Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Integrin-associated protein (IAP) is a receptor for the carboxyl-terminal "cell-binding domain" (CBD) of thrombospondin 1 (TS1). IAP associates with alpha v beta 3 integrin and mAbs against IAP inhibit certain integrin functions. Here we examine the effects of the TS1 CBD and 4N1K (KRFYVVMWKK), a cell-binding peptide derived from it, on the adhesion and spreading on vitronectin (VN) of C32 human melanoma cells which express IAP, alpha v beta 3, and alpha v beta 5. Cells adhere to VN at low surface densities via alpha v beta 5 and spread very slowly while adhesion to higher density VN involves both alpha v beta 5 and alpha v beta 3 and results in rapid spreading. Spreading of the cells, but not adhesion, on sparse VN coatings is markedly enhanced by the presence of soluble TS1, the recombinant CBD and 4N1K, but not the "mutant" peptide 4NGG, KRFYGGMWKK, which fails to bind IAP. This enhanced spreading is completely blocked by mAb LM609 against alpha v beta 3 and the anti-IAP mAb B6H12. Correlated with this enhanced spreading is increased tyrosine phosphorylation of focal adhesion kinase (FAK), paxillin, and a protein of ca. 90 kD. The enhanced spreading induced by TS1 and 4N1K and the constitutive spreading on higher density VN are both blocked by calphostin C (100 nM), wortmannin (10 nM), and tyrosine kinase inhibitors. In contrast, pertussis toxin specifically blocks only the TS1 stimulated spreading on low density VN, indicating that IAP exerts its effects on signal transduction via a heterotrimeric Gi protein acting upstream of a common cell spreading pathway which includes PI-3 kinase, PKC, and tyrosine kinases.
 ...
PMID:Thrombospondin modulates alpha v beta 3 function through integrin-associated protein. 889 8

Tumour cell arrest and the formation of stable adhesive interactions between tumour cells and endothelial cells or underlying matrix in the microvasculature are crucial steps in the metastatic process. We have developed a sensitive hydrodynamic adhesion assay to investigate the regulation of melanoma cell adhesion stabilization to the extracellular matrix protein fibronectin. Modulators of human MeWo melanoma Ca2+ concentration and stores, including ionomycin, thapsigargin, dantrolene and caffeine, inhibited cell adhesion stabilization to fibronectin; however, removal of Ca2+ from the extracellular medium did not affect stabilization. The calmodulin inhibitor W-7 and the protein kinase C inhibitor chelerythrine also blocked MeWo adhesion stabilization to fibronectin, as did the tyrosine kinase inhibitor genistein and the cytoskeletal inhibitor cytochalasin D. Manipulation of MeWo cell intracellular CAMP levels had no effect of adhesion stabilization to fibronectin, nor did treatment of cells with phorbol ester, pertussis toxin or cholera toxin. Drug treatments that inhibited adhesion stabilization also had significant effects on the actin cytoskeleton organization of the melanoma cells. This study suggests a role for calcium, calmodulin, protein kinase C and tyrosine kinases in the intracellular regulation of MeWo adhesive stabilization.
Melanoma Res 1996 Oct
PMID:Regulation of melanoma cell adhesion stabilization to fibronectin. 890 95

Internalization of the urokinase-type plasminogen activator (uPA) requires two receptors, the uPA receptor (uPAR) and the low density lipoprotein receptor-related protein (LRP)/alpha2-macroglobulin (alpha2M) receptor. Here, we address whether protein kinases are involved in the internalization of uPA by human melanoma cells. Initially, we found that the internalization of uPA was significantly inhibited by the serine/threonine protein kinase inhibitors staurosporine, K-252a and H-89, but not by the tyrosine kinase inhibitors, genistein and lavendustin A. Internalization of uPA was also inhibited by a pseudosubstrate peptide for cAMP-dependent protein kinase (PKA), but not by a pseudosubstrate peptide for protein kinase C. We confirmed a requirement for PKA-activity and implicated a specific isoform by using an antisense oligonucleotide against the regulatory subunit RI alpha of PKA which suppresses PKA-I activity. Exposure of cells to this oligonucleotide led to a specific, dose-dependent decrease in RI alpha protein and to a significant inhibition in the rate of uPA internalization. We further demonstrate that treatment of melanoma cells with either H-89 or PKA RI alpha antisense oligonucleotides also resulted in a decreased internalization of two other ligands of LRP, activated alpha2M and lactoferrin, indicating that PKA activity is associated with LRP. Finally, we demonstrate that PKA activity is also required for the internalization of transferrin, but not for the internalization of the epidermal growth factor or adenovirus 2, suggesting that in melanoma cells, PKA activity is not generally required for clathrin-mediated endocytosis, but is rather associated with specific internalization receptors.
 ...
PMID:Receptor-mediated endocytosis of urokinase-type plasminogen activator is regulated by cAMP-dependent protein kinase. 921 25

