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)

Planarians (Dugesia dorotocephala) were evaluated as bioassay organisms to detect inhibition of tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of catecholamines. Thirty planaria per dose were exposed to 0 (control), 0.001, 0.01, 0.1, or 1 mM 3-iodo-L-tyrosine (monoiodotyrosine or MIT) in standard test media beginning 24 hr before decapitation and continuing for 13 days. Complete regeneration of normal heads occurred over the first 6 days in all dose groups, a response reported to be partially dependent on catecholamines. Beginning on Day 7, the black eye pigments began fading in the 0.1 and 1 mM dose groups and were completely absent macroscopically and histologically by Day 11. The 0, 0.001, and 0.01 mM dose groups did not lose visible eye pigments. On Day 13, 3 planaria/dose were harvested for histopathology; 15 planaria/dose were decapitated a second time and remained in MIT solutions; and 12 planaria/dose were left intact, placed in fresh control media, and evaluated for eye repigmentation. Normal head regeneration (including eyes) was detected grossly in all groups, even in those animals devoid of eye pigments at the time of decapitation. As before, eye pigments began fading 7 days after decapitation (Day 20 of experiment) and were completely absent in 73 and 33% of the animals in the 0.1 and 1 mM groups, respectively, on Day 25. All animals moved to control media reformed eye pigments, beginning within 48 hr. Analysis of the decapitated heads by HPLC-ECD on Day 13 revealed a significant decrease in dopamine and 5-hydroxytryptamine (serotonin) concentrations in MIT-exposed animals. Tyrosine hydroxylase activity (and possibly tyrosinase activity) was shown to be inhibited by the highest two concentrations for whole planaria homogenates in vitro.
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PMID:Effects of 3-iodo-L-tyrosine, a tyrosine hydroxylase inhibitor, on eye pigmentation and biogenic amines in the planarian, Dugesia dorotocephala. 881 61

Melanocytic cells can produce two types of pigment, pheomelanin or eumelanin. We used two types of human melanoma cell lines to explore the regulation of pigmentation by biochemical and enzymatic studies. These two cell lines were previously designated as either pheomelanotic or of mixed type when cultured in a medium rich in cysteine. We analyzed the effects of L-cysteine depletion on melanin synthesis and the involvement of the tyrosinase-related proteins in the production of both eumelanin and pheomelanin. Cultures were exposed to L-cysteine concentrations ranging from 206 to 2.06 microM, and the following parameters were measured: tyrosine hydroxylase activity, intracellular L-cysteine and glutathione concentrations, eumelanin and pheomelanin formation, and tyrosinase-related protein-1 and -2 mRNA levels. Extracellular L-cysteine depletion significantly increased tyrosine hydroxylase activity and promoted both eumelanogenesis and visible pigmentation in both lines. In contrast, pheomelanogenesis was increased only in the pheomelanotic cell line. Whereas eumelanogenesis was apparent upon L-cysteine depletion, tyrosinase-related protein-1 expression was not induced in the pheomelanotic cells, and tyrosinase-related protein-2 expression remained unchanged. Thus, tyrosinase-related protein-1 mRNA expression seems to be concomitant with eumelanogenesis when the L-cysteine concentration is high, but does not appear essential for eumelanogenesis at low L-cysteine concentrations. The mechanisms governing pheomelanin to eumelanin balance are dependent on L-cysteine, glutathione, and tyrosinase-related protein-1 expression, but none of these factors alone appears to be dominant in directing the synthesis of a particular type of melanin.
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PMID:Cysteine deprivation promotes eumelanogenesis in human melanoma cells. 887 52

Tyrosinase is one of the key enzymes in mammalian melanin synthesis. The pigment is produced in two different cell types: the pigmented epithelial cell of the retina, and the melanocyte, a cell of neural-crest origin. We recently showed that a fusion gene between regulatory sequences of tyrosinase gene (tyr) and the beta-galactosidase gene (lacZ), when introduced into transgenic mice, resulted in embryonic expression in presumptive pigment cells but also in cells populations along the entire neural tube. This expression in the developing brain was striking, and we therefore asked whether this would still be detectable after birth. Transgenic mice carrying the tyr-lacZ fusion gene showed beta-galactosidase expression in adult brain. On Western blots, we detected tyrosinase-specific bands of 65-68 kDa in brain and eye. Using an affinity-purified antibody, we showed that detection of tyrosinase is specific and competed off by the presence of the cognate tyrosinase-derived peptide. However, neither tyrosine hydroxylase nor Dopa oxidase activity were detected in protein extracts of brain. We therefore suggest that tyrosinase is present in brain but either not functional or catalyzing different reactions compared to pigment cells.
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PMID:Tyrosinase, the key enzyme in melanin synthesis, is expressed in murine brain. 889 82

