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)

The tyrosinase family in vertebrates consists of three related melanogenic enzymes: tyrosinase, tyrosinase-related protein-1 (TRP-1), and TRP-2. These proteins control melanin production in pigment cells and play a crucial role in determining vertebrate coloration. We have isolated a gene from the ascidian Halocynthia roretzi which encodes a tyrosinase-related protein (HrTRP) with 45-49% identity with vertebrate TRP-1 and TRP-2. The expression of the HrTRP gene in pigment lineage a8.25 cells starts at the early-mid gastrula stage, which coincides with the stage when these cells are determined as pigment precursor cells; therefore, it provides the earliest pigment lineage-specific marker, which enables us to trace the complete cell lineage leading to two pigment cells in the larval brain. In addition, the expression pattern of the HrTRP gene appears to share similar characteristics with the mouse TRP-2 gene although structurally the HrTRP gene is more closely related to mammalian TRP-1 genes. Based on these observations and on results from molecular phylogenetic and hybridization analyses, we suggest that triplication of the tyrosinase family occurred during the early radiation of chordates. Initially, duplication of an ancestral tyrosinase gene produced a single TRP gene before the urochordate and cephalochordate-vertebrate divergence, and a subsequent duplication of the ancestral TRP gene in the vertebrate lineage gave rise to two TRP genes before the emergence of teleost fishes. Evolution of the melanin synthetic pathway and possible phylogenetic relationships among chordate pigment cells that accommodate the metabolic process are discussed. Dev Dyn 1999;215:225-237.
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PMID:Structure and developmental expression of the ascidian TRP gene: insights into the evolution of pigment cell-specific gene expression. 1039 33

Oral vitamin E (alpha-tocopherol, alpha-T) supplementation has been reported to improve facial hyperpigmentation. alpha-Tocopheryl ferulate (alpha-TF) is a compound of alpha-T and ferulic acid connected by an ester bond; ferulic acid is also an antioxidant, and could scavenge free radicals induced by ultraviolet (UV) radiation, and thus maintain the long-lasting antioxidative effect of alpha-T. Our aim was to see whether alpha-TF might be useful as a whitening agent and an antioxidant to improve and prevent facial hyperpigmentation following UV exposure. In this study, the inhibitory effect of alpha-TF on melanogenesis was examined biochemically using human melanoma cells in culture. The results show that alpha-TF, solubilized in ethanol or in 0.5% lecithin, inhibited melanization significantly, as did alpha-T at a concentration of 100 microg/mL, without inhibiting cell growth. This phenotypic change was associated with inhibition of tyrosinase and 5, 6-dihydroxyindole-2-carboxylic acid polymerase activities, and the degree of inhibition was dose dependent. No significant effect on DOPAchrome tautomerase activity was observed. alpha-TF did not directly inhibit tyrosinase activity of the large granule fraction extracted from human melanoma cells, and Western blotting revealed that there were no changes in protein content or in molecular size of tyrosinase, tyrosinase-related protein (TRP)-1 or TRP-2. Therefore, the inhibition of tyrosinase activity by alpha-TF might be due to effects at the post-translational level, and possibly by a secondary molecule activated by alpha-TF. These results suggest that alpha-TF is a candidate for an efficient whitening agent which suppresses melanogenesis and inhibits biological reactions induced by reactive oxygen species.
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PMID:The depigmenting effect of alpha-tocopheryl ferulate on human melanoma cells. 1041 11