The c-kit gene encodes a transmembrane receptor that has tyrosine kinase activity. c-kit plays a role in hematopoiesis, gametogenesis, and melanogenesis. c-kit is found in melanocytes, and there is evidence that expression is lost in melanoma. We studied 85 melanocytic lesions for c-kit by immunohistochemical techniques using a monoclonal antibody. The lesions included banal nevi, junctional and compound nevi with melanocytic dysplasia, nontumorigenic radial growth phase melanoma, tumorigenic vertical growth phase melanoma, and metastatic melanoma. We found intense membrane staining in normal melanocytes and mast cells. Staining in compound nevi was strongest in junctional and superficial dermal components, whereas dermal nevi showed weak reactivity. Dysplastic nevi stained strongly, particularly in junctional cells. In melanoma, strong reactivity was most prominent in radial growth phase disease, but there was little or no staining in vertical growth phase and metastatic melanomas. In summary, c-kit protein is expressed in normal melanocytes, benign nevi, dysplastic nevi and nontumorigenic melanoma, but expression is lost in tumorigenic primary melanomas and metastases. The role of c-kit loss in advanced melanoma requires additional investigation.
 ...
PMID:Proto-oncogene c-kit expression in malignant melanoma: protein loss with tumor progression. 931 Sep 59

Small peptides, 8-10 amino acids long, derived from degradation of cytoplasmic proteins by a proteasome-proteinase complex, are usually presented and recognized by CD8+ cytolytic T lymphocytes (CTLs) associated with major histocompatibility complex (MHC) class I molecules. Recently synthetic peptides were used for the in vitro induction of tumor-specific CTLs, offering another strategy in the study of the immune-response repertoire and providing a new tool in cancer vaccination and immunotherapy. Peptides derived from otherwise normal proteins, overexpressed in many tumors as products of the protooncogene, may represent a target for an immune response. This is the case of HER-2/neu gene (also known as ErbB-2), encoding a cysteine-rich glycoprotein transmembrane receptor with tyrosine kinase activity (gp185neu). Recent data, demonstrating that HLA-A2.1-related peptides are able to stimulate in vitro CD8+ lymphocytes, Prompted us to study the binding to HLA-A2.1 molecules of several gp185 synthetic peptides containing a cystein residue and to define the relevance of this amino acid residue in the reduced or oxidated form of the sulfhydryl group. We found that monomers and their homodimers, linked by a disulfide bridge, bind to HLA-A2.1 molecules with overlapping affinity. These results suggest that additional amino acids of the nonapeptide do not prevent the binding and the HLA refolding through chemical or sterical interactions. This might be of particular relevance for the in vivo processing of cysteine-rich proteins. Because ErbB-2 molecules, as tumor-differentiation antigens in melanoma, are cysteine-rich molecules, it may be relevant to evaluate the possible role of the cystine residues interacting with the T-cell receptor. The recognition of these heterodimers by CD8+ lymphocytes will require functional in vivo studies.
 ...
PMID:MHC-peptide binding: dimers of cysteine-containing nonapeptides bind with high affinity to HLA-A2.1 class I molecules. 940 48

