Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Melanogenesis in melanoma cells can be enhanced by psoralens in the absence of UV light. Melanin biosynthesis is regulated by a number of melanocyte-specific proteins, including tyrosinase, DOPAchrome tautomerase (DCT), and tyrosinase-related protein-1 (TRP-1, gp75). To get more insight on the molecular mechanisms involved in psoralens-induced melanogenesis, we determined tyrosinase and DCT activities as well as mRNA and protein levels of tyrosinase, DCT, and TRP-1 in S91 mouse melanoma cells treated by 5-MOP. High concentration of 5-MOP (5 x 10(-5) M) induced a time-dependent increase of tyrosinase activity and melanin content, which was correlated to an increase of both mRNA and protein levels of tyrosinase. These results demonstrate that the 5-MOP stimulation of melanogenesis is related to increased tyrosinase synthesis. In addition, 5-MOP stimulated TRP-1 synthesis and induced a dose-dependent decrease of DCT activity without any modification in the expression of the protein. We explored then the signalling pathways involved in 5-MOP-induced melanogenesis and, particularly, the role of cyclic AMP and protein kinase C (PKC). A small stimulation of cyclic AMP production was observed in presence of 5-MOP. Furthermore, 1-oleoyl-2-acetylglycerol (OAG), a PKC activator, potentiated the 5-MOP stimulation of tyrosinase activity, while calphostin, a specific PKC inhibitor, inhibited the 5-MOP induction of tyrosinase activity. Phorbol-myristate acetate (PMA), described as a strong activator of PKC, inhibited also the effect of 5-MOP when used at long term. Taken together, these results demonstrate that in murine melanoma cells 5-MOP stimulates melanogenesis by increasing activity and synthesis of tyrosinase. Tyrosinase and TRP-1 expression are coordinately regulated by 5-MOP. Furthermore, a negative correlation between melanogenesis and DCT activity was observed under 5-MOP stimulation. At least, PKA and PKC systems appear to play an important role in the melanogenic effect of 5-MOP.
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PMID:Regulation of melanogenesis induced by 5-methoxypsoralen without ultraviolet light in murine melanoma cells. 785 73

The major stimulus for human melanin production is ultraviolet (UV) radiation. Little is known about the mechanisms underlying this response and the eventual enzyme regulation resulting from this activation. We treated normal human melanocytes in culture with daily UVB radiations. Cumulative increases in UVB doses resulted in proportional increases in tyrosinase activity over the first few days whereas an intermittent pattern of tyrosinase activation was observed after the fifth day of irradiation. This intermittent pattern consisted of latency periods where no melanogenic response was elicited despite exposure to UVB. Tyrosinase activity in cellular extracts increased shortly after an effective irradiation, peaked at 3 hours and thereafter decreased to below basal levels. Increased tyrosinase activity was associated with increased amounts of both the newly synthesized and mature forms of the enzyme. Decreased tyrosinase activity following an activation period was correlated with decreases in both the expression of tyrosinase mRNA and the amount of the newly synthesized form of the enzyme present in the melanocytes 24 hours after six irradiations. This particular pattern of stimulation of tyrosinase was not observed in S-91 murine melanoma cells after repeated UVB irradiations. Taken together these results may suggest a photo-protective mechanism developed by irradiated normal human melanocytes.
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PMID:Repeated UVB irradiations do not have the same potential to promote stimulation of melanogenesis in cultured normal human melanocytes. 790 36

