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)

Cutaneous melanomas of Tyr-SV40E transgenic mice (mice whose transgene consists of the tyrosinase promoter fused to the coding regions of simian virus 40 early genes) strikingly resemble human melanomas in their development and progression. Unlike human melanomas, the mouse tumors all arise in genetically identical individuals, thereby better enabling expression of specific genes to be characterized in relation to advancing malignancy. The products of pigment genes are of particular interest because peptides derived from these proteins have been reported to function as autoantigens with immunotherapeutic potential in some melanoma patients. However, the diminished pigmentation characteristic of many advanced melanomas raises the possibility that some of the relevant products may no longer be expressed in the most malignant cells. We have therefore investigated the contributions of several pigment genes in melanotic vs. relatively amelanotic components of primary and metastatic mouse melanomas. The analyses reveal marked differences within and among tumors in levels of mRNAs and proteins encoded by the wild-type alleles at the albino, brown, slaty, and silver loci. Tyrosinase (the protein encoded by the albino locus) was most often either absent or undetectable as melanization declined. The protein encoded by the slaty locus (tyrosinase-related protein 2) was the only one of those tested that was clearly present in all the tumor samples. These results suggest that sole reliance on targeting tyrosinase-based antigens might selectively favor survival of more malignant cells, whereas targeting the ensemble of the antigens tested might contribute toward a more inclusive and effective antimelanoma strategy.
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PMID:Changes in expression of putative antigens encoded by pigment genes in mouse melanomas at different stages of malignant progression. 747 44

Several genes critical to the enzymatic regulation of melanin production in mammals have recently been cloned and mapped to the albino, brown and slaty loci in mice. All three genes encode proteins with similar structures and features, but with distinct catalytic capacities; the functions of two of those gene products have previously been identified. The albino locus encodes tyrosinase, an enzyme with three distinct melanogenic functions, while the slaty locus encodes tyrosinase-related protein 2 (TRP2), an enzyme with a single specific, but distinct, function as DOPAchrome tautomerase. Although the brown locus, encoding TRP1, was actually the first member of the tyrosinase gene family to be cloned, its catalytic function (which results in the production of black rather than brown melanin) has been in general dispute. In this study we have used two different techniques (expression of TRP1 in transfected fibroblasts and immunoaffinity purification of TRP1 from melanocytes) to examine the enzymatic function(s) of TRP1. The data demonstrate that the specific melanogenic function of TRP1 is the oxidation of 5,6-dihydroxyindole-2-carboxylic acid (DHICA) to a carboxylated indole-quinone at a down-stream point in the melanin biosynthetic pathway. This enzyme activity appears to be essential to the further metabolism of DHICA to a high molecular weight pigmented biopolymer.
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PMID:Tyrosinase related protein 1 (TRP1) functions as a DHICA oxidase in melanin biosynthesis. 781 20

We have cloned and sequenced the human genomic DNA segments encoding the 5'-flanking region and the first two exons of the DOPAchrome tautomerase (DT)/tyrosinase-related protein 2 (TRP-2) gene. The DT gene is a member of the tyrosinase gene family and specifically expressed in melanin-producing cells. A transcriptional initiation site of the DT gene was identified by S1 nuclease-mapping and primer-extension analyses using RNA prepared from human pigmented melanoma cells. To study the mechanism for pigment cell-specific expression of the human DT gene, we analyzed the promoter function of its 5'-flanking region by transient expression assays. The fusion genes, containing the DT gene promoter upstream from a firefly luciferase reporter gene, were introduced into human pigmented melanoma cells and HeLa cells, and the pigment cell-specific promoter activity was evaluated by comparing the luciferase activity expressed in both cell lines. A series of 5' deletion studies of the human DT gene promoter revealed that the 32-bp element, located between -447 and -415, is sufficient to confer pigment cell-specific expression of a reporter gene on a homologous promoter, but not on a heterologous simian virus 40 promoter. Internal deletion studies using a homologous or a heterologous promoter revealed that the pigment cell-specific expression of a reporter gene mediated by the 32-bp element is dependent on the presence of another region of the DT gene spanning from -268 to -56, which was termed the proximal region. However, the proximal region by itself is not sufficient to confer cell type-specific expression. These results indicate that the presence of two regulatory regions, the 32-bp element and the proximal region, is required for pigment cell-specific expression of the DT gene. Both regulatory regions contain a CANNTG motif, a well known binding site for a large family of transcription factors possessing a basic helix-loop-helix structure.
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PMID:Cloning of the human DOPAchrome tautomerase/tyrosinase-related protein 2 gene and identification of two regulatory regions required for its pigment cell-specific expression. 792 51

Expression of basic fibroblast growth factor cDNA or dominantly acting oncogenes, e.g., E1A, in immortalized mouse melanocytes leads to autonomous growth in vitro, depigmentation, and in the case of the oncogenes, tumorigenesis. Because downregulation of pigmentation is a common event in human metastatic melanoma cells grown in culture, we determined the molecular basis of depigmentation in a mouse melanocyte model system. We tested the effect of E1A mutants deficient in their ability to neutralize several regulatory proteins and determined changes in melanogenic gene expression. We identified Microphthalmia as the affected, downregulated transcription factor in melanocytes rendered amelanotic by E1A, basic fibroblast growth factor, or the oncogenes ras or neu, and in an amelanotic cell variant of Cloudman S91 mouse melanoma. Against expectations, sequestration of p300, a transcriptional adaptor that mediates responses to cyclic adenosine monophosphate, was not required for the full transforming effects of E1A. Our results suggest that in addition to controlling tyrosinase (albino locus) and tyrosinase-related protein 1 (TR-P1/gp75/brown locus), both known to possess the DNA consensus site for binding the Microphthalmia protein, this transcription factor also controls other melanocyte-specific genes such as pink-eyed dilution and Pmel 17 (silver), but not tyrosinase-related protein 2 (slaty locus). Furthermore, these findings show that microphthalmia is downregulated not only by experimentally introduced dominantly acting oncogenes but also by the aberrant expression of basic fibroblast growth factor and by spontaneous tumorigenic transformation.
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PMID:Growth regulatory proteins that repress differentiation markers in melanocytes also downregulate the transcription factor microphthalmia. 875 68

The inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) is present in the dermal and epidermal layers of normal skin [Kilgus, O., Payer, E., Schreiber, S., Elbe, A., Strohal, R. & Stingl, G. (1993) J. Invest. Dermatol. 100, 674-680]. Its local concentrations are modified by several stimuli, including wound healing and ultraviolet irradiation. Moreover, TNF-alpha inhibits melanogenesis in normal melanocytes [Swope, V., Abdel-Malek, Z., Kassem, L. & Norlund, J. (1991) J. Invest. Dermatol. 96, 180-185], and is, therefore, a potential autocrine/paracrine regulator of pigmentation. We have analyzed the mechanisms of this effect using B16/F10 melanoma cells as a model. Nanomolar concentrations of TNF-alpha inhibit the tyrosine hydroxylase and dopa oxidase activities of B16/F10 melanocytes, to less than 30% control levels, without effects on tyrosinase-related protein 2/dopachrome tautomerase (TRP2/DCT). The 50% inhibition was obtained at 1 nM TNF-alpha and 48 h treatment. The effect of TNF-alpha was noticeable after 6 h treatment, and maximal after 24 h. This inhibition is explained by decreased intracellular levels of tyrosinase and tyrosinase-related protein 1 (TRP1), but not of TRP2/DCT as detected by Western blotting. Northern-blot experiments showed that the inhibitory effect is partially explained by a reduced accumulation of the corresponding mRNAs, that dropped to about 50% of control values (48 h treatment, 5 nM TNF-alpha). Moreover, the tyrosine hydroxylase and dopa oxidase activities decreased more rapidly in TNF-alpha-treated cells than in control cells, under conditions of inhibition of protein synthesis. This suggests a TNF-mediated reduction of tyrosinase half-life. However, the possibility of an inhibitory post-translational modification of the enzyme induced by TNF cannot be ruled out. Therefore, the inhibitory effect of TNF-alpha on tyrosinase and TRP-1 results from combined effect on mRNA levels and enzymatic activity or protein stability.
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PMID:Mechanisms of melanogenesis inhibition by tumor necrosis factor-alpha in B16/F10 mouse melanoma cells. 969 12

The effects of lincosamide, and interference between the effects of glucocorticoid and lincosamide, on melanogenesis were determined in B16 melanoma cells. Cells were treated for 4 days with lincomycin (LM) and/or dexamethasone (DX) at equimolar concentrations ranging from 10(-9) M to 10(-5) M, or at various concentrations of DX with 10(-6) M LM. Effects on proliferation, tyrosinase activity, melanin biosynthesis, and levels of mRNA for tyrosinase, tyrosinase-related protein 1 (TRP1), and tyrosinase-related protein 2 (TRP2) were examined. Treatment with LM or LM + DX stimulated proliferation of melanoma cells with minimal cytotoxicity, while DX did not influence cell proliferation either alone or in combination with LM. Treatment with LM alone increased tyrosinase activity slightly and reduced melanin content in a dose-dependent manner. However, LM counteracted the pronounced increase in tyrosinase elicited by DX and also abrogated the dose-dependent increase in melanin content elicited by DX. Treatment with LM alone did not affect mRNA levels for tyrosinase, TRP1, or TRP2. Furthermore, LM abrogated the DX-induced up-regulation of mRNAs for tyrosinase and the down-regulation of TRP1 mRNA. These results suggest that LM inhibits melanogenesis post-transcriptionally and abrogates glucocorticoid-induced melanogenesis at the transcriptional level in B16 melanoma cells.
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PMID:Lincomycin abrogates dexamethasone-enhanced melanogenesis in B16 melanoma cells. 973 Mar 21

The purpose of this study was to investigate the mechanism of fatty acid-induced regulation of melanogenesis. An apparent regulatory effect on melanogenesis was observed when cultured B16F10 melanoma cells were incubated with fatty acids, i.e., linoleic acid (unsaturated, C18:2) decreased melanin synthesis while palmitic acid (saturated, C16:0) increased it. However, mRNA levels of the melanogenic enzymes, tyrosinase, tyrosinase-related protein 1 (TRP1), and tyrosinase-related protein 2 (TRP2), were not altered. Regarding protein levels of these enzymes, the amount of tyrosinase was decreased by linoleic acid and increased by palmitic acid, whereas the amounts of TRP1 and TRP2 did not change after incubation with fatty acids. Pulse-chase assay by [35S]methionine metabolic labeling revealed that neither linoleic acid nor palmitic acid altered the synthesis of tyrosinase. Further, it was shown that linoleic acid accelerated, while palmitic acid decelerated, the proteolytic degradation of tyrosinase. These results suggest that modification of proteolytic degradation of tyrosinase is involved in regulatory effects of fatty acids on melanogenesis in cultured melanoma cells.
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PMID:Possible involvement of proteolytic degradation of tyrosinase in the regulatory effect of fatty acids on melanogenesis. 1039 16

Mice vaccinated with Mycobacterium tuberculosis Ag38 gene-transduced B16 melanoma cells showed significant protection from intravenous challenge with parental B16 melanoma cells. No cytotoxic T-cell activity was found against melanoma cells, although the endogenous presence of the mycobacterial gene induced a preferential Th1 response. After immunization, a low serological response against melanoma cells was detected, while a high titer of antibodies directed to parental B16 cells, mainly of IgG2(a) isotype, was found in protected mice after challenge. These antibodies exhibited complement-dependent cytotoxicity against melanoma cells in vitro, while in vivo, used in passive immunization, they induced a decrease in a number of experimental B16 lung metastases. Most of the antibodies were directed against endogenous murine leukemia viruses. No reactivity against melanocyte lineage-specific antigens was observed. In particular, no reactivity was found in sera from protected mice against tyrosinase-related protein 2 (TRP-2), either stably expressed in a non-melanoma cell line or obtained by in vitro transcription-translation, or against tyrosinase, TRP-1 and gp100 antigens immunoprecipitated from B16 cells. Thus, in the B16 murine model, the presence of dominant viral antigens induces a very strong humoral response that might be protective and may inhibit or mask the presence of minor clonotypes.
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PMID:High level antibody response to retrovirus-associated but not to melanocyte lineage-specific antigens in mice protected against B16 melanoma. 1044 16

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

The albino (tyrosinase, Tyrc), brown (tyrosinase-related protein 1, Tyrp1b) and slaty (tyrosinase-related protein 2, tyrp2slt) loci are all involved in the regulation of melanogenesis. Phenotypes of inbred mice mutant at two or more of these loci are not always explicable by simple summation of the established or suspected catalytic functions of the gene products. These phenotypes suggest that relationships among the proteins extend beyond the obvious fact that they catalyze different steps in the same melanogenic pathway, and that they may also interact intimately in such a way that a mutation in one impacts the function of the other(s). Previous studies have attributed catalytic activities to each member of this trio; however, it has been difficult to study the proteins individually, either in vivo or in tissues or cells. Therefore, we undertook to transfect the genes, in revealing combinations, into COS-7 cells (which have no melanogenic apparatus of their own) to clarify the interacting functions of their encoded proteins. Specifically, we attempted to evaluate the effects of Tyrp1 and Tyrp2 proteins on tyrosinase protein. We report evidence that Tyrp1 stabilizes tyrosinase, confirming previous observations, and, in addition, demonstrate that Tyrp1 decreases tyrosinase activity. By contrast, Tyrp2 increases tyrosinase activity by stabilizing the protein. We conclude that both Tyrp1 and Tyrp2, in addition to other catalytic functions they may possess, act together to modulate tyrosinase activity.
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PMID:Mutational analysis of the modulation of tyrosinase by tyrosinase-related proteins 1 and 2 in vitro. 1104 Dec 14


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