Self-antigens, in the form of differentiation antigens, are commonly recognized by the immune system on melanoma and other cancers. We have shown previously that active immunization of mice against the melanocyte differentiation antigen, a tyrosinase-related protein (TRP) gp75(TRP-1) (the brown locus protein) expressed by melanomas, could induce tumor immunity and autoimmunity manifested as depigmentation. In this system, tumor immunity and autoimmunity were mediated by autoantibodies. Here, we characterize immunity against another tyrosinase family glycoprotein TRP-2 (the slaty locus protein), using the same mouse model and method of immunization. As observed previously for gp75(TRP-1), immunity was induced by DNA immunization against a xenogeneic form of TRP-2, but not against the syngeneic gene, and depended on CD4(+) cells. Immunization against TRP-2 induced autoantibodies and autoreactive cytotoxic T cells. In contrast to immunization against gp75(TRP-1), both tumor immunity and autoimmunity required CD8(+) T cells, but not antibodies. Only autoimmunity required perforin, whereas tumor immunity proceeded in the absence of perforin. Thus, immunity induced against two closely related autoantigens that are highly conserved throughout vertebrate evolution involved qualitatively different mechanisms, i.e., antibody versus CD8(+) T cell. However, both pathways led to tumor immunity and identical phenotypic manifestations of autoimmunity.
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PMID:Coupling and uncoupling of tumor immunity and autoimmunity. 1058 62

Tyrosinase related protein (TRP)-1 and TRP-2 are known to regulate the quality of melanin, and recently their potential role in inhibiting apoptosis have also been reported. To study the role of tyrosinase, TRP-1 and TRP-2 in the growth, differentiation and cell death of ultraviolet B (UVB) irradiated melanocytes, the expression of these proteins in amelanotic and melanotic cells was examined. Expression of tyrosinase and TRP-1 correlated with melanin content, which was upregulated after repeated irradiation of melanotic cells by low doses of UVB. In contrast, the expression and activity of TRP-2 correlated with cell proliferation, but not with pigmentation. In one melanotic melanoma cell line, significant suppression of cell proliferation was observed after low or high doses of UVB irradiation, possibly due to apoptotic changes. TRP-2 expression was remarkably reduced in UVB-irradiated cells, and transfection with TRP-2 expression vector rescued these cells from UVB-induced apoptosis. These results indicate that TRP-2 expression is closely associated with the regulation of cell growth/survival of melanocytes exposed to UVB and that TRP-2 plays a role in protecting melanoma cells from UVB-induced apoptosis.
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PMID:Expression of tyrosinase, TRP-1 and TRP-2 in ultraviolet-irradiated human melanomas and melanocytes: TRP-2 protects melanoma cells from ultraviolet B induced apoptosis. 1059 9

Fusion of mouse peritoneal macrophages or human blood monocytes with weakly metastatic mouse Cloudman S91 melanoma cells resulted in hybrids with enhanced metastatic potential (Rachkovsky et al., 1998. Clin. Exp. Metastasis, 16: 299-312). With few exceptions, such hybrids also showed increased basal- and MSH-induced pigmentation, at least in part through increased N-glycosylation of melanogenic proteins (Sodi et al., 1998. Pigment Cell Res., 11: 299-309). Here we report analyses regarding expression of the melanocyte-stimulating hormone (MSH) receptor (melanocortin-1 receptor, MC1-R) and the melanogenic proteins, tyrosinase (E.C. 1.14.18.1), tyrosinase-related protein 1 (TRP-1), and the tyrosinase-related protein 2 (TRP-2, E.C. 5.3.2.3), by a panel of cell lines consisting of parental Cloudman S91 melanoma cells, macrophages from DBA/2J mice, artificially derived macrophage x melanoma hybrids of high and low metastatic potential, and a naturally occurring highly metastatic hybrid between a Cloudman S91 tumor cell and a DBA/2J tumor-infiltrating cell. We show that incubation of cells with MSH/isobutylmethylxanthine (IBMX) resulted in strong melanogenic and morphologic responses in high metastatic hybrids compared to parental cells and the low metastatic hybrid, and that high metastatic hybrids exhibit increased mRNA expression for MC1-R accompanied by increased 125I-alphaMSH binding. Although tyrosinase activity and the protein level for tyrosinase and TRP-2, but not for TRP-1, were increased in the high metastatic hybrids versus the other cells, no significant changes in mRNA either for tyrosinase or for TRPs were observed in them. Furthermore, unlike tyrosinase, the abundance and gel mobility pattern of TRP-2 did not correlate with changes in activity in all hybrids and parental melanoma cells. The results suggest that although the activity MC1-R and tyrosinase correlate with enhanced basal as well as MSH-induced melanogenesis in metastatic/melanotic hybrids, their expression is differentially regulated, i.e., regulation of MC1-R while at transcriptional level, the TRPs are primarily regulated via post-transcriptional mechanisms in high metastatic hybrids.
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PMID:Upregulation of mRNA for the melanocortin-1 receptor but not for melanogenic proteins in macrophage x melanoma fusion hybrids exhibiting increased melanogenic and metastatic potential. 1061 75

