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 pigmented subclone of Cloudman S91 melanoma cells, PS1-wild type, can grow in medium lacking tyrosine. This ability is conferred by phenylalanine hydroxylase activity, and not by tryptophan hydroxylase, tyrosine hydroxylase or tyrosinase activities, although the latter activity is also present in these cells. Conversion of phenylalanine to tyrosine was measured in living cells by chromatographic identification of the metabolites of [14C]phenylalanine and in cell extracts using a sensitive assay for phenylalanine hydroxylase. Phenylalanine hydroxylase activity in melanoma cell extracts was identified by its inhibition with p-chlorophenylalanine and not with 6-fluorotryptophan, 3-iodotyrosine, phenylthiourea, tyrosine or tryptophan; and by adsorption with antiserum prepared against purified rat liver phenylalanine hydroxylase, and migration of immunoprecipitable activity with authentic phenylalanine hydroxylase subunits in sodium dodecyl sulfate-polyacrylamide gel electrophoresis.
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PMID:Phenylalanine hydroxylase in melanoma cells. 2 86

D,L-tryptophan[benzene ring-14C (U)] and D,L-tryptophan (methylene-14C) are incorporated significantly into melanin of Harding-Passey mouse melanoma. D,L-5-hydroxytryptophan (methylene-14C) and 5-hydroxytryptamine-3-14C (serotonin) gave an incorporation of radioactivity into melanin significantly lower than tryptophan. D,L-tyrosine-2-14C was incorporated into melanin as well as tryptophan. Therefore tryptophan must be considered an important precursor in the biogenesis of melanins too.
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PMID:Studies on melanogenesis of tryptophan in Harding-Passey mouse melanoma. 124 96

Human melanoma cells secrete a 21 kDa protein which binds with 1:1 molar stoichiometry to the matrix metalloproteinase type IV collagenase proenzyme (70 kDa gelatinase) secreted by the same cells. We have purified this binding protein and determined its complete primary structure by directly sequencing overlapping peptide fragments which span the entire protein. We refer to this protein as CSC-21K based on the amino-terminal amino acids CSC and the apparent molecular weight of 21,000 daltons on gel electrophoresis. The amino acid sequence of CSC-21K demonstrates that this protein shares significant homology with human TIMP (tissue inhibitor of metalloproteinase), including conservation of the positions of the twelve cysteine residues and three of four tryptophan residues. The identification of CSC-21K now indicates that a family of TIMP-related proteins exists. Individual members of this family may possess selective affinities for different members of the matrix metalloproteinase family. Based on its sequence homology to TIMP and ability to inhibit type IV collagenolysis we propose the name TIMP-2 for this inhibitor. TIMP-2 produced by tumor cells can also be considered as an onco-suppressor gene product, because it could play an important role in regulating the metalloproteinases involved in tumor invasion and angiogenesis.
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PMID:TIMP-2: identification and characterization of a new member of the metalloproteinase inhibitor family. 148 41

Peptides from the three type I repeats of human endothelial cell thrombospondin, containing the consensus sequence-Trp-Ser-Xaa-Trp-, bind to sulfated glycoconjugates including heparin and sulfatide. The peptides are potent inhibitors for the binding of thrombospondin, laminin, or apolipoprotein E to these ligands. The thrombospondin peptides that inhibit heparin binding, but not adjacent peptides from the thrombospondin sequence containing the previously identified adhesive motif Val-Thr-Cys-Gly, promote melanoma cell adhesion when immobilized on plastic. Melanoma cell adhesion to the immobilized peptides is inhibited by soluble recombinant heparin-binding fragment of thrombospondin. The peptides also inhibit heparin-dependent binding of thrombospondin or laminin to human melanoma cells. The active peptides lack any previously identified heparin-binding consensus sequences and most do not contain any basic amino acids. Studies with homologous peptides showed that the tryptophan residues are required for binding. Adjacent basic residues in the second type I repeat enhance binding to heparin but not to sulfatide. Thus the type I peptides of thrombospondin define a distinct class of heparin-binding peptides.
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PMID:Heparin- and sulfatide-binding peptides from the type I repeats of human thrombospondin promote melanoma cell adhesion. 155 10

