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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In certain fish hybrids, malignant transformation of pigment cells is due to the presence of a tumor gene (Tu), the action of which is controlled by several regulatory elements. Absence of these controlling genes causes rapid proliferation of the Tu-transformed cells and ultimately results in melanoma formation. One of these genes has been identified as a differentiation gene (Diff), since it seems to control the differentiation of the transformed pigment cells. Light and electron microscopy of Tu-transformed cells of fish differing in the dosage of Diff, and the determination of tyrosinase activity in homogenates of the respective tissues revealed that the degree of cellular differentiation depends on the dosage of Diff present in the genome. It is concluded that the gene Diff promotes the differentiation of malignant melanoma cells into benign melanophores.
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PMID:Genetic control of cell differentiation in platyfish-swordtail melanomas. 81 38

Since our first report showing that the phenotype of tyrosinase-negative or type IA oculocutaneous albinism (OCA) is a consequence of a mutation in the tyrosinase gene (Tomita et al., Biochem. Biophys. Res. Commun., 164:990-996, 1989), a number of mutations were found in the tyrosinase gene of OCA patients. However, to establish the molecular basis of OCA in each patient, we must carry out several important experiments as summarized here. First, we should confirm that the cloned or amplified genomic DNA segments are not derived from the pseudogene or related gene. It should be noted that the putative tyrosinase pseudogene contains the sequence almost identical to exons 4 and 5, including their exon/intron boundaries of the authentic tyrosinase gene. Thus, the mutations, detected in exon 4 or 5 amplified from genomic DNA, must be carefully analyzed to exclude a possibility that the mutation is located in the pseudogene. Second, it is of significance to confirm the promoter activity of the patients' tyrosinase gene. Accordingly, we established the cell-free transcription system derived from melanoma cells where the cloned tyrosinase gene is faithfully transcribed. Finally, transient expression assay of mutant tyrosinase is invaluable to conclude that OCA phenotypes are associated with the mutant tyrosinase alleles. I also discuss the implications of a cluster of mutation sites in exon 1 coding for the amino-terminus of tyrosinase.
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PMID:Mutations of the tyrosinase gene in oculocutaneous albinism. 129 10

Substituted phenolic compounds were previously shown to exhibit cytotoxicity towards epithelial cells in the presence of the enzyme tyrosinase as a result of the formation of their quinone products. Seventeen of these compounds were tested for cytotoxic properties towards three different melanoma cell lines. The compounds were split into four groups of phenol derivatives, A; alkoxyethers, including 4-hydroxyanisole (4HA), B; oxyethers derivatized at the acyl side chain, C; oxyethers derivatized at the phenol, and D; acyl thioethers. Toxicity was determined by total cell counts after 3 days exposure to the compounds. Large reductions in cell numbers were observed with 4HA (the methoxy-), ethoxy-, propoxy and iso-butoxyethers of group A and the methyl- and propyl thioethers of phenol of group D. Derivatization of the ethoxy- and propoxy side chains (group B) did not seem to increase the cytotoxic effects, as determined by cell counts. Compounds of group C, which need intracellular esterase activity to release the phenols, showed moderate toxicities. Toxicity of certain compounds was confirmed by LDH release into the culture medium and by increased trypan blue uptake of cells exposed to the compounds. Flow cytometric investigations of cells after exposure for 24 h revealed that most compounds caused an increase in the proportion of cells in G1 phase. A complete accumulation of cells in S-phase was observed after exposure to 4-ethoxyphenol. Inhibition of DNA synthesis was also shown by inhibition of bromodeoxyuridine incorporation. The results presented show that phenolic compounds exhibit cytotoxic properties towards melanoma cells some of which may be mediated by tyrosinase activity. Toxicity of the compounds was shown to be exerted during DNA replication but their toxic action may also be due to membrane damage and inhibition of cell metabolism.
Melanoma Res 1992 Dec
PMID:Cytotoxicity of a selected series of substituted phenols towards cultured melanoma cells. 129 81

