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

A number of antigens recognized by tumor-reactive T cells have recently been identified. The antigens identified in mouse model systems appear, with one exception, to represent the products of mutated genes. In contrast, most of the antigens recognized by human tumor-reactive T cells reported to date appear to represent the products of non-mutated genes. Here we report the isolation of a cDNA clone encoding beta-catenin, which was shown to be recognized by the tumor-infiltrating lymphocyte (TIL) 1290, a HLA-A24 restricted melanoma-specific CTL line from patient 888. The cDNA clone, which was isolated from the autologous melanoma cDNA library, differed by a single base pair from the published beta-catenin sequence, resulting in a change from a serine to a phenylalanine residue at position 37. Normal tissues from this patient did not express the altered sequence, nor did 12 allogeneic melanomas, indicating that this represented a unique mutation in this patient's melanoma. A peptide corresponding to the sequence between amino acids 29 and 37 of the mutant gene product was identified as the T cell epitope recognized by TIL 1290. The observation that HLA-A24 binding peptides contain an aromatic or hydrophobic residue at position 9 suggested that the change at position 37 may have generated a peptide (SYLDSGIHF) which was capable of binding to HLA-A24, and a competitive binding assay confirmed this hypothesis. The beta-catenin protein has been shown previously to be involved in cell adhesion mediated through the cadherin family of cell surface adhesion molecules. The high frequency of mutations found in members of cellular adhesion complexes in a variety of cancers suggests that these molecules may play a role in development of the malignant phenotype.
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PMID:A mutated beta-catenin gene encodes a melanoma-specific antigen recognized by tumor infiltrating lymphocytes. 864 60

Proteolytic enzymes are believed to be necessary for tumor cell invasion. We have studied the effects of the cysteine proteinase inhibitor E-64 and the serine and cysteine proteinase inhibitor leupeptin, on the ability of human malignant melanoma cells (LOX) to pass through an artificial basement membrane. Transwell chambers containing filters coated with the reconstituted basement membrane, Matrigel, were used. Nontoxic concentrations of the proteinase inhibitors reduced the invasion of LOX cells through Matrigel. E-64 (250 mumol/l) by 27% and leupepetin (250 micrograms/ml) by 46%. The proteinase inhibitors did not alter the growth rate of the tumor cells, their motility through uncoated filters, or their attachment to the Matrigel coated wells. Our results indicate that cysteine proteinases are involved in the degradation of basement membranes and thus contribute to the invasion of malignant melanoma cells.
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PMID:Cysteine proteinase inhibitors reduce malignant melanoma cell invasion in vitro. 871 80

Chlorophyll (Chl) and bacteriochlorophyll (Bchl) have been made water soluble by transesterification with serine (Ser) at the propionyl residue and tested as potential reagents for photodynamic therapy (PDT). Photocytotoxicity of the conjugates Chl-Ser and Bchl-Ser in M2R mouse melanoma was tested in cell cultures. Tissue uptake and clearance of the photosensitizers in CD1 nude and C57B1 mice implanted with M2R tumors are described. Photocytotoxicity in cell cultures was determined microscopically and by [3H]thymidine incorporation. The LD50 values in vitro were 0.05-0.1 microM for both sensitizers while that of the commercially available hematoporphyrin derivative (HPD, Photosan) was over 100 times higher for the same light intensity (45 mW/cm2). Pigment concentrations were determined fluorometrically in acetone extracts of the tissues of interest at different times after intraperitoneal injection of 20 mg pigment/kg body weight. The distribution pattern of Chl-Ser in the different tissues resembled that reported for Photofrin, chlorin and bacteriochlorin derivatives. Clearance from normal tissues was essentially completed within 16 h for Bchl-Ser and 72 h for Chl-Ser with mean half-lives (t 1/2) of about 2 and 7 h, respectively. In contrast, the clearance rates of these pigments and their metabolites from melanoma tumor tissue were significantly longer: t 1/2 = 20 h for Chl-Ser and 15 h for Bchl-Ser and metabolites. The clearance rates showed biphasic or single exponential decay patterns in normal tissues and in tumors, respectively. Cumulatively the high phototoxicity, simple mode of delivery and fast tissue clearance rates reported here suggest that polar conjugates of Chl and Bchl promise to be highly effective PDT reagents.
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PMID:Serine conjugates of chlorophyll and bacteriochlorophyll: photocytotoxicity in vitro and tissue distribution in mice bearing melanoma tumors. 878 11

