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: EC:1.10.3.1 (tyrosinase)
9,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Incidence and mortality of human malignant melanoma has risen rapidly over recent decades. Although the notorious resistance to treatment is characteristic for metastatic malignant melanoma, only a few experimental models have been established to study the metastatic cascade or to test new alternative treatment modalities. Thus, new human models are wanted. Here, we describe the metastatic behaviour of seven human melanoma cell lines derived from two primary cutaneous melanomas (WM 98-1, WM 1341) and five metastases established from liver (UKRV-Mel-4), skin (M7, M13), pleural effusion (UKRV-Mel-2) and lymph node (MV3). All cell lines were analysed for their capacity to grow in nude mice after s.c. and i.v. administration. M13 cells developed liver metastases spontaneously after s.c. injection, and subsequent passages of M13 and M7 melanoma cells caused liver metastases after i.v. injection, whereas MV3 and WM98-1 gave rise to lung metastases, using the same inoculation route. In contrast, WM 1341, UKRV-Mel-2 and UKRV-Mel-4 grew only very slowly in nude mice after s.c. injection and did not cause any metastases after i.v. or s.c. administration. The pattern of metastases or growth kinetics did not correlate with the interleukin 8 or tumour necrosis factor secretion of cell lines. Adhesion molecules and growth factor receptor expression on the cell lines differed widely, as determined by flow cytometry, with the low metastatic cell lines (UKRV-Mel-2, UKRV-Mel-4 and WM 1341) demonstrating a marked reduction in VLA-1 and VLA-5 expression compared with the metastatic lines (M7, M13, MV3 and WM 98-1). Expression of pigment-related proteins such as tyrosinase, TRP-1, TRP-2, Melan-A/MART-1, gp100, MAGE1 or MAGE-3 was not associated with growth and metastatic characteristics of the melanoma cell lines analysed. In conclusion, the established human melanoma cell lines exhibited diverse growth behaviour in nude mice in congruence with some early established prognostic markers such as VLA-1 and VLA-5. The xenografts provide good models for further study of metastatic processes as well as for evaluation of alternative treatment modalities including new pharmaceutical drugs and gene therapeutic targeting using tissue-specific gene regulatory elements for gene targeting.
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PMID:Metastatic potential of human melanoma cells in nude mice--characterisation of phenotype, cytokine secretion and tumour-associated antigens. 868 21

The two major types of mammalian melanin are pheomelanin (yellow or red pigment) and eumelanin (black or brown). The agouti (A) and extension (E) loci determine whether follicular melanocytes will deposit pheomelanin or eumelanin within their melanosomes. Mutations at the murine pinkeyed-dilution (P) locus cause a striking reduction in deposition of eumelanic, but not pheomelanic, pigment. The mRNA encoded at the P locus is not expressed in skin that exclusively produces pheomelanic pigment as a result of mutation at the agouti locus. We have suggested, based upon both genetic and biochemical evidence, that three key melanogenic proteins--tyrosinase, tyrosinase-related-protein-1 (TRP-1), and TRP-2, encoded at the albino (C), brown (B), and slaty (Slt) loci, respectively--form a high-molecular-weight "melanogenic complex" within the melanosome. High-molecular-weight forms of tyrosinase, TRP-1 and TRP-2, are absent from eumelanic ocular tissues of p(un)/p(un) mice that fail to produce normal P-locus transcript, even though these mice are genetically normal at the loci that regulate production of the three melanogenic proteins. We have hypothesized that the presence of the p-locus protein is important for the integrity of the melanogenic complex and for the levels of members of the TRP family. We show here that the yellow skins of mice mutant at the agouti or extension loci, as well as the nonyellow skins of pinkeyed-unstable (p(un)/p(un)) mice, demonstrate greatly diminished levels of tyrosinase, TRP-1 and TRP-2, and an absence or markedly decreased proportion of high-molecular-weight forms of melanogenic proteins. We conclude that normal levels of wild-type P-locus protein are necessary for eumelanogenesis and that the absence of this protein may be necessary, but is not sufficient to cause the melanosome to switch to the production of pheomelanin. We discuss the implications of our results in relation to the interacting genetic controls regulating melanogenesis.
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PMID:The pinkeyed-dilution protein and the eumelanin/pheomelanin switch: in support of a unifying hypothesis. 878 1