The sensitivity and resistance of six human melanoma cell lines to gamma-interferon (gamma-IFN) and tumour necrosis factor-alpha (TNF-alpha) have been examined. Amelanotic cell lines were more sensitive to gamma-IFN and TNF-alpha than melanotic cells. The cytotoxicity of gamma-IFN and TNF-alpha could be reversed in all cells by the addition of L- or D-tryptophan to the culture medium. Melanoma cells resistant to gamma-IFN excrete calcium activated neutral protease (CANP) and as a consequence, make L-tryptophan available by the hydrolysis of serum proteins in the culture medium. Resistance to gamma-IFN could be reversed by the addition of specific CANP inhibitor, whereas gamma-IFN-sensitive strains became more resistant with the addition of CANP to the culture medium. It has been confirmed that gamma-IFN induces indoleamine 2,3-dioxygenase in melanoma cells. This enzyme utilizes the superoxide anion (O2-) as a substrate for the oxidation of either L- or D-tryptophan to N-formylkynurenic acid leading to cell death. The induction of this degradative pathway for L-tryptophan kills cells by starvation of this essential and relatively scarce amino acid. TNF-alpha induces manganese-containing superoxide dismutase (MnSOD) which also uses O2- to produce cytotoxic concentrations of hydrogen peroxide. Therefore, it can be concluded that the cytotoxicity of both gamma-IFN and TNF-alpha depends on the availability of L-tryptophan as the substrate for the removal of O2- via indoleamine 2,3-dioxygenase.
Melanoma Res
PMID:Tryptophan protects human melanoma cells against gamma-interferon and tumour necrosis factor-alpha: a unifying mechanism of action. 166 25

Tyrosine is an essential amino acid for the initial step of melanin synthesis, yet little is known concerning its transport in melanocytes. As an important first step in the development of new anti-melanoma agents based upon chemical and pharmacological modifications of melanin synthesis, the present study characterized the transport mechanism of tyrosine in vitro using the human melanoma cell line SK-MEL 23. Several tyrosine transport systems may be involved in melanocytes: systems L and T, which transport neutral amino acids with branched or aromatic side chains, and systems A and ASC, which transport neutral amino acids with smaller side chains. In order to determine which system or combination of systems is involved in tyrosine transport in melanoma cells, studies of kinetics, Na(+)-dependence and competitive inhibition were undertaken. The Km and Vmax. for the Na(+)-independent transport system were found to be 0.164 +/- 0.016 mM and 21.6 +/- 1.1 nmol/min per mg of protein respectively. This transport was preferentially inhibited by the system L specific analogue, 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid, the system T substrate tryptophan, and the sulphur homologue of tyrosine, 4-S-cysteinylphenol. Sequential addition of these inhibitors at increasing concentrations indicated that they inhibit the same transporter. Our results suggest that tyrosine transport in SK-MEL 23 melanoma cells is similar to system L transport previously characterized in other cell types. This one transport system appears to supply all the tyrosine required for both cell growth and melanin synthesis. The transport system may be subject to manipulation by melanogenic stimulating factors, making the transport of cytotoxic tyrosine analogues an important area for further study.
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PMID:Tyrosine transport in a human melanoma cell line as a basis for selective transport of cytotoxic analogues. 176 36

The effect of a number of L-tyrosine (L-Tyr) analogues on L-Tyr uptake by B16/F10 malignant melanocytes is reported. This amino acid can be taken up by two of the most ubiquitous transport systems found in animals cells, L and presumably ASC. L-Tyr analogues devoid of the amino group, like p-hydroxyphenyl pyruvic acid and related compounds, and L-Tyr analogues devoid of the carboxyl group, such as tyramine, do not affect L-Tyr uptake. The other aromatic amino acids, L-Phe and L-Trp, and the L-Tyr analogues DL-m-Tyr, L-diiodotyrosine and L-dopa, strongly inhibit the uptake of L-Tyr. This suggests that these chemicals are transported more efficiently than L-Tyr. The ASC system does not show stereospecificity, but the L system has greater affinity for L-Tyr than for D-Tyr. The ASC system also has greater affinity for tyrosine isomers with the hydroxyl group in the ortho and meta positions. The presence of a methyl group at the alpha-carbon of L-Tyr and L-dopa also increases the affinity of the ASC system for these agents. In contrast, alpha-methylation decreases the affinity of the L system in comparison to L-Tyr. Finally, L-Tyr esters do not inhibit, but stimulate the transport of L-Tyr, mainly by the ASC system.
Melanoma Res
PMID:Inhibition by analogues of L-tyrosine transport by B16/F10 melanoma cells. 182 66