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

While not all circulating tumor cells survive, one could postulate that patients with circulating tumor cells might be candidates for adjuvant chemotherapy because of the risk of relapse. Recently, reverse transcriptase-polymerase chain reaction (RT-PCR) for the detection of circulating tumor cells has been suggested as a potential technique for staging of cancer. In malignant melanoma, the detection of circulating melanoma cells by tyrosinase RT-PCR correlated with the clinical stage of patients and was an independent prognostic factor for recurrence. A strong association was found between the detection of neuroblastoma cells in circulation by tyrosine hydroxylase RT-PCR with bone marrow micrometastasis. This method may be of use to identify early signs of relapse in disease-free patients. In prostatic cancer, the frequency of positivity for detection of circulating tumor cells in peripheral blood by PSA RT-PCR increased with tumor stages but a significant proportion of patients with metastatic disease were negative. The prognostic significance of the detection of tumor cell in blood in other epithelial tumors is not established and will require further long-term follow-up study.
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PMID:[Molecular diagnostic detection of circulating tumor cells and their prognostic implications]. 905 Nov 25

The enzyme tyrosinase is indispensable for pigmentation and the gene is expressed mainly in pigment cells. Regulatory elements, at -12 to -15 kb (enhancer) and within the 270 bp directly upstream of the transcription start site, have been described recently and their importance demonstrated in transgenic experiments. We were interested in tyrosinase promoter activity during development and used beta-galactosidase as reporter gene. Transgenic mice were generated carrying a tyrosinase-lacZ fusion gene, containing 6.1 kb of tyrosinase 5' sequences. In transgenic embryos, beta-galactosidase activity was detected along the entire neural tube, with the most prominent expression in the developing telencephalon, and also in the adult brain. Equivalent expression was observed in the developing retina. Tyrosinase protein was identified in embryonic and adult brain, but no DOPAoxidase or tyrosine hydroxylase activity was detected. From our results we conclude that 1) tyrosinase protein is present in embryonic and adult mouse brain and 2) the tyrosinase promoter can direct expression of a reporter gene to pigment cells and neural tissues.
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PMID:Regulation of the tyrosinase promoter in transgenic mice: expression of a tyrosinase-lacZ fusion gene in embryonic and adult brain. 926 2

Detergent solubilized extracts of the cochleae of adult gerbils (Meriones unguiculatus) contain a tyrosine hydroxylase activity measurable by the radiometric method of Pomerantz. This activity is not related to Fenton-type reactions, since it is not inhibited by free radical scavengers and is heat and protease sensitive. It does not appear to be related to a peroxidase (EC 1.11.1.7) since it is neither dependent on H2O2, nor inhibited by catalase (EC 1.11.1.6). The involvement of a tyrosine hydroxylase (EC 1.14.16.2) related to catecholamine synthesis is also unlikely, since the activity is highly sensitive to 2-mercaptoethanol and is not increased by addition of tetrahydrobiopterin. The activity in crude inner ear extracts displayed an unusual maturation behaviour, with a slow activation upon aging at 4 degrees C. Fully active enzyme displayed Michaelis-Menten kinetics, with a Km for L-tyrosine of 47 microM. Cochlear tyrosine hydroxylase, but not melanoma tyrosinase (EC 1.14.18.1), was inhibited by o-phenanthroline, and was not dependent on L-DOPA as cofactor for full enzymatic activity. Crude extracts were also able to catalyze L-DOPA oxidation and melanin formation from either L-tyrosine or L-DOPA. The tyrosine hydroxylase, DOPA oxidase and melanin formation activities most probably resided in the same molecule, as suggested by inhibