Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Integrin beta4”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 235 records · Page 13Linked to original sources
PubMed2000

1,25-Dihydroxyvitamin D3 decreases human prostate cancer cell adhesion and migration.

1,25-Dihydroxyvitamin-D3 [1,25(OH)2D3], the active hormonal metabolite of vitamin D, acts through a specific nuclear receptor to inhibit proliferation and promote differentiation of several tumor cell types including the LNCaP, DU145 and PC-3 prostate cancer cell lines as well as primary prostate tumor lines. 1,25(OH)2D3 can also decrease invasion of breast and prostate cancer cell lines in vitro. We confirm this latter finding in the DU145 and PC-3 prostate cancer cell lines, and further show that 1,25(OH)2D3 inhibits overall invasion, cell adhesion and migration to the basement membrane matrix protein laminin. These changes appear to be due in part to a 1,25(OH)2D3-induced decrease in expression of alpha6 and beta4 integrins, both of which are receptors for laminin and associated with increased migration and invasion of prostate cancer cells in vitro. Blocking function of these particular integrins with antibodies inhibits both adhesion and migration of the cells. Collectively, these data demonstrate that 1,25(OH)2D3, in addition to decreasing proliferation of tumor cells, can also inhibit prostate cancer cell invasion through modulation of select cell surface adhesion molecules.

Calcitriol↗
PubMed2001

Downregulation of hemidesmosomal proteins in nasopharyngeal carcinoma cells.

Hemidesmosome (HD) is a transmembrane complex that mediates attachment of epithelial cells to the basement membrane. Abnormal expression of HD components has been reported in several types of human cancers and is believed to play a role in tumor invasion and metastasis. Using differential gene display, we have identified downregulation of BPAG1 expression in nasopharyngeal carcinoma cells. BPAG1 is a major component of hemidesmosome. In the present study, we have extended our work to investigate the expression pattern of other components in the HD complex, namely, BPAG2, ITGalpha6 and ITGbeta4 in three distinct biological groups of nasopharyngeal epithelial cells: (a) non-malignant nasopharyngeal epithelial cells established from primary culture of nasopharyngeal explants, (b) non-malignant nasopharyngeal epithelial cells immortalized by viral oncogenes, SV40 or HPV16E6E7, and (c) nasopharyngeal carcinoma (NPC) cells. Both non-malignant primary cultured nasopharyngeal epithelial cells and immortalized nasopharyngeal epithelial cell lines expressed all the HD components examined, although the immortalized cells expressed a lower level of HD components compared with the non-malignant nasopharyngeal cells established from primary culture. In contrast, downregulation of HD components is commonly observed in nasopharyngeal carcinoma cells. Loss of HD expression in NPC may be associated with the undifferentiated properties of NPC cells and may have prognostic significance.

Antigens, CD↗
PubMed2001

The human ITGB4BP gene is constitutively expressed in vitro, but highly modulated in vivo.

The ITGB4BP gene encodes for a highly conserved protein, named p27BBP (also known as eIF6), originally identified in mammals as a cytoplasmic interactor of beta4 integrin. In vitro and in vivo studies demonstrated that p27BBP is essential for cell viability and has a primary function in the biogenesis of the 60S ribosomal subunit. Here we report the genomic organization of the human ITGB4BP gene and show that its gene product is expressed with features of a housekeeping element in vitro, but is regulated in a cell specific fashion in vivo. The human gene spans 10 kb and comprises seven exons and six introns. The 5' flanking region shows a TATA-less promoter, canonical CpG islands, and binding sites for serum responsive elements. In cultured cells, p27BBP mRNA and protein are constitutively expressed and stable. A gradual loss of p27BBP mRNA can be observed only after prolonged serum starvation, and heat shock treatment. In contrast, p27BBP mRNA and protein levels in vivo are variable among different organs. More strikingly, immunohistochemical analysis shows that the p27BBP protein is present in a cell specific fashion, even within the same tissue. Taken together, these data show that ITGB4BP gene expression is highly regulated in vivo, possibly by the combination of tissue specific factors and protein synthesis pathways.

Amino Acid Sequence↗
PubMed1996

Expression of cell adhesion molecules in lung cancer cell lines.

Cell adhesion mechanisms are among the basic aspects in organism development. Adhesion molecules are involved in the building of complex structures and of association of the tissue. They also mediate as substratum adhesion molecules and are involved in the building of the scaffold. The process of tumor growth and metastasis is a complex cascade of events (FIDLER 1989). For many of these steps the tumor cells must be able to change their degree of adherence. Tumor progression and metastatic dissemination are tightly linked with the ability of the tumor cells to interact with other cells and with the extracellular matrix. The first step of metastasis is the active migration of tumor cells into the surrounding tissue.

Antigens, CD↗
PubMed2000

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

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

Animals↗
PubMed1997

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

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

Amino Acid Sequence↗
PubMed1999

Biology and function of hemidesmosomes.

Hemidesmosomes are cell-substratum adhesion sites that connect the extracellular matrix to the keratin cytoskeleton. Our knowledge of the function of these structures has greatly increased as a result of studies on patients with aberrant expression of hemidesmosome components and studies using targeted inactivation of mouse genes encoding these components. Insight into the formation of hemidesmosomes, as well as into protein-protein interactions that occur in these junctional complexes, has recently been gained by in vitro cell transfections, blot overlay and yeast two-hybrid assays. In addition, recent results indicate that the alpha6 beta4 integrin is involved in the transduction of signals that are induced by the extracellular matrix and which modulate processes as diverse as cell proliferation, differentiation, apoptosis, migration and tissue morphogenesis. Thus it seems that hemidesmosomes do not merely maintain dermo-epidermal adhesion and tissue integrity, but that they are also implicated in intracellular signaling. Here we discuss recently published data on the biology and function of hemidesmosomes.

Animals↗
PubMed1999

Mutation analysis and molecular genetics of epidermolysis bullosa.

Cutaneous basement membrane zone (BMZ) consists of a number of attachment structures that are critical for stable association of the epidermis to the underlying dermis. These include hemidesmosomes, anchoring filaments and anchoring fibrils which form an interconnecting network extending from the intracellular milieu of basal keratinocytes across the dermal-epidermal basement membrane to the underlying dermis. Aberrations in this network structure, e.g. due to genetic lesions in the corresponding genes, can result in fragility of the skin at the level of the cutaneous BMZ. The prototype of such diseases is epidermolysis bullosa (EB), a heterogeneous group of genodermatoses characterized by fragility and blistering of the skin, often associated with extracutaneous manifestations, and inherited either in an autosomal dominant or autosomal recessive manner. Based on constellations of the phenotypic manifestations, severity of the disease, and the level of tissue separation within the cutaneous BMZ, EB has been divided into clinically distinct subcategories, including the simplex, hemidesmosomal, junctional and dystrophic variants. Elucidation of BMZ gene/protein systems and development of mutation detection strategies have allowed identification of mutations in 10 different BMZ genes which can explain the clinical heterogeneity of EB. These include mutations in the type VII collagen gene (COL7A1) in the dystrophic (severely scarring) forms of EB; mutations in the laminin 5 genes (LAMA3, LAMB3 and LAMC2) in a lethal (Herlitz) variant of junctional EB; aberrations in the type XVII collagen gene (COL17A1) in non-lethal forms of junctional EB; mutations in the alpha6 and beta4 integrin genes in a distinct hemidesmosomal variant of EB with congenital pyloric atresia; and mutations in the plectin gene (PLEC1) in a form of EB associated with late-onset muscular dystrophy. Identification of mutations in these gene/protein systems attests to their critical importance in the overall stability of the cutaneous BMZ. Furthermore, elucidation of mutations in different variants of EB has direct clinical applications in terms of refined classification, improved genetic counseling, and development of DNA-based prenatal testing in families with EB.

Basement Membrane↗
PubMed2005

Epidermolysis bullosa simplex associated with pyloric atresia is a novel clinical subtype caused by mutations in the plectin gene (PLEC1).