Tyrosinase, the key enzyme in melanin synthesis, is expressed specifically in pigment-producing cells. Studies with transgenic mice and gene transfer experiments have demonstrated that the 270-base pair 5'-flanking sequence of the mouse tyrosinase gene leads to weak but cell type-specific and developmentally regulated expression. To elucidate the underlying transcriptional control, we focused on the identification of cis-acting elements within this 270-base pair minimal promoter. We also addressed the potential role of promoter elements in the control of cAMP regulation of the tyrosinase gene. Deletion and linker scanning mutagenesis revealed that promoter activity is modulated by two positive elements and one negative element. One of the positive elements includes the M-box, a sequence motif shared with the promoter of two other melanocyte-specific genes, trp-1 and trp-2. Cotransfection experiments provide evidence that a basic helix-loop-helix-zipper protein, encoded at the microphthalmia gene locus, transactivates the tyrosinase promoter, probably by binding to the M-box. Activating cis elements are bound by nuclear factors in vitro and confer increased expression to a reporter gene both in melanoma cells and in fibroblasts. We therefore suggest that the positive promoter elements modulate tyrosinase expression rather than determine cell specificity in vivo, whereas the negative element acts cell type specifically.
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PMID:The mouse tyrosinase gene. Promoter modulation by positive and negative regulatory elements. 796 73

Tyrosinase is a rate-limiting enzyme in melanin biosynthesis and is specifically expressed in differentiated melanocytes. We have identified the enhancer element in the 5'-flanking region of the human tyrosinase gene that is responsible for its pigment cell-specific transcription and have termed it tyrosinase distal element (TDE) (positions -1861 to -1842). Transient expression assays showed that TDE confers efficient expression of a firefly luciferase reporter gene linked to the tyrosinase gene promoter in MeWo pigmented melanoma cells but not in HeLa cells, which do not express tyrosinase. TDE was specifically bound by nuclear proteins of MeWo and HeLa cells, the binding properties of which were indistinguishable in gel mobility shift assays. TDE contains the CATGTG motif in its center, and mutation analysis indicates that the CA dinucleotides of this motif are crucial for protein binding and pigment cell-specific enhancer function. The CATGTG motif is consistent with the consensus sequence recognized by a large family of transcription factors with a basic helix-loop-helix structure, which prompted us to examine the possible involvement of a ubiquitous transcription factor, USF, and a novel factor, microphthalmia-associated transcription factor (MITF), recently cloned as the human homolog of the mouse microphthalmia (mi) gene product. The mi phenotype is associated with a mutant mi locus and characterized by small eyes and loss of melanin pigments. Both USF and MITF are predicted to contain a basic helix-loop-helix structure and a leucine zipper structure. We provide evidence that USF binds to TDE, whereas we were unable to detect the DNA-binding activity of MITF. Transient coexpression assays showed that MITF specifically transactivates the promoter activity of the tyrosinase gene through the CATGTG motif of TDE but not the promoter of the ubiquitously expressed heme oxygenase gene, while USF is able to activate both promoters. These results indicate that MITF is a cell-type-specific factor that is capable of activating transcription of the tyrosinase gene.
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PMID:Microphthalmia-associated transcription factor as a regulator for melanocyte-specific transcription of the human tyrosinase gene. 786 73

Tyrosinase, tyrosinase-related protein-1 (TRP-1), and tyrosinase-related protein-2, (TRP-2, dopachrome tautomerase) were shown by immunoblotting and enzyme assays to copurify from extracts of Cloudman S91 melanoma cells. Antibodies to TRP-1 and TRP-2 immunoprecipitated tyrosinase activity, suggesting a stable interaction (complex) among these proteins. The tyrosine hydroxylase activity of tyrosinase was reduced in the complexed form; treatment with Triton X-100 dissociated the complex and activated the tyrosinase present within it. To further study this complex, we employed sucrose gradient density centrifugation of extracts from cultured murine melanocytes. Tyrosinase, TRP-1, and TRP-2 all existed in high molecular weight "multimers" of approximately 200 to > 700 kilodaltons. Extraction of cells with buffers containing the detergent CHAPS preserved the high molecular weight multimers; Triton X-100 caused their dissociation into monomers. Low pH, low ionic strength, and millimolar concentrations of calcium ions favored the maintenance of multimers. The results of this study demonstrate that the participation of tyrosinase, TRP-1, and TRP-2 in a multimeric complex could have important physiologic consequences, and raise the possibility that some of the well-known interactions between coat color genes may be explained by intermolecular interactions between the gene products.
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PMID:High-molecular-weight forms of tyrosinase and the tyrosinase-related proteins: evidence for a melanogenic complex. 804 Jun 9