We reported previously that stereoisomers of 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), the D-threo and L-threo forms, exerted inhibitory and stimulatory effects on glycosphingolipid (GSL) biosynthesis in B16 melanoma cells, respectively. In the present study, the primary cultured rat neocortical explants were treated with L- or D-threo-PDMP. These isomers exhibited opposite effects on neurite outgrowth: D-PDMP was inhibitory at concentrations ranging from 5 to 20 microM, whereas L-PDMP was stimulatory over the same concentration range, and the maximal effect was observed at 10-15 microM. Rat neocortical explants were doubly labeled with [14C]serine and [3H]galactose at 15 microM L- or D-PDMP. L-PDMP increased the incorporations of both labels into sphinganine, sphingosine, ceramide, sphingomyelin, neutral GSLs, and gangliosides, whereas D-PDMP inhibited the glucosylation of ceramide resulting in a reduction of ganglioside biosynthesis and accumulation of precursors of glucosylceramide, ceramide, and sphingomyelin. To clarify the stimulatory effect of L-PDMP on GSL biosynthesis, serine palmitoyltransferase, sphingosine N-acyltransferase, glucosylceramide synthase, lactosylceramide synthase, GM3 synthase, and GD3 synthase were quantified in cell lysates of explants pretreated with this agent. Serine palmitoyltransferase was fully activated up to 150% of the control. Furthermore, marked increases in the activities of lactosylceramide synthase (200%), GM3 synthase (240%), and GD3 synthase (300%) were observed. These results suggest that the neurotrophic action of L-PDMP may be ascribable to its stimulatory effect on the biosynthesis of GSLs, especially that of gangliosides.
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PMID:Induction of ganglioside biosynthesis and neurite outgrowth of primary cultured neurons by L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol. 886 86

The 170-kDa membrane-bound gelatinase, seprase, is a cell surface protease, the expression of which correlates with the invasive phenotype of human melanoma and carcinoma cells. We have isolated seprase from cell membranes and shed vesicles of LOX human melanoma cells. The active enzyme is a dimer of N-glycosylated 97-kDa subunits. Sequence analysis of three internal proteolytic fragments of the 97-kDa polypeptide revealed up to 87.5% identity to the 95-kDa fibroblast activation protein alpha (FAPalpha), the function of which is unknown. Thus, we used reverse transcription-polymerase chain reaction to generate a 2.4-kilobase cDNA from LOX mRNA with FAPalpha primers. COS-7 cells transfected with this cDNA expressed a 170-kDa gelatinase that is recognized by monoclonal antibodies directed against seprase. Sequence analysis also showed similarities to the 110-kDa subunit of dipeptidyl peptidase IV (DPPIV). Like DPPIV, the gelatinase activity of seprase was completely blocked by serine-protease inhibitors, including diisopropyl fluorophosphate. Seprase could be affinity-labeled by [3H]diisopropyl fluorophosphate, but the proteolytically inactive 97-kDa subunit could not, confirming the existence of a serine protease active site on the dimeric form. Proteolytic activity is lost upon dissociation into its 97-kDa subunit following treatment with acid, heat, or cysteine and histidine-modifying agents. We conclude that seprase, FAPalpha, and DPPIV are related serine integral membrane proteases and that seprase is similar to DPPIV, the proteolytic activities of which are dependent upon subunit association.
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PMID:Identification of the 170-kDa melanoma membrane-bound gelatinase (seprase) as a serine integral membrane protease. 906 13

We have characterized the ligand-enhanced phosphorylation of the CXC chemokine receptor-2 (CXCR2) in a series of clonal 3ASubE cell lines expressing receptors truncated or mutated in the carboxyl-terminal domain. Truncation of CXCR2 by substitution of a stop codon for Ser-342 (342T) or Ser-331 (331T) results in total loss of melanoma growth stimulatory activity/growth-related protein (MGSA/GRO)-enhanced receptor phosphorylation, which cannot be explained based upon altered ligand binding affinity or receptor number. 3ASubE cells expressing 342T or CXCR2 with mutation of Ser-342, -346, -347, and -348 to alanine (4A) exhibit strong mobilization of Ca2+ in response to ligand (interleukin-8 or MGSA/GRO), with a recovery phase significantly slower than that of cells expressing wild type (WT) CXCR2. In contrast to the WT CXCR2, which is 93% desensitized by 20 nM ligand, the 331T, 342T, and 4A CXCR2 mutants do not undergo significant ligand-induced desensitization, and respond to a second ligand challenge by mobilizing Ca2+. The 3ASubE cells expressing CXCR2 with mutation of Ser-346, -347, and -348 to alanine, or with mutation of only one serine in this domain, continue to be phosphorylated in response to ligand and are 60-70% desensitized following the initial ligand challenge. WT CXCR2 phosphorylation and desensitization occur in <1 min, while receptor sequestration is a much later event (30-60 min). However, mutant receptors that are neither phosphorylated nor desensitized in response to ligand are <10% sequestered 60 min following ligand challenge. These data demonstrate for the first time that ligand binding to CXCR2 results in receptor phosphorylation, desensitization, and sequestration and that serine residues 342 and 346-348 participate in the desensitization and sequestration processes.
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PMID:Ligand-induced desensitization of the human CXC chemokine receptor-2 is modulated by multiple serine residues in the carboxyl-terminal domain of the receptor. 907 38