Epidermolysis bullosa (EB) is an inherited mechano-bullous disorder of the skin, and is divided into three major categories: EB simplex (EBS), dystrophic EB, and junctional EB (JEB). Mutations in the plectin gene (PLEC1) cause EBS associated with muscular dystrophy, whereas JEB associated with pyloric atresia (PA) results from mutations in the alpha6 and beta4 integrin genes. In this study, we examined three EB patients associated with PA from two distinct families. Electron microscopy detected blister formation within the basal keratinocytes leading to the diagnosis of EBS. Surprisingly, immunohistochemical studies using monoclonal antibodies to a range of basement membrane proteins showed that the expression of plectin was absent or markedly attenuated. Sequence analysis demonstrated four novel PLEC1 mutations. One proband was a compound heterozygote for a nonsense mutation of Q305X and a splice-site mutation of 1344G-->A. An exon-trapping experiment suggested that the splice-site mutation induced aberrant splicing of the gene. The second proband harbored a heterozygous maternal nonsense mutation, Q2538X and homozygous nonsense mutations R1189X. Analysis of the intragenic polymorphisms of PLEC1 suggested that R1189X mutations were due to paternal segmental uniparental isodisomy. These results indicate that PLEC1 is a possible causative gene in this clinical subtype, EBS associated with PA. Furthermore, two patients out of our three cases died in infancy. In terms of clinical prognosis, this novel subtype is the lethal variant in the EBS category.

Epidermolysis Bullosa Simplex↗
PubMed2003

Characteristic immunohistochemical and ultrastructural findings indicate that Kindler's syndrome is an apoptotic skin disorder.

BACKGROUND: Kindler's syndrome is a rare genodermatosis mainly characterized by the onset of skin blistering in early childhood, web formation of fingers and toes, photosensitivity, and progressive poikiloderma. There is still debate whether this disease represents a distinctive entity in the spectrum of congenital bullous poikilodermas or a variant of dystrophic epidermolysis bullosa. OBJECTIVE: To evaluate the recently proposed and debated characteristic immunohistochemical and ultrastructural features of Kindler's syndrome. PATIENT/METHODS: Immunofluorescence (IF) antigen mapping and transmission electron microscopy (TEM) were performed on a skin specimen from non-sun-exposed inner aspect of the upper arm of a 49-year-old patient with characteristic clinical features of Kindler's syndrome. RESULTS: IF studies revealed focally an extensively broadened, partly reticular staining pattern in the dermoepidermal basement membrane zone (BMZ) with antibodies against laminin-5 and type IV as well as type VII collagen. Anti-alpha6 and beta4 integrin staining revealed small gaps in the linear reactivity in the BMZ. Abundant keratin bodies, as detected by anti-immunoglobulin M (IgM) staining, were focally present in the dermis, indicating prominent epidermal apoptosis. This was verified by a histochemical apoptosis stain [terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) reaction]. Transmission electron microscopic examination showed manifold reduplications of the lamina densa (with attached anchoring fibrils) as well as a keratin body surrounded by a fibroblast in the upper dermis. CONCLUSION: We present characteristic immunohistochemical and ultrastructural features of Kindler's syndrome identical to those described by Shimizu et al. and provide evidence that Kindler's syndrome might primarily be an apoptotic disorder of basal keratinocytes.

Apoptosis↗
PubMed2006

p63 regulates an adhesion programme and cell survival in epithelial cells.

p63 is critical for epithelial development yet little is known about the transcriptional programmes it regulates. By characterising transcriptional changes and cellular effects following modulation of p63 expression, we have defined a vital role for p63 in cellular adhesion. Knockdown of p63 expression caused downregulation of cell adhesion-associated genes, cell detachment and anoikis in mammary epithelial cells and keratinocytes. Conversely, overexpression of the TAp63gamma or deltaNp63alpha isoforms of p63 upregulated cell adhesion molecules, increased cellular adhesion and conferred resistance to anoikis. Apoptosis induced by loss of p63 was rescued by signalling downstream of beta4 integrin. Our results implicate p63 as a key regulator of cellular adhesion and survival in basal cells of the mammary gland and other stratified epithelial tissues.

Anoikis↗
PubMed1995

Integrin beta 4 mutations associated with junctional epidermolysis bullosa with pyloric atresia.

Pyloric atresia associated with junctional epidermolysis bullosa (PA-JEB), is a rare inherited disorder characterized by pyloric stenosis and blistering of the skin as primary manifestations. We demonstrate that in one PA-JEB patient the disease resulted from two distinct mutations in the beta 4 integrin gene alleles. The paternal mutation consists of a one base pair deletion causing a shift in the open reading frame, and a downstream premature termination codon. The maternal mutation occurs in a donor splice site, and results in in-frame exon skipping involving the cytoplasmic domain of the polypeptide. Our results implicate mutations in the beta 4 integrin gene in some forms of PA-JEB.

Alleles↗
PubMed2002

Differential gene expression profiles of gastric cancer cells established from primary tumour and malignant ascites.

Advanced gastric cancer is often accompanied by metastasis to the peritoneum, resulting in a high mortality rate. Mechanisms involved in gastric cancer metastasis have not been fully clarified because metastasis involves multiple steps and requires a combination of altered expressions of many different genes. Thus, independent analysis of any single gene would be insufficient to understand all of the aspects of gastric cancer peritoneal dissemination. In this study, we performed a global analysis of the differential gene expression of a gastric cancer cell line established from a primary main tumour (SNU-1) and of other cell lines established from the metastasis to the peritoneal cavity (SNU-5, SNU-16, SNU-620, KATO-III and GT3TKB). The application of a high-density cDNA microarray method made it possible to analyse the expression of approximately 21 168 genes. Our examinations of SNU-5, SNU-16, SNU-620, KATO-III and GT3TKB showed that 24 genes were up-regulated and 17 genes down-regulated besides expression sequence tags. The analysis revealed the following altered expression such as: (a) up-regulation of CD44 (cell adhesion), keratins 7, 8, and 14 (epitherial marker), aldehyde dehydrogenase (drug metabolism), CD9 and IP3 receptor type3 (signal transduction); (b) down-regulation of IL2 receptor gamma, IL4-Stat (immune response), p27 (cell cycle) and integrin beta4 (adhesion) in gastric cancer cells from malignant ascites. We then analysed eight gastric cancer cell lines with Northern blot and observed preferential up-regulation and down-regulation of these selected genes in cells prone to peritoneal dissemination. Reverse transcriptase-polymerase chain reaction confirmed that several genes selected by DNA microarray were also overexpressed in clinical samples of malignant ascites. It is therefore considered that these genes may be related to the peritoneal dissemination of gastric cancers. The results of this global gene expression analysis of gastric cancer cells with peritoneal dissemination, promise to provide a new insight into the study of human gastric cancer peritoneal dissemination.

Animals↗
PubMed2000

Linear IgA disease with IgA antibodies directed against 200- and 280-kDa epidermal antigens.

We report an 80-year-old man with the lamina lucida type of linear IgA disease, with IgA autoantibodies reactive with 200-kDa and 280-kDa epidermal proteins. The patient presented with widespread bullous lesions on his trunk and extremities without mucosal involvement. Histopathology of lesional skin showed a subepidermal blister with papillary microabscesses of neutrophils and a few eosinophils. Direct immunofluorescence microscopy of perilesional skin showed linear deposits of IgA and C3 at the basement membrane zone. The patient's serum contained IgA autoantibodies that bound exclusively to the epidermal side of 1 mol L-1 NaCl split skin as determined by indirect immunofluorescence microscopy. Circulating IgA autoantibodies to 200- and 280-kDa antigens were detected in the patient's serum by immunoblot analysis using extracts from normal human epidermis and human epidermal keratinocytes. These two antibodies, eluted from individual nitrocellulose membranes, reacted with the epidermal side of 1 mol L-1 NaCl split skin on indirect immunofluorescence microscopy, and bound to hemidesmosomes as determined by immunoperoxidase electron microscopy. This observation suggests the presence of hitherto uncharacterized 200- and 280-kDa hemidesmosomal proteins distinct from BPAG1, BPAG2 and beta4 integrin as target antigens in linear IgA disease.

Aged↗
PubMed1998

Successful prenatal exclusion of an unspecified subtype of severe epidermolysis bullosa.

BACKGROUND: In most cases of prenatal diagnosis of epidermolysis bullosa (EB), the subtype of severe EB from which the fetus is at risk is identified by studying the specimens of the proband. In this study, the parents of a child with an unspecified subtype of severe EB sought prenatal diagnosis for their second and third pregnancies. METHODS: The firstborn of a couple (the proband) suffered generalized blistering and erosions of the skin present from delivery, and died on the 11th postnatal day of severe EB of an unspecified type. The only diagnostic specimen available from the first infant was a conventionally stained skin section for light microscopy that showed the dermo-epidermal separation. For prenatal diagnosis in the second and third pregnancies, fetal skin biopsies were performed at 19 weeks of gestation. RESULTS: In both cases, fetal skin showed no ultrastructural abnormalities and no evidence of dermo-epidermal separation. Indirect immunofluorescence was positive for monoclonal antibodies against type VII collagen, laminin 5, uncein, alpha6 and beta4 integrins, BPAG2, and HD1/plectin, which are known to be reduced or absent in specific subsets of severe EB. The pregnancies were therefore continued, and normal healthy second and third children were delivered. CONCLUSIONS: Fetal skin biopsy, together with a panel of newly developed monoclonal antibodies, provided reliable prenatal diagnosis in the present family in which preliminary information of the EB proband was limited.

Biopsy↗
PubMed1998

The 97 kDa linear IgA bullous dermatosis antigen is not expressed in a patient with generalized atrophic benign epidermolysis bullosa with a novel homozygous G258X mutation in COL17A1.

The nature and expression pattern of the 97 kDa linear IgA bullous dermatosis antigen (LAD-1) and its role in epidermolysis bullosa have not been fully elucidated. In this study, we examined the expression of LAD-1 in the skin specimens of 70 patients with the various subtypes of epidermolysis bullosa, including simplex (n = 23), junctional (n = 15), and dystrophic variants (n = 32). For immunolabeling, we used two recently developed monoclonal antibodies to LAD-1 whose epitopes were ultrastructurally localized in the lamina lucida between NC16A and carboxyterminal domains of BPAG2, as well as autoantibodies against LAD-1 from the sera of two patients with linear IgA dermatosis. Among the 70 patients, only one patient with generalized atrophic benign epidermolysis bullosa failed to demonstrate LAD-1 expression. Although other major basement membrane components, including laminin 5, BPAG1, plectin, alpha6 and beta4 integrins, as well as type IV and type VII collagens were normally expressed, BPAG2/type XVII collagen was absent from the skin of this patient. Mutation analysis on COL17A1 using polymerase chain reaction amplification, heteroduplex scanning, and direct nucleotide sequencing revealed that this patient was homozygous for a novel nonsense mutation G258X in exon 11, and her parents were heterozygous carriers for this mutation. This is the first mutation located in the intracellular domain of BPAG2, and resides 817 bp upstream from the N-terminal amino acid sequence of LAD-1. These findings indicate that the absent expression of LAD-1 is observed in a BPAG2-deficient generalized atrophic benign epidermolysis bullosa patient with mutations in both alleles of COL17A1, and not in other epidermolysis bullosa subtypes. These findings also support the notion that LAD-1 is a degradation product of BPAG2.

Antigens↗
PubMed2001

Interactions of human prostatic epithelial cells with bone marrow endothelium: binding and invasion.

Prostate cancer shows a propensity to form secondary tumours within the bone marrow. Such tumours are the major cause of mortality in this disease. We have developed an in vitro system to study the binding of prostate epithelial cells to bone marrow endothelium (BME) and stroma (BMS). The metastatic prostate cancer cell line, PC3 (derived from a bone metastasis), was seeded onto confluent layers of BME and its binding characteristics compared to human umbilical vein endothelial cells (HUVEC), lung endothelium (Hs888Lu) and BMS. The PC3 cell line showed significantly increased binding to BME (P< 0.05) compared to endothelium derived from HUVEC and lung or BMS with maximal binding occurring at 1 h. Following pre-incubation with a beta1 integrin antibody PC3 binding to BME was inhibited by 64% (P< 0.001). Antibodies directed against the integrins beta4, alpha2, alpha4, alpha5 and the cellular adhesion molecules P-selectin, CD31, VCAM-1 and sialy Lewis X showed no effect on blocking PC3 binding. Primary prostatic epithelial cells from both malignant (n = 11) and non-malignant tissue (n = 11) also demonstrated equivalent levels of increased adhesion to BME and BMS compared to HUVEC, peaking at 24 h. Further studies examined the invasive ability of prostate epithelial cells in response to bone marrow endothelium using Matrigel invasion chamber assays. In contrast to the previous results, malignant cells showed an increase (1000 fold) in invasive ability, whilst non-malignant prostate epithelia did not respond. We have shown that both malignant and non-malignant prostate epithelial cells can bind at equivalent levels and preferentially to primary human bone marrow endothelium in comparison to controls. However, only malignant prostate epithelia show increased invasive ability in response to BME.

Adenocarcinoma↗