 4-fold greater (IC50 = 4.8 microM) than that of SVSRNRDAPEG. These GPIIIa peptides also inhibited the binding of two monoclonal antibodies, pl-55 and PAC-1, which are directed against the activated conformer of GPIIb-IIIa. To determine whether these peptides bound directly to GPIIb-IIIa, an affinity matrix was prepared by coupling RNRDAPEGC to Sepharose. Fibrinogen or purified GPIIb-IIIa was applied to the affinity column. Only GPIIb-IIIa was retained on the column, and it could be specifically eluted by GPIIIa peptide or RGDV but not by an irrelevant peptide. Additionally, we observed that the binding of GPIIIa peptides to purified GPIIb-IIIa induced exposure of a neoepitope on GPIIb that was recognized by the monoclonal antibody pl-80. These data suggest that sequences within the loop structure of GPIIIa can interact with the ligand binding domain of GPIIb-IIIa. Thus, this GPIIIa domain may be involved in regulating the accessibility of ligands to GPIIb-IIIa following platelet activation.

Amino Acid Sequence↗
PubMed1996

Integrin activation suppresses etoposide-induced DNA strand breakage in cultured murine tumor-derived endothelial cells.

Tumor endothelium is critical for solid tumor growth and is a potential site for anticancer drug action. Within 2 h, etoposide caused marked DNA strand breakage in xenograft tumor-derived endothelial cells (TDECs). Etoposide-induced DNA breakage was inhibited by culturing TDECs on gelatin, type IV collagen, laminin, fibronectin, and the integrin ligand hexapeptide, GRGDSP, but not the inactive peptide, GRADSP. It was also inhibited when TDECs were on surfaces coated with antibodies to alpha 5, beta 1, or beta 3 integrin subunits and by clustering integrins with soluble antibodies. After 8 h with etoposide, TDECs detached from the monolayer, and 50-kb DNA fragments were seen. Fibronectin inhibited both processes. Thus, integrins are survival factors for TDEC that inhibit the genotoxicity of etoposide and may influence the sensitivity of tumors to drugs.

Animals↗