Sequence analysis of two clones found repressed in melanoma cell lines in earlier studies showed 9F2 to be identical with the TRP-1 gene and 6F5 with TRP-2 containing a long untranslated 3' end. For further investigation of the expression of the tyrosinase gene family in normal and malignant melanocytic cells, a series of melanoma cell lines and of cultured melanocytes were analyzed by Northern blotting and by reverse transcriptase-polymerase chain reaction (RT-PCR). The Northern blots were probed with cDNA fragments specific for TRP-1, TRP-2, and tyrosinase, for nested tyrosinase-PCR the outer primers specified a 284 bp and the nested primers a 207 bp fragment. Investigations on 14 established melanoma cell lines grown in different media compared with seven normal human melanocyte (NHM) cultures revealed that all three pigment genes were expressed in NHM, whereas pigment gene expression was found repressed in nearly all melanoma cell lines and was completely absent in 4 of 14 specimen. In particular, tyrosinase and TRP-2 genes were found always to be expressed together, and TRP-1 mRNA alone was absent in four melanoma cell lines. Negativity of cultured melanoma cells for tyrosinase mRNA was confirmed by nested RT-PCR, and gene deletion was ruled out by genomic Southern blots. The gene expression seemed independent from the type of medium used for cultivation. These findings indicate repressed or lacking expression of pigment genes in melanoma cell lines, most likely due to regulatory mechanisms, and that differences may exist between tyrosinase and TRP-2 on one hand and TRP-1 on the other. Overall, it seemed that RT-PCR for tyrosinase has limited value for identifying melanoma cells in the peripheral blood of melanoma patients; TRP-1, TRP-2, and other, additional markers may be required.
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PMID:Incomplete expression of the tyrosinase gene family (tyrosinase, TRP-1, and TRP-2) in human malignant melanoma cells in vitro. 878 39

Melanogenesis is regulated by a variety of environmental and hormonal factors. In this study, we showed that protein kinase C (PKC) plays a major role in regulating melanogenesis in B16 mouse melanoma cells. Chronic treatment of B16 cells with phorbol dibutyrate resulted in a concentration-dependent loss of density-dependent induction of tyrosinase activity, which correlated positively with a concentration-dependent loss of PKC enzyme activity. In contrast, B16 clones overexpressing PKC alpha had increased tyrosinase activity. Different phorbol derivatives inhibited tyrosinase activity and depleted cellular PKC alpha in a manner that reflected their reported tumor-promoting activity. Western blotting analysis showed that phorbol dibutyrate decreased the amount of the brown locus gene product (TRP-1) by 50% and lowered the amount of the albino locus gene product (tyrosinase) to undetectable levels. None of the phorbol derivatives affected the level of the slaty locus protein (TRP-2). The decrease in tyrosinase and TRP-1 protein levels was found to be due to a decrease in the mRNA encoded by these genes. In addition to inhibiting the density-dependent increase in tyrosinase activity, phorbol dibutyrate inhibited some, but not all, of the 8-bromocyclic AMP-induced increase in tyrosinase activity. This was accompanied by a decrease in the amount of tyrosinase protein induced by 8-bromocyclic AMP. Although 8-bromocyclic AMP did not change the level of TRP-1, it did reverse the decrease in the amount of this protein induced by phorbol dibutyrate. The amount of TRP-2 was not altered by any of these agents. These data suggest that PKC regulates melanogenesis primarily by controlling the constitutive expression of tyrosinase and, to a lesser extent, TRP-1.
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PMID:Regulation of melanogenesis in B16 mouse melanoma cells by protein kinase C. 881 9

