Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epidemiological and experimental studies suggest that diesel exhaust particles (DEPs) may be associated with increased respiratory mortality and morbidity. Several recent studies have also shown that DEPs increase the production of inflammatory cytokines by human bronchial epithelium (HBE) cells in vitro. The present study investigates the effects of DEPs on the interaction of l-HBE cells (16HBE14o-) with the cell and matrix microenvironment based on evaluation of integrin-type cell/matrix ligand expression, cytoskeleton (CSK) stiffness, and matrix remodeling via matrix metalloproteinase (MMP)-1, MMP-2, and MMP-9 expression. The results showed that DEP exposure induced: 1) a net dose-dependent decrease in CSK stiffness through actin fibers, 2) a concomitant specific reduction of both alpha(3)- and beta(1)-integrin subunits extensively expressed on the HBE cell surface, 3) a decrease in the level of CD44, which is a major HBE cell-cell and HBE cell-matrix adhesion molecule; and 4) an isolated decrease in MMP-1 expression without any change in tissue inhibitor of matrix metalloproteinase (TIMP)-1 or TIMP-2 tissue inhibitors. Restrictive modulation of cell-matrix interaction, cell-cell connection, CSK stiffness, and fibrillary collagen remodeling results in a decreased wound closure capacity and an increased deadhesion capacity. In conclusion, on the basis of these results, we can propose that, in addition to their ability to increase the production of inflammatory cytokines, DEPs could also alter the links between actin CSK and the extracellular matrix, suggesting that they might facilitate HBE cell detachment in vivo.
Am J Physiol Lung Cell Mol Physiol 2003 Jan
PMID:Negative impact of DEP exposure on human airway epithelial cell adhesion, stiffness, and repair. 1247 Oct 14

The development of cell polarity in response to chemoattractant stimulation in human polymorphonuclear neutrophils (PMNs) is characterized by the rapid conversion from round to polarized morphology with a leading lamellipod at the front and a uropod at the rear. During PMN polarization, the microtubule (MT) array undergoes a dramatic reorientation toward the uropod that is maintained during motility and does not require large-scale MT disassembly or cell adhesion to the substratum. MTs are excluded from the leading lamella during polarization and motility, but treatment with a myosin light chain kinase inhibitor (ML-7) or the actin-disrupting drug cytochalasin D causes an expansion of the MT array and penetration of MTs into the lamellipod. Depolymerization of the MT array before stimulation caused 10% of the cells to lose their polarity by extending two opposing lateral lamellipodia. These multipolar cells showed altered localization of a leading lamella-specific marker, talin, and a uropod-specific marker, CD44. In summary, these results indicate that F-actin- and myosin II-dependent forces lead to the development and maintenance of MT asymmetry that may act to reinforce cell polarity during PMN migration.
Mol Biol Cell 2002 Dec
PMID:Microtubule asymmetry during neutrophil polarization and migration. 1247 66

Prostate stem cell antigen (PSCA, named for its strong sequence homology to the thymocyte marker stem cell antigen 2) is a cell surface antigen expressed in normal prostate and associated with human and murine prostate cancer. To begin to investigate a possible link between PSCA expression in normal prostate and prostate carcinogenesis, we characterized the phenotype and proliferative behavior of normal PSCA-expressing prostate epithelial cells (PrEC) in tissue culture. PSCA was expressed in a subset of prostate epithelial cells that coexpress basal and secretory cytokeratins. PSCA-positive cells were the direct progeny of PSCA-negative cells and were characterized by a more differentiated morphology and a slower proliferative rate than PSCA-negative cells. Although PSCA-positive cells continued to express basal cell markers such as CD44, they lost expression of the basal cell marker p63. In contrast, expression of prostate specific antigen and androgen receptor transcripts was detectable in PSCA-positive PrEC. These findings suggest that PSCA is a unique marker of an intermediate subpopulation of PrEC in transition from a basal to a terminally differentiated secretory phenotype and may be a useful marker for the study of normal and malignant prostate development.
Mol Cancer Res 2002 Dec
PMID:Prostate stem cell antigen is a marker of late intermediate prostate epithelial cells. 1249 58

Cell-adhesion molecules, once believed to function primarily in tethering cells to extracellular ligands, are now recognized as having broader functions in cellular signalling cascades. The CD44 transmembrane glycoprotein family adds new aspects to these roles by participating in signal-transduction processes--not only by establishing specific transmembrane complexes, but also by organizing signalling cascades through association with the actin cytoskeleton. CD44 and its associated partner proteins monitor changes in the extracellular matrix that influence cell growth, survival and differentiation.
Nat Rev Mol Cell Biol 2003 Jan
PMID:CD44: from adhesion molecules to signalling regulators. 1251 67

Osteopontin (OPN) was expressed in murine wild-type osteoclasts, localized to the basolateral, clear zone, and ruffled border membranes, and deposited in the resorption pits during bone resorption. The lack of OPN secretion into the resorption bay of avian osteoclasts may be a component of their functional resorption deficiency in vitro. Osteoclasts deficient in OPN were hypomotile and exhibited decreased capacity for bone resorption in vitro. OPN stimulated CD44 expression on the osteoclast surface, and CD44 was shown to be required for osteoclast motility and bone resorption. Exogenous addition of OPN to OPN-/- osteoclasts increased the surface expression of CD44, and it rescued osteoclast motility due to activation of the alpha(v)beta(3) integrin. Exogenous OPN only partially restored bone resorption because addition of OPN failed to produce OPN secretion into resorption bays as seen in wild-type osteoclasts. As expected with these in vitro findings of osteoclast dysfunction, a bone phenotype, heretofore unappreciated, was characterized in OPN-deficient mice. Delayed bone resorption in metaphyseal trabeculae and diminished eroded perimeters despite an increase in osteoclast number were observed in histomorphometric measurements of tibiae isolated from OPN-deficient mice. The histomorphometric findings correlated with an increase in bone rigidity and moment of inertia revealed by load-to-failure testing of femurs. These findings demonstrate the role of OPN in osteoclast function and the requirement for OPN as an osteoclast autocrine factor during bone remodeling.
Mol Biol Cell 2003 Jan
PMID:Osteopontin deficiency produces osteoclast dysfunction due to reduced CD44 surface expression. 1252 35

Hybridization with cDNA arrays was used to obtain expression profiles of 263 protein-tyrosine kinase (PTK), protein-tyrosine phosphatase (PTP), dual-specific phosphatase (DuSP), and other genes for the normal prostate tissue, primary prostate carcinomas (PC) of 84 patients, 7 xenografts, and 5 carcinoma cell lines. Analysis of 96 profiles revealed eight clusters of genes coexpressed in PC (coefficient of correlation r > 0.7). According to the known functions of their genes, the clusters were designated as proliferating-cell (CDC42, TOP2A, FGFR3, MYC, etc.), neoangiogenesis and blood-cell (LCK, VAV1, KDR, VEGF, MMP9, SYK, PTPRS, and FLT4), invasion-1 and invasion-2 (ADAM17, TRPM2, DUSP6, VIM, CAV1, CAV2, JAK1, PTPNS1, FYN, and PDGFB), HER2, and PSA/PSM/HER3. Basing on expression profiles of 66 genes, a molecular classification of PC was constructed and allowed discrimination between PC and cell lines or xenografts at 98.9% probability. The results suggested that, along with PSA, PSM (FOLH1), kallikrein-2, and a-2-macroglobulin, cell signaling genes EGFR, HER2, HER3, TOP2, KRT8, KRT18, VEGF, CD44, VIM, CAV1, and CAV2 may serve as diagnostic and prognostic markers in PC. The HER2, VEGF, and CD44 genes and the MMP and ADAM families were assumed to be promising targets for inhibitors of PC cell proliferation and metastasis.
Mol Biol (Mosk)
PMID:[Gene expression profiles of protein kinases and phosphatases obtained by hybridization with cDNA arrays: molecular portrait of human prostate carcinoma]. 1262 52

With an own histological classification of rheumatoid arthritis (RA) in synovial membranes (SM) of two main types: type I (B-lymphocytic and plasma cellular, local non-destructive, better prognosis); type II (T-lymphocytic, macrophacytic, local destructive, worse prognosis) and type III as a mixed one we examined whether there is a relation between special adhesion molecules and any of this histological types. 32 fresh cryo-conserved RA-SM (type I, II, III; n = 9, 11, 12, respectively) were investigated immunohistochemically using the APAAP method in order to obtain the expression of LFA-1, VCAM-1, CD44 and E-selectin. Positive cells were counted morphometrically within six histological areas: lining layer, subintimal, perivascular, lymphatic follicles, perifollicular and interstitial. Type II showed a significant higher expression than type I for LFA-1 in lining layer and subintimal II (65%; 53% vs 0%; 32%); for VCAM-1 in subintimal, perifollicular, perivascular and interstitial areas (61%, 54%, 58%, 61% vs 6%, 8%, 5%, 6%). In lining layer and lymphatic follicles no significant difference between both types was detected. CD44 and E-selectin: No statistical differences could be found. RA-SM type II shows high expression of LFA-1 and VCAM-1, this is related to a higher destructive process.
Cell Mol Biol (Noisy-le-grand) 2002
PMID:Strong LFA-1 and VCAM-1 expression in histological type II of rheumatoid arthritis. 1264 40