Human melanocytes were cultivated under different conditions with phorbol ester (TPA), or with bovine pituitary extract (BPE). The cells altered their morphology with the different culture conditions. With TPA they were predominantly bipolar, while with BPE most of the cells had a dendritic cell shape. In order to investigate the effect of UV irradiation, the cells were irradiated with 50, 100 and 200 mJ/cm2 UVA/B. After irradiation with 200 mJ/cm2 UVA/B the cells cultured with TPA also showed a dendritic shape. We determined the tyrosinase activity, the cellular melanin content and the cell number 3 days after irradiation. In all cases the number of cells decreased depending on the UVA/B doses. In melanocytes we found a marked increase in tyrosinase activity and melanin content after irradiation with 200 mJ/cm2. The UV-induced effect on tyrosinase activity was higher in melanocytes cultured with BPE than in those cultured with TPA. The results were compared with two human melanoma cell lines. Only little pigment formation could be measured in the tested melanoma cell lines without change after UV irradiation.
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PMID:Effect of the dose of ultraviolet radiation on the pigment formation by human melanocytes in vitro. 129 24

The activities of mushroom and melanoma tyrosinases towards the estrogens were compared. While the fungal enzyme is capable of hydroxylating estradiol to the 2-hydroxy compound and to oxidize the latter to the quinone, the mammalian enzyme does not have this ability. With dopa as substrate and an estrogen present in the reaction mixture, both enzyme reactions yield melanin with the steroid firmly incorporated into the pigment, although with the mammalian enzyme the incorporation is small. The steroid appears to be incorporated by covalent linkage. It is suggested that the incorporation of estrogens into melanin produced by mammalian tyrosinase is via their oxidation by oxidized intermediates of the dopa to melanin transformation. Melanin itself may function as oxidant for the estrogens. Whole melanoma cells are capable of binding estrogens and incorporating small amounts into melanosomes. Similarly, fresh melanosomes in isolation can incorporate estrogens into their structure, presumably by covalent bonding to their melanin.
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PMID:Incorporation and binding of estrogens into melanin: comparison of mushroom and mammalian tyrosinases. 131 67

Melanocytes are specialized cells residing in the hair follicles, the eye, and the basal layer of the human epidermis whose primary function is the production of the pigment melanin, giving rise to skin, hair, and eye color. Melanogenesis, a process unique to melanocytes that involves the processing of tyrosine by a number of melanocyte-specific enzymes, including tyrosinase and tyrosinase-related protein 1 (TRP-1), occurs only after differentiation from the melanocyte precursor, the melanoblast. In humans, melanogenesis is inducible by UV irradiation, with melanin being transferred from the melanocyte in the epidermis to the surrounding keratinocytes as protection from UV-induced damage. Excessive exposure to UV, however, is the primary cause of malignant melanoma, an increasingly common and highly aggressive disease. As an initial approach to understanding the regulation of melanocyte differentiation and melanocyte-specific transcription, we have isolated the gene encoding TRP-1 and examined the cis- and trans-acting factors required for cell-type-specific expression. We find that the TRP-1 promoter comprises both positive and negative regulatory elements which confer efficient expression in a TRP-1-expressing, pigmented melanoma cell line but not in NIH 3T3 or JEG3 cells and that a minimal promoter extending between -44 and +107 is sufficient for cell-type-specific expression. Assays for DNA-protein interactions coupled with extensive mutagenesis identified three factors, whose binding correlated with the function of two positive and one negative regulatory element. One of these factors, termed M-box-binding factor 1, binds to an 11-bp motif, the M box, which acts as a positive regulatory element both in TRP-1-expressing and -nonexpressing cell lines, despite being entirely conserved between the melanocyte-specific tyrosinase and TRP-1 promoters. The possible mechanisms underlying melanocyte-specific gene expression are discussed.
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PMID:Positive and negative elements regulate a melanocyte-specific promoter. 132 44

The differentiation-inducing activity of doxorubicin on B16 melanoma cells grown in vitro was compared with that of other known differentiation inducers, such as theophylline, retinoic acid, and melanocyte-stimulating hormone (MSH). At drug concentrations resulting in cytostatic effects, doxorubicin and theophylline induced morphological changes (dendritic-like structures with a terminal melanin granule) with an enhancement of total melanin content and tyrosinase activity. Retinoic acid did not alter melanin content and cell morphology, although it affected cell growth. MSH enhanced total melanin content and tyrosinase activity, with no significant morphological changes. Flow cytometric analysis showed that MSH led to an accumulation of cells in G1 phase whereas doxorubicin induced an accumulation of cells in G2 + M. Studies on DNA content in doxorubicin-treated cells, selected on the basis of a morphologically differentiated pattern, showed a clustering of these cells in G2 + M, probably due to a cytokinesis block. Thus doxorubicin can induce cell differentiation comparable with other differentiation inducers.
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PMID:Comparative studies on the effects of doxorubicin and differentiation inducing agents on B16 melanoma cells. 132 7