Oral vitamin E (alpha-tocopherol) supplementation has been reported to improve facial hyperpigmentation. The compound of alpha-tocopherol and ferulic acid, also an antioxidant connected with an ester bond, alpha-tocopheryl ferulate (alpha-TF) can absorb ultraviolet (UV) radiation and thus maintain tocopherol in a stable state. Our aim was to determine whether alpha-TF can be applied to improve and prevent facial hyperpigmentation induced by UV as a whitening agent as well as an antioxidant. In this study, the effects of alpha-TF on melanogenesis were examined using cultured human melanoma cells and normal human melanocytes in vitro. alpha-TF solubilized in 0.5% lecithin inhibited melanization significantly at the concentration of 30 micrograms/ml compared with arbutin (100 micrograms/ml), kojic acid (100 micrograms/ml), ascorbic acid (600 micrograms/ml), and tranexamic acid (600 micrograms/ml). alpha-TF had no effect on the protein amounts of tyrosinase, TRP (tyrosinase related protein)-1, and TRP-2 of human melanoma cells exposed to UV radiation, but inhibited tyrosine hydroxylase activity. alpha-TF neither directly inhibited tyrosinase activity of the large granule fraction extracted from melanoma cells, nor modulated glycosylation of tyrosinase. These results suggest that alpha-TF may be a candidate for whitening agent which suppresses melanogenesis, possibly by inhibiting tyrosine hydroxylase activity in an indirect manner. Further, alpha-TF decreased the amount of 8-hydroxydeoxyguanosine produced indirectly through active oxygen species (AOS) in guinea pig skin exposed to 2 times the minimal erythema dose of UVB radiation, but did not suppress the direct formation of cyclobutane pyrimidine dimers and (6-4) photoproducts. Thus alpha-TF may reduce AOS-induced DNA damage and thereby contribute at least in part to suppressing or retarding skin cancer development.
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PMID:The inhibitory effect of DL-alpha-tocopheryl ferulate in lecithin on melanogenesis. 1062 56

It was recently reported that a majority of hybrids generated in vitro between weakly metastatic mouse Cloudman S91 melanoma cells and human or mouse macrophages showed enhanced metastatic potential (Rachkovsky et al., 1998). With few exceptions, hybrids with enhanced metastatic potential also had elevated basal melanin content, enhanced chemotactic responses to fibroblast-conditioned media, and stronger responsiveness to MSH compared to parental cells. Analyses revealed that altered N-glycosylation in metastatic hybrids could explain the multiple phenotypic changes. Tyrosinase, TRP-2 and LAMP-1 from hybrids migrated more slowly on gels compared to the same proteins from parental melanoma cells, consistent with increased glycosylation. Migration of LAMP-1 from hybrids was similar to that from peritoneal macrophages which also appeared to be more heavily glycosylated than LAMP-1 from Cloudman cells. The incorporation of 3H-glucosamine, as a marker of N-glycosylation, into tyrosinase and LAMP-1 was found to be elevated in hybrids, suppressed by N-glycosylation inhibitors and stimulated by MSH to a greater degree in hybrids compared to parental cells. These results indicate N-glycosylation as an important regulatory pathway for MSH-induced melanogenesis, and further suggest that altered N-linked glycosylation may be an underlying mechanism for regulation of both melanogenesis and metastasis in macrophage x melanoma hybrids.
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PMID:Altered N-glycosylation in macrophage x melanoma fusion hybrids. 1064 5