The neural POU-domain proteins N-Oct 3 and N-Oct 5 were first identified in electrophoretic mobility retardation assays through their ability to bind to the octamer sequence ATGCAAAT. These two N-Oct factors are detected in extracts from tumor-derived and normal neural cells. They are present differentially, however, in extracts from melanocytes and melanoma cells: N-Oct 3 is present in extracts from both melanocytes and melanoma cells, whereas N-Oct 5 is more evident in extracts from metastatic melanoma cells. We show here that a cDNA encoding N-Oct 3 directs synthesis of both the N-Oct 3 and N-Oct 5 proteins and that the N-Oct 5 protein in neural and melanoma-cell extracts is also related to N-Oct 3. N-Oct 5, however, is apparently not expressed in vivo: It is not detected if cells are rapidly lysed in SDS or if extracts are prepared with a cocktail of protease inhibitors that includes the serine-protease inhibitor 4-(2-Aminoethyl)benzenesulfonyl fluoride hydrochloride (AEBSF). These data suggest that N-Oct 5 is a specific in vitro proteolytic cleavage product of N-Oct 3 and is not directly related to melanocyte malignancy.
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PMID:N-Oct 5 is generated by in vitro proteolysis of the neural POU-domain protein N-Oct 3. 917 89

Successful application of anticancer therapy, and especially photodynamic therapy (PDT) mediated by type II (PDTII) processes, depends on the oxygen content within the tumor before, during and after treatment. The high consumption of oxygen during type II PDT imposes constraints on therapy strategies. Although rates of oxygen consumption and repletion during PDTII were suggested by theoretical studies, direct measurements have not been reported. Application of a novel oxygen sensor allowed continuous and direct in situ measurements (up to a depth of 8-9 mm from the tumor surface and for several hours) of temporal variations in the oxygen partial pressure (pO2) during PDT. Highly pigmented M2R mouse melanoma tumors implanted in CD1 nude mice were treated with bacteriochlorophyll-serine (Bchl-Ser; a new photodynamic reagent) and were subjected to fractionated illumination (700 < lambda < 900 nm) at a fluence rate of 12 mW cm-2. This illumination led to total oxygen depletion with an average consumption rate of 7.2 microM(O2) s-1. Spontaneous reoxygenation (at an average rate of 2.5 microM(O2)/s) was observed during the following dark period. These rates are in good agreement with theoretical considerations (Foster et al., Radiat. Res. 126, 296, 1991 and Henning et al., Radiat. Res. 142, 221, 1995). The observed patterns of oxygen consumption and recovery during prolonged periods of light/dark cycles were interpreted in terms of vasculature damage and sensitizer clearance. The presented data support the previously suggested advantages of fractionated illumination for type II photodynamic processes.
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PMID:Light-dependent oxygen consumption in bacteriochlorophyll-serine-treated melanoma tumors: on-line determination using a tissue-inserted oxygen microsensor. 918 81

Seprase is a homodimeric 170 kDa integral membrane gelatinase whose expression correlates with the invasiveness of the human melanoma cell line LOX. Here, we report the molecular cloning of a cDNA that encodes the 97 kDa subunit of seprase. Its deduced amino acid sequence predicts a type II integral membrane protein with a cytoplasmic tail of 6 amino acids, followed by a transmembrane domain of 20 amino acids and an extracellular domain of 734 amino acids. The carboxyl terminus contains a putative catalytic region (approximately 200 amino acids) which is homologous (68% identity) to that of the nonclassical serine protease dipeptidyl peptidase IV (DPPIV). The conserved serine protease motif G-X-S-X-G is present as G-W-S-Y-G. However, sequence analysis of seprase cDNA from LOX and other cell lines strongly suggests that seprase and human fibroblast activation protein alpha (FAP alpha) are products of the same gene. We propose that seprase/FAP alpha and DPPIV represent a new subfamily of serine integral membrane proteases (SIMP).
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PMID:Molecular cloning of seprase: a serine integral membrane protease from human melanoma. 924 85

Our previous studies have shown that a peptide corresponding to the residue sequence 185-203 of the NC1 domain of the alpha3 chain of basement membrane collagen (type IV) inhibits the activation of polymorphonuclear leukocytes. Peptides from the same region of the alpha1, alpha2, alpha4, and alpha5(IV) chains did not exhibit this property. Because of the intimate relationship between metastasizing neoplastic cells and vascular as well as epithelial basement membranes, we measured the cell adhesion-promoting activity of peptides from the NC1 domain of type IV collagen and their effect on proliferation of human melanoma cells. We found that peptide alpha3(IV)185-203 (CNYYSNSYSFWLASLNPER) not only promotes adhesion of human melanoma cells but also inhibits their proliferation. Adhesion increased by 50-60% over control. Melanoma cell proliferation was inhibited by 40% when cells were grown in a medium containing 5 microg/ml peptide for 5 days. Studies showed that replacement of serine in position 189 or 191 by alanine resulted in significantly reduced adhesion. Similarly, serine replacement resulted in reduced ability to inhibit proliferation. Our data suggest that a region of the NC1 domain of the alpha3(IV) chain, contained within the sequence 185-203, not only specifically promotes adhesion but also inhibits proliferation of melanoma cells. These properties appear to be dependent on the presence of the triplet sequence -SNS- (residues 189-191), which is unique to the alpha3 chain and may represent an important functional epitope.
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PMID:A cell binding domain from the alpha3 chain of type IV collagen inhibits proliferation of melanoma cells. 925 46


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