alpha-MSH was found to decrease the recently characterized dopachrome tautomerase activity in cultures of B16/F10 mouse melanoma cells. Other stimulating agents of melanogenesis, like dibutyryl cyclic AMP, 3-isobutyl-1-methylxanthine, theophylline, retinol, and retinoic acid, caused the same effect. The grade of inhibition depended on the nature of the agent and the time of exposure. In all cases, both melanin production and tyrosinase activity were activated by these treatments, although the grade of tyrosine hydroxylase and dopa oxidase stimulation was different. Moreover, no correlation among the intensities of dopachrome tautomerase inhibition and tyrosinase activation by the tested agents could be obtained. The significance of these results in the regulation of mammalian melanogenesis is discussed.
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PMID:Alpha-MSH and other melanogenic activators mediate opposite effects on tyrosinase and dopachrome tautomerase in B16/F10 mouse melanoma cells. 132 99

Our previous work indicated that IR-alpha-MSH (immunoreactive alpha-melanocyte-stimulating hormone) plasma levels are three times as high in melanoma patients with progressing disease than in disease-free patients, and that the melanoma tumor itself may be the source of IR-alpha-MSH. Further identification of the material in tumor extracts has been carried out in this study, and the results presented here show that the immunoreactivity is associated with a major fraction of about 16 kDa and another of 5-9 kDa. Significant amounts of the immunoreactive material were also found in human melanoma cells but not in culture supernatants. The presence of this material may be related to the melanogenic status of the tumor cells. We have estimated the intracellular IR-alpha-MSH to be within a 0.4 to 2.3 nM range in melanoma tumor cells. We have investigated the melanogenic effect of the IR-alpha-MSH material and its relationship to alpha-MSH. Purified extracts both from metastases and cultured cells were found to promote frog skin darkening as well as tyrosinase activity in Cloudman S91 melanoma cells. The IR material could also displace labeled alpha-MSH from its binding sites in human melanoma cells. Our data clearly indicate that melanoma cells engage in an autocrine production of alpha-MSH-like bioactive peptides by melanoma cells, of larger mol.wt., which are able to bind to MSH receptors. These peptides may be involved in the regulation of melanogenesis and possibly in the growth and proliferation of melanoma cells by an autocrine/paracrine mechanism.
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PMID:Partial characterization of IR-alpha-MSH peptides found in melanoma tumors. 133 93

It may be possible to use the melanogenic pathway as a therapeutic targeting strategy for melanoma, and encouraging clinical pilot studies of 4-hydroxyanisole have led to the search for more active analogue substrates of tyrosinase. A recent study of a range of alkoxy- and alkylthio-phenol analogues of tyrosine has shown that sulphur-containing compounds exhibit different behaviour to that of similar oxygen-containing compounds, indicating modified reactivities of their corresponding tyrosinase-induced o-quinones towards crucial cellular targets, in particular, thiols. We have therefore examined by pulse radiolysis the reactivities of a group of unstable alkylthio- and alkoxy-substituted o-quinones towards the biologically relevant thiols, cysteine and glutathione. The o-quinones were generated by rapid (microsecond) one-electron oxidation of the corresponding stable synthesized catechols, forming semiquinones which disproportionated over milliseconds to o-quinones. The latter reacted with the thiols in a pH-dependent manner, indicative of increased nucleophilicity of the thiolate anions as compared with their protonated forms, with rate constants in the region of 10(5)-10(6) M-1s-1. At pH 7.2, within the physiological range, the alkylthio-substituted o-quinones reacted with the thiols approximately 5-10 times faster than the alkoxy-substituted o-quinones. The corresponding alkylthio-substituted phenols might, therefore, in principle, be expected to be more effective targeted anti-melanoma drugs than their alkoxy-substituted counterparts. NMR studies of the reactions of several of the quinones with cysteine indicate that, where addition occurs, the product is exclusively the 6-S-cysteinyl-4-substituted-catechol.
Melanoma Res 1992 Dec
PMID:Reactivity of orthoquinones involved in tyrosinase-dependent cytotoxicity: differences between alkylthio- and alkoxy-substituents. 133 96


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