Microphthalmia (MITF) gene product, a transcription factor of the basic-helix-loop-helix type, is thought to play a role in the regulation of genes encoding the enzymes necessary for melanogenesis. These include tyrosinase, TRP-1 and TRP-2. Melanocyte-specific isoform of microphthalmia, MITF-M, is expressed in normal and malignant melanocytes. The presence of two other isoforms of microphthalmia, MITF-A and MITF-H, which differ from MITF-M in the amino-terminus, was demonstrated also in some non-melanocytic lineages. Here we have analyzed the presence of all three known isoforms of MITF mRNA in a panel of 17 human melanoma cell lines by a reverse transcriptase-polymerase chain reaction using isoform-specific primers. While, as expected, the predominant form in melanoma cell lines was MITF-M, low amounts of MITF-A mRNA was found in almost all melanomas, as well as in most of 20 tumor cell lines of the non-melanocyte origin (lung and colon carcinomas, osteosarcomas and neuroblastomas). The expression of MITF-H was not detected, with a few exceptions, in the tested cell lines. Pax3 transcription factor was reported earlier to regulate positively the melanocyte-specific promoter of the MITF gene. We found here that the Pax 3 mRNA was expressed in all melanoma cell lines, even in those that had repressed the MITF-M and were amelanotic. This suggests that additional factors, besides Pax3, are required for the MITF expression. The MSG1 (melanocyte-specific gene 1), a gene originally isolated from melanocytes and containing a strong transcription activation domain, was also found expressed in all melanomas and most non-melanocyte tumor cell lines. Together, these data indicate that the MITF-M isoform is the major type of MITF mRNA present in human melanoma cell lines and show that the expression of the isoform MITF-A and the MSG1 is not restricted to malignant melanocytes and occurs in a wide range of tumor cell lines.
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PMID:Expression of genes for microphthalmia isoforms, Pax3 and MSG1, in human melanomas. 1064 12

The level of expression of melanoma antigens (MA) may modulate the host immunologic response. Thus, the accurate measurement of MA expression may allow proper patient selection for antigen-specific therapies and yield important information for the evaluation of clinical results. In this study, we measured the absolute levels of MA messenger ribonucleic acid (mRNA) in tumor cell lines utilizing real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). mRNA levels of MART-1, gp100, tyrosinase, TRP-1 and TRP-2 melanoma differentiation antigens and MAGE-1, MAGE-3 and ESO-1 cancer testis (CT) antigens were compared in 24 early-passage (<5 passages in culture) and 12 archival melanoma cell lines. MA mRNA expression was extremely variable among cell lines, occasionally reaching levels comparable to ribosomal RNA (rRNA). gp100 and MART-1 mRNA levels correlated with protein expression measurement obtained by FACS analysis. More significantly, a threshold of gp100 mRNA expression required for T-cell stimulation and target-cell killing was identified. This threshold level corresponded to approximately 500 mRNA copies per 10(8) copies of rRNA. Our results suggest that the measurements of MA mRNA levels may yield useful information relevant to the interpretation of clinical outcome during antigen-specific treatments.
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PMID:Threshold levels of gene expression of the melanoma antigen gp100 correlate with tumor cell recognition by cytotoxic T lymphocytes. 1084 96

Melanin pigments are found in all biological kingdoms. At the cellular level, correct pigmentation depends not only on correct migration of pigment cells (melanocytes) and their precursors (melanoblasts), but also on specialized cytoplasmic organelles, melanosomes. Three pigment cell-specific enzymes inside melanosomes are involved in melanogenesis: tyrosinase, TRP-1 and TRP-2/DOPA-chrome tautomerase. A point mutation of tyrosinase is sufficient to give rise to a nonfunctional enzyme, leading to albinism and associated decreased visual acuity. Several regulatory elements have been identified within the promoters of the genes encoding these three enzymes. These promoter fragments have been used to target the expression of heterogeneous genes in pigment cells of transgenic mice.
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PMID:[Cellular and molecular features of mammalian pigmentation--tyrosinase and TRP]. 1096 38


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