Although hyaluronan (HA), a high molecular weight glycosaminoglycan, is generally believed to regulate tumor growth, invasion, and metastasis, functional roles of HA have only been speculated indirectly from the outcome of blocking HA receptors (e.g., CD44). Using a phage display technique, we recently developed a synthetic peptide (GAHWQFNALTVR; Pep-1) that binds to and inhibits the function of HA. In this study, we have used Pep-1 to determine whether HA directly regulates the behavior of tumor cells. B16-F10 melanoma cells, which constitutively expressed CD44, showed significant adhesion to HA-coated plates, and this adhesion was blocked almost completely either by neutralizing antibodies against CD44 or by Pep-1. These results imply that CD44 is the primary HA receptor mediating the adhesive interaction of the melanoma cells with HA substrates. In contrast, Pep-1 failed to inhibit in vitro proliferation of B16-F10 melanoma cells or the in vitro growth of the cells after s.c. inoculation in mice. Importantly, single injection of Pep-1 significantly reduced the incidence of lung metastasis of i.v. inoculated melanoma cells and prolonged the survival of the tumor-bearing animals. These results suggest a direct contribution of HA to one or more steps in the initial seeding of melanoma cells in the lung microenvironment. Our observations also introduce a new concept that synthetic inhibitors of HA may represent unique tools for studying the roles of HA in tumor biology and perhaps a new class of therapeutic reagents.
Mol Cancer Ther 2003 Mar
PMID:Functional roles of hyaluronan in B16-F10 melanoma growth and experimental metastasis in mice. 1265 24

Overexpression of the cell adhesion protein CD44v6 has been demonstrated in colorectal cancer and other gastrointestinal tumors. While CD44v6 is upregulated in benign colorectal adenomas and well-differentiated colorectal cancer tissues, downregulation frequently occurs during disease progression. The mechanism of downregulation, however, is unknown. Therefore, we evaluated the methylation status of the CD44 promoter as a mechanism for decreased CD44v6 expression in advanced colorectal carcinomas. We demonstrated by methylation-sensitive restriction enzyme digestion that the CpG islands of the CD44 promoter were methylated in 6/21 (28%) of benign colorectal adenomas. Interestingly, in colorectal carcinomas the frequency of promoter methylation was significantly increased (10/19; 53%) compared to 7/21 (33%) in the corresponding normal mucosa. Methylation seems to be associated with a more advanced cancer stage, but the trend did not reach statistical significance. In colorectal carcinomas with CD44 promoter methylation CD44v6 mRNA was detected by reverse transcription-polymerase chain reaction in 3/10 carcinomas, whereas in tumors without CD44 promoter methylation CD44v6 expression was observed in 8/9 (P <or= 0.05). These results demonstrated that methylation of the 5'CpG island of the CD44 gene is closely associated with decreased expression of CD44v6 in human colorectal carcinomas.
Exp Mol Pathol 2003 Jun
PMID:Downregulation of CD44v6 in colorectal carcinomas is associated with hypermethylation of the CD44 promoter region. 1278 13

In airways, the cell surface molecule CD44 is upregulated on bronchial epithelial cells in areas of damage. We have shown that a blocking standard CD44 (CD44s) antibody caused a 77% (+/- 19%) inhibition of cell migration at 3 h after mechanical damage and decreased epithelial cell repair of cells grown on cell culture filter inserts. With the use of primary human bronchial epithelial cells and the bronchial epithelial cell line 16HBE 14o-, a CD44s antibody inhibited >95% (P < 0.01) of cell binding to hyaluronic acid (HA). The cytokines TNF-alpha, IFN-gamma, IL-1 beta, and IL-4 stimulated a 2- to 3.5-fold increase in CD44-dependent cell binding to HA. IFN-gamma treatment did not increase CD44 expression as assessed by flow cytometry, although phorbol myristate acetate treatment did. This indicates that IFN-gamma-induced cell binding to HA did not require increased CD44 expression. These data indicate that CD44 is important for bronchial epithelial cell binding to HA and that cytokines known to be expressed in inflammation can increase HA binding independently of the level of CD44 expression.
Am J Physiol Lung Cell Mol Physiol 2003 Dec
PMID:Inflammatory cytokines can enhance CD44-mediated airway epithelial cell adhesion independently of CD44 expression. 1290 89


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