Recently, a highly sensitive assay combining reverse transcription and polymerase chain reaction (PCR) to assess for melanoma cells in peripheral blood has been developed. Detection of tyrosinase mRNA, a tissue-specific enzyme in melanocytes and melanoma cells, indicates the presence of melanoma cells in peripheral blood. We examined blood samples and bone marrow aspirates from 28 patients with metastatic malignant melanoma for presence of melanoma cells prior to and after therapy with interferon (IFN)-alpha and interleukin (IL)-2. Ten patients showed antitumor response to immunotherapy, including three complete (CR) and seven partial remissions (PR). Four patients (three PR, one stable disease) underwent subsequent resection of residual tumor lesions and had no clinical evidence of disease after surgery. Tyrosinase mRNA was detected in blood and bone marrow samples from all patients with malignant melanoma prior to and after immunotherapy, including those with no clinical evidence of disease (median disease-free survival 21 months, range 19-28 months). Tyrosinase transcripts were also detected in all patients with amelanotic melanoma. In contrast, no tyrosinase mRNA was detectable in any of 30 healthy persons or in six patients with other malignancies. The presence of residual melanoma cells may be an important indicator of occurrence of delayed relapse.
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PMID:Detection of residual tumor cells in patients with malignant melanoma responding to immunotherapy. 811 Jul 29

Tyrosinase is the principal enzyme in the biosynthesis of melanin. The expression of tyrosinase is tissue-specific and appears to be regulated by various hormonal and environmental factors. Elucidation of the genomic structure and molecular basis of control of tyrosinase gene expression will greatly enhance our understanding of the regulation of human pigmentation. To this end, we have isolated and performed restriction mapping of recombinant cosmid and lambda phage clones containing the human tyrosinase gene, sequenced a 2.2-kilobase (kb) region of its promoter, and determined the potential regions regulating the tyrosinase gene expression in transient-expression system. The human tyrosinase gene is comprised of five exons and four introns. Based on our restriction mapping studies, the gene spans a distance of over 65-kb on chromosome 11 (q14-->q21). We constructed a series of plasmids (pHTY-CAT) that contain 5' sequential deletions of the human tyrosinase 5' flanking sequence fused to the reporter gene, chloramphenicol acetyltransferase (CAT). The plasmids were used to locate promoter regions that are potential regulators of tyrosinase gene expression in a transient expression system using melanoma cell lines. In human melanoma cells, the plasmid construct with a -2020 base pair (bp) promoter yielded the highest CAT activity. When the deletions reached -1739 bp, the CAT activity was dramatically reduced, indicating that important enhancer elements for transcription control are present between -1739 and -2020 bp. Further deletions up to -550 bp also resulted in dramatic decreases of CAT activity. However, when the deletion included -550 bp of the 5' flanking sequence, there was 26 percent of the CAT activity compared to that of the -2020 bp promoter. Deletions beyond -550 bp also showed markedly decreased CAT activity. Based on our data, we suggest that human tyrosinase gene expression is governed by both tissue-specific and multiple regulatory elements.
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PMID:Structural organization of the human tyrosinase gene and sequence analysis and characterization of its promoter region. 817 57

Patients with malignant melanoma and distant metastases generally have an unfavorable prognosis, with a median survival of about 6 months. The mechanisms of hematogenous spread and implantation of melanoma cells are, however, poorly understood, because the standard diagnostic methods are not sensitive enough to detect oligocellular micrometastases. Recently a method using reverse transcription and polymerase chain reaction to determine tyrosinase mRNA in peripheral blood, which indicates the presence of circulating melanoma cells, has been developed. We utilized this assay to examine blood samples of 56 patients with malignant melanoma in different stages of disease. In one of 10 patients in stage I (localized disease) and in six of 17 patients with regional lymph nodes metastases (stage II) tyrosinase mRNA was detected. Tyrosinase transcripts were found in all 29 patients with distant metastases (stage III). Interestingly, tyrosinase mRNA was also detected in six patients with metastatic amelanotic malignant melanoma. In contrast, tyrosinase mRNA was not detectable in any of 39 healthy subjects or 17 patients with other malignancies. These findings may be helpful to define a patient group at high risk for systemic spread of disease.
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PMID:Hematogenous spread of malignant melanoma cells in different stages of disease. 824 18

Monoclonal antibodies against melanosomal components (human melanosome specific antigens; HMSAs) have been developed in our laboratory. HMSA-1-4 recognizes structural matrix proteins of melanosomes. HMSA-5 is identical to TRP-1, equivalent to the b (brown) locus of murine melanocytes and expressed in early stages of melanosomal maturation. HMSA-6 is a protein associated with melanosomes but its role is still unclarified, and HMSA-7 is identical to the lysosomal protein CD63. We have also recently identified p90 calnexin-like, Ca(2+)-binding protein p97 melanotransferrin, and p64 beta-D-galactosidase-like protein associated with melanosomes through immunological screening of our melanocytes (melanoma cells) cDNA library. Approximately 150 genes and 60 loci are known to influence eye, skin and hair colour in mammals. Tyrosinase is a rate-limiting enzyme responsible for melanin synthesis. In addition, tyrosine-related proteins (TRPs) and their genes have been identified and cloned. Tyrosinase and TRPS (e.g., TRP-1; b-locus protein identical to HMSA-5 and TRP-2; dopachrome tautomerase) are synthesized according to underlying genetic programmes, and are up- and/or down-regulated to create various forms of abnormal melanin pigmentation. We herein propose the importance of investigating the role of non-tyrosinase related proteins such as those which we have recently identified.
Melanoma Res 1993 Oct
PMID:Characterization of melanosome-associated proteins by establishment of monoclonal antibodies and immunoscreening of a melanoma cDNA library through an anti-melanosome antibody. 829 89

5-Bromodeoxyuridine (BrdU), a thymidine analog, suppresses melanogenesis in Syrian hamster melanoma cells. Tyrosinase, which is the key enzyme for the synthesis of melanin, is suppressed by exposure to BrdU, and the drop in enzyme activity is correlated with a drop in tyrosinase mRNA level. In order to investigate whether suppression of tyrosinase mRNA by BrdU is due to BrdU substitution into coding sequences or upstream sequences of the tyrosinase gene, we carried out stable and transient transfection assays with constructs containing either the human tyrosinase cDNA sequence under the control of a nontyrosinase promoter or a chloramphenicol acetyltransferase (CAT) reporter gene under the control of 5' flanking sequences of the mouse tyrosinase gene. When the plasmid containing the tyrosinase cDNA was stably transfected into mouse fibroblasts, tyrosinase activity in the transfectants was not suppressed by BrdU. Since BrdU would be incorporated into the tyrosinase cDNA integrated in these transfectants, the results suggest that BrdU suppression of tyrosinase gene expression is not due to its incorporation into coding sequences of the tyrosinase gene. When plasmids with tyrosinase regulatory sequences were transfected into melanoma cells for transient expression assays, CAT gene expression was suppressed by BrdU. Because the CAT plasmids do not contain a mammalian origin of replication and should not replicate under the conditions of transient transfection, BrdU would not be incorporated into the DNA of those plasmids. Therefore, these results suggest that the suppression of tyrosinase gene expression by BrdU also is not due to the incorporation of BrdU into upstream sequences of the tyrosinase gene.
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PMID:Suppression of tyrosinase gene expression by bromodeoxyuridine in Syrian hamster melanoma cells is not due to its incorporation into upstream or coding sequences of the tyrosinase gene. 833 36


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