Human skin grafted on to athymic nude mice (BALB/C-nu/nu) spontaneously hyperpigments. We wished to identify the morphological and molecular bases for the hyperpigmentation for this phenomenon. We present data on the relationship of healing, regeneration of melanocytes and production of some melanogenic stimuli. Biopsies were taken at preset times post-graft and studied by histological and immunohistochemical methods. DOPA-positive melanocytes first became visible 120 h post-graft and melanin deposition became visible along the basal cell layer 2 weeks post-graft and increased in quantity with time. By immunochemical stains the quantity of three melanocyte specific enzymes, i.e. tyrosinase, tyrosinase-related protein-1 (TRP-1) and DOPA-chrome tautomerase (TRP-2), was markedly enhanced 1 week after grafting and persisted until 4 weeks post-graft. alpha-Melanocyte-stimulating hormone and adrenocorticotrophic hormone were clearly detected in the epidermis soon after grafting. They were still strongly detected in the epidermis and in the dermis 2-4 weeks post-graft. We conclude that hyperpigmentation in the grafted skin accompanies a marked increase in the quantity of melanogenic enzymes and melanogenic peptides. The neuropeptides might be one of many factors which stimulate melanogenesis.
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PMID:Hyperpigmentation of human skin grafted on to athymic nude mice: immunohistochemical study. 894 35

Tyrosinase, tyrosinase-related protein-1 (TRP-1), and TRP-2 are the enzymes involved in melanin biosynthesis and are preferentially expressed in pigment cells. Their human gene promoters share the 11-base pair M box containing a CATGTG motif, which was shown here to be bound in vitro by microphthalmia-associated transcription factor (MITF). Transient cotransfection analysis showed that MITF overexpression increased the expression of a reporter gene under the control of the human tyrosinase or TRP-1 gene promoter but not the TRP-2 promoter. The promoter activation caused by MITF is dependent on each CATGTG motif of the distal enhancer element, the M box, and the initiator E box of the tyrosinase gene and the TRP-1 M box. Furthermore, a truncated MITF lacking the carboxyl-terminal 125 amino acid residues transactivated the tyrosinase promoter less efficiently than did MITF, suggesting that MITF's carboxyl terminus contains a transcriptional activation domain, but unexpectedly such a truncated MITF remarkably transactivated the TRP-2 gene promoter. These results suggest that MITF is sufficient to direct pigment cell-specific transcription of the tyrosinase and TRP-1 genes but not the TRP-2 gene.
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PMID:Functional analysis of microphthalmia-associated transcription factor in pigment cell-specific transcription of the human tyrosinase family genes. 899 90

Current evidence suggests that melanogenesis is controlled by epidermal paracrine modulators. We have analyzed the effects of transforming growth factor-beta1 (TGF-beta1) on the basal melanogenic activities of B16/F10 mouse melanoma cells. TGF-beta1 treatment (48 h) elicited a concentration-dependent decrease in basal tyrosine hydroxylase and 3,4-dihydroxyphenylalanine (Dopa) oxidase activities, to less than 30% of the control values but had no effect on dopachrome tautomerase activity (TRP-2). The inhibition affected to similar extents the Dopa oxidase activity associated to tyrosinase-related protein-1 (TRP-1) and tyrosinase. This inhibition was noticeable between 1 and 3 h after the addition of the cytokine, and maximal after 6 h of treatment. The decrease in the enzymatic activity was paralleled by a decrease in the abundance of the TRP-1 and tyrosinase proteins. TGF-beta1 mediated this effect by increasing the rate of degradation of tyrosinase and TRP-1. Conversely, after 48 h of treatment, the expression of the tyrosinase gene decreased only slightly, while TRP-1 and TRP-2 gene expression was not affected. An increased rate of proteolytic degradation of TRP-1 and tyrosinase seems the main mechanism accounting for the inhibitory effect of TGF-beta1 on the melanogenic activity of B16/F10 cells.
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PMID:Transforming growth factor-beta1 inhibits basal melanogenesis in B16/F10 mouse melanoma cells by increasing the rate of degradation of tyrosinase and tyrosinase-related protein-1. 902 Jan 1

Both melanocytes and glial cells are derived embryologically from the neural ectoderm. Their malignant transformed counterparts, melanoma and glioma cells, respectively, may share common antigens. Numerous tumor-associated antigens have been identified in melanomas but only a few a gliomas. Using an established reverse transcriptase polymerase chain reaction plus Southern blot assay, we compared the mRNA expression of melanoma-associated antigens (MAAs) of melanomas to brain tumors primarily derived from glial cells. The MAAs studied included tyrosinase (Tyr), tyrosinase-related protein-1 and -2 (TRP-1 and TRP-2), gp100, human melanoma antigen-encoding genes 1 and 3 (MAGE-1 and MAGE-3), and melanotransferrin (p97). Glioblastoma multiforme (n = 21), anaplastic astrocytoma (n = 3), ependymoma (n = 2), meningioma (n = 3), oligodendroglioma (n = 1), and melanoma (n = 12) tumor specimens were assayed for MAA mRNA expression. Glioblastoma multiforme, astrocytoma, and melanoma cell lines were also assayed. We observed that individual MAA mRNAs were expressed in these brain tumors and cell lines at varying frequencies. The melanogenesis-pathway-related MAAs Tyr, TRP-1, TRP-2, and gp100 mRNAs were also expressed at different levels in normal brain tissues but at a much lower frequency than in glioblastoma multiforme and melanoma. MAGE-1 and MAGE-3 mRNA were expressed in different types of tumor specimens and cell lines but never in normal brain tissue. Tumor antigen p97 was expressed in all types of tumors and also in normal brain tissues. These studies demonstrate that melanomas and primary brain tumors express common MAAs and could be exploited in patients with malignant glioma by active specific immunotherapy against these common MAAs.
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PMID:Molecular detection of tumor-associated antigens shared by human cutaneous melanomas and gliomas. 917 5

In the present study we describe the detection of TRP-2 antibodies in vitiligo patients using in vitro 35S-labelled human TRP-2 in a radioimmunoassay. Of 53 vitiligo sera examined in the assay, three (5 9%) were found to be positive for TRP-2 antibodies. In contrast, 20 control sera, sera from 10 patients with Hashimoto's thyroiditis and sera from 10 patients with Graves' disease were all negative. All three patients positive for TRP-2 antibodies (mean age 54 years, age range 50-63 years) had had vitiligo of the symmetrical type for more than 1 year and all of them also had an associated autoimmune disorder: Graves' disease in one and autoimmune hypothyroidism in two. In addition, antibodies to the melanogenic enzyme tyrosinase were present in their serum. To examine any immunological cross-reactivity between TRP-2 and tyrosinase, the three vitiligo sera positive for TRP-2 antibodies were preabsorbed with COS-7 cell extract containing either expressed TRP-2 or tyrosinase, and subsequently used in the radioimmunoassay. These absorption studies indicated that preincubation with both proteins inhibited the immunoreactivity of the positive sera in the immunoassay using in vitro translated 35S-TRP-2. This antibody cross-reactivity suggests the humoral response to the two melanogenic enzymes in these patients may not be entirely independent.
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PMID:Immunoprecipitation of melanogenic enzyme autoantigens with vitiligo sera: evidence for cross-reactive autoantibodies to tyrosinase and tyrosinase-related protein-2 (TRP-2). 932 28

Tyrosinase and tyrosinase-related proteins (TRP-1 and TRP-2) are essential for melanin synthesis and are expressed in neural crest-derived melanocytes and in the pigment epithelium of the retina. Recent results suggest expression of all three proteins within the central nervous system. We performed a transgenic assay using beta-galactosidase as reporter gene to monitor tyrosinase promoter activity in vivo. During embryogenesis, we found expression in several locations of developing forebrain and midbrain. Tyrosinase, TRP-1 and TRP-2 had been equally found in extracts of adult mouse brain. In adult brain, we detected tyrosinase promoter activity in cortex, olfactory system, hippocampus, epithalamus and substantia nigra, areas corresponding to positive staining during embryogenesis. Thus, tyrosinase promoter is active throughout murine brain development, and tyrosinase could be implicated in neuromelanin formation in the substantia nigra, and in neurodegenerative disorders like Parkinson's disease.
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PMID:New evidence for presence of tyrosinase in substantia nigra, forebrain and midbrain. 947 5


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