The ligation of available alpha6beta1 integrin in adherent LOX melanoma cells by laminin G peptides and integrin stimulatory antibodies induced cell invasiveness, independent of adhesion activity of integrins that were pre-bound to extracellular matrix (Nakahara, H., Nomizu, M., Akiyama, S. K., Yamada, Y., Yeh, Y., and Chen, W.-T. (1996) J. Biol. Chem. 271, 27221-27224). Here, we show that this induced invasion involves an increase in tyrosine phosphorylation of a 190-kDa GTPase-activating protein for Rho family members (p190(RhoGAP); p190) and membrane-protrusive activities at invadopodia. This tyrosine phosphorylation does not occur when the adherent cells are treated with non-activating antibody against beta1 integrin, control laminin peptides, or tyrosine kinase inhibitors genistein and herbimycin A. Although p190 and F-actin co-distribute in all cell cortex extensions, tyrosine-phosphorylated proteins including p190 appear to associate with F-actin specifically in invadopodia. In addition, the localized matrix degradation and membrane-protrusive activities were blocked by treatment of LOX cells with tyrosine kinase inhibitors as well as microinjection of antibodies directed against p190 but not by non-perturbing antibodies or control buffers. We suggest that activation of the alpha6beta1 integrin signaling regulates the tyrosine phosphorylation state of p190 which in turn connects downstream signaling pathways through Rho family GTPases to actin cytoskeleton in invadopodia, thus promoting membrane-protrusive and degradative activities necessary for cell invasion.
 ...
PMID:Activation of beta1 integrin signaling stimulates tyrosine phosphorylation of p190RhoGAP and membrane-protrusive activities at invadopodia. 941 37

Recent reports show that alpha-MSH (melanocyte-stimulating hormone) is mitogenic and melanogenic for normal human melanocytes, and that this effect is mediated through binding to the melanocortin receptor (MC1R) and activation of cAMP formation. alpha-MSH has also been shown to induce changes in cell shape in melanocytes and melanoma cells, particularly increased dendricity, suggesting a potential role for alpha-MSH in melanocyte-matrix interactions and pigment transfer through reorganization of the melanocyte actin filament cytoskeleton. In this report we show that the potent alpha-MSH analog (Nle4, D-Phe7)-alpha-MSH (NDP-MSH) induces reorganization of the actin stress fiber cytoskeleton in treated human melanocytes and that this reorganization is associated with increased adhesion to fibronectin (FN). Because most melanocyte growth factors act synergistically on melanocyte mitogenesis, we also sought to determine the effect of the melanocyte mitogen endothelin-1 (ET-1) on the melanocyte actin cytoskeleton, melanocyte adhesion, and melanocyte migration. We show that ET-1, which increases melanocyte migration on FN, has opposite effects on melanocyte adhesion to FN compared with NDP-MSH and that endothelin-1-induced actin reorganization is distinct from that observed following NDP-MSH treatment. Finally, we show that focal adhesion kinase (pp125FAK), a nonreceptor tyrosine kinase associated with focal contact formation and cell migration, is phosphorylated on tyrosine residues after treatment of melanocytes with ET-1, but not NDP-MSH. These data indicate that while alpha-MSH and ET-1 act synergistically to modulate melanocyte proliferation, they have opposite effects on melanocyte-matrix interactions.
 ...
PMID:Alpha-melanocyte-stimulating hormone and endothelin-1 have opposing effects on melanocyte adhesion, migration, and pp125FAK phosphorylation. 941 62