Nine metastatic melanoma cell lines and two melanocyte cell lines were analyzed for point mutations in highly conserved regions of the p53 gene. No mutations were detected in the two melanocytic cell lines and in eight melanoma cell lines. However, a C----T transition at codon 248, resulting in a substitution of tryptophan for arginine, was found in one melanoma cell line. On immunohistochemical staining, only this cell line showed reactivity for mouse monoclonal antibody 1801, which is immunoreactive with human p53 protein. The original paraffin-embedded specimen from which this mutant cell line was established was obtained, and sequence analysis detected the identical mutation in the p53 gene as that seen in the derived cell line. This is the first report indicating point mutations in the p53 gene in malignant melanocytic tissues.
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PMID:Mutational analysis of the human p53 gene in malignant melanoma. 192 72

Human melanoma cells secret a 21-kDa protein, termed CSC-21K, which binds with 1:1 molar stoichiometry to the matrix metalloproteinase type IV collagenase proenzyme (70-kDa gelatinase) secreted by the same cells. This binding protein has been purified and its complete primary structure determined by sequencing overlapping peptides which span the entire protein. The amino acid sequence demonstrates that this protein shares significant homology with human TIMP (tissue inhibitor of metalloproteinase), including conservation of the positions of the 12 cysteine residues and 3 of 4 tryptophan residues. The identification of CSC-21K now indicates that a family of TIMP-related proteins exists. Individual members of this family may possess selective affinities for different members of the matrix metalloproteinase family. CSC-21K produced by tumor cells is isolated as a 1:1 molar complex with type IV procollagenase, as demonstrated by amino acid composition analysis. Addition of purified CSC-21K to the activated metalloproteinase results in inhibition of the collagenolytic activity in a stoichiometric fashion. Based on its sequence homology to TIMP and ability to inhibit type IV collagenolysis we propose the name TIMP-2 for this inhibitor.
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PMID:Tissue inhibitor of metalloproteinase (TIMP-2). A new member of the metalloproteinase inhibitor family. 279 61

We describe results demonstrating the positive regulation of melanogenesis by two substrates of the melanogenic pathway. We have found that L-tyrosine and L-dihydroxyphenylalanine (L-dopa), whose metabolic fates are affected by the activity of that pathway, can also act as its regulators. In living pigment cells, tyrosinase (EC 1.14.18.1), a crucial and rate-limiting enzyme of melanogenesis, acts in subcellular organelles known as melanosomes. Melanin is laid down only in these organelles. We demonstrate that supplementing Ham's F-10 medium with additional L-tyrosine or L-dopa during the culture of amelanotic Bomirski hamster melanoma cells results in a rapid increase in melanin formation, which is not simply due to greater availability of substrate. There is a rapid increase in tyrosinase activity and a large scale synthesis of melanosomes. The effects of L-tyrosine and L-dopa are prevented by the addition of cycloheximide. The actions of L-tyrosine and L-dopa are specific in that under similar conditions D-tyrosine, D-dopa, N-acetyl-L-tyrosine, L-phenylalanine, L-tryptophan and L-valine have little or no effect. The two substrates, L-tyrosine and L-dopa, appear to act through related but distinct mechanisms. Our findings provide an example of a little-known phenomenon: regulation of a differentiated eukaryotic phenotype through positive control by substrates in the pathway.
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PMID:Positive regulation of melanin pigmentation by two key substrates of the melanogenic pathway, L-tyrosine and L-dopa. 314 38


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