The 9E3/CEF4 gene codes for a chemokine that is highly homologous to human interleukin-8 and melanoma growth-stimulating activity/groalpha. These chemokines belong to a family of molecular mediators that are importantly involved in inflammation, wound healing, tumor development, and viral entry into cells. On the chorioallantoic membrane the 9E3 protein is chemotactic for monocyte/macrophages and lymphocytes and is angiogenic. In cultured chicken embryo fibroblasts, which have many of the properties of wound fibroblasts, the gene is stimulated by a variety of agents including oncogenes, growth factors, phorbol esters, and thrombin. The strong stimulation of 9E3 by thrombin in culture correlates well with the observation that in young chicks this gene is stimulated to very high levels in fibroblasts upon wounding and remains high throughout wound repair. Activation of 9E3 by thrombin: (i) occurs very rapidly, one minute exposure to thrombin is sufficient to initiate the signals necessary for gene activation; (ii) is independent of mitogenesis; (iii) operates through the proteolytically activated receptor for thrombin; (iv) is mediated by tyrosine kinases, including c-src and the epidermal growth factor (EGF) receptor, rather than Ser/Thr kinases such as protein kinase C and protein kinase A. Inhibition of either c-src or the EGF receptor tyrosine kinase inhibits the stimulation of 9E3 by thrombin. We show here for the first time that activation of the EGF receptor through a cell-surface receptor that does not have tyrosine kinase activity can lead to expression of an immediate early response gene which encodes for a secreted protein, a chemokine. This rapidly activated tyrosine kinase pathway may be a general stress response by which in vivo a localized cell population reacts to emergency situations such as viral infection, wounding, or tumor growth.
 ...
PMID:Thrombin aivation of the 9E3/CEF4 chemokine involves tyrosine kinases including c-src and the epidermal growth factor receptor. 947 78

Differentiation therapy is an attractive option for malignant melanoma, as traditional forms of chemotherapy seem to have little effect on this type of tumour. Among the several pathways for the experimental induction of differentiation of melanoma, we have focused on signal transduction mediated by protein kinases. We have examined the effects of calphostin C (a protein kinase C inhibitor), genistein and methyl 2,5-dihydroxycinnamate (tyrosine kinase inhibitors), and exogenous phosphotyrosine (an activator of protein tyrosine phosphatases) on the growth, morphology and differentiation of malignant melanomas in vitro. All four compounds tested were able to inhibit cell proliferation, but only genistein and methyl 2,5-dihydroxycinnamate were able to induce morphological changes, yielding a more dendritic or a rounder phenotype, respectively. The latter two drugs were also able to induce specific cell-cycle alterations, in contrast to calphostin C and phosphotyrosine. Melanin content was increased greatly in phophotyrosine treated cells and, to a smaller extent, in cells treated with genistein. RNA expression of specific genes encoding cytolytic T-cell antigens was not altered by the two tyrosine kinase inhibitors, in spite of the phenotypic changes observed. Together, these results suggest that tyrosine kinases are involved in cell cycle, growth, and differentiation pathways in malignant melanomas; however, these pathways may not be co-dependent. The results also suggest that these pathways may be sensitive to specific tyrosine kinase inhibitors or activators of protein tyrosine phosphatases.
Melanoma Res 1997 Aug
PMID:Cell differentiation and cell-cycle alterations by tyrosine kinase inhibitors in human melanoma cells. 957 14

Thrombospondin 1 (TSP1) is an angiogenesis inhibitor that decreases tumor growth. We now report that TSP1 directly inhibits the proliferation of human melanoma cells. TSP1, peptides, and a recombinant fragment from the type I repeats, but not peptides that bind CD36 or CD47, inhibit the proliferation of A2058 melanoma cells. In contrast, chemotaxis is mediated by peptides or recombinant fragments from the procollagen, type I, type II, and cell-binding domains. The antiproliferative activity of TSP1 is mediated by a different signal transduction pathway than those mediating motility responses to the same protein. Activators of protein kinase A and protein kinase C inhibit chemotaxis but not the antiproliferative activity of TSP1, whereas the antiproliferative activity is reversed by inhibiting the tyrosine kinase or phosphatase activities. TSP1-mediated chemotaxis is partially dependent on a pertussis toxin (PT)-sensitive G-binding protein, whereas haptotaxis is not. Chemotaxis stimulated by the procollagen domain and the CD47-binding sequences from the COOH-terminal domain are also sensitive to PT, but responses to the type I and type III domains are not sensitive to PT. Residual chemotaxis to TSP1 in the presence of PT may therefore be mediated by the activities of the type I or type III repeats. Thus, TSP1 elicits several intracellular signals in melanoma cells that result from interactions with several domains of this protein and differentially affect growth and motility.
 ...
PMID:Differential roles of protein kinase C and pertussis toxin-sensitive G-binding proteins in modulation of melanoma cell proliferation and motility by thrombospondin 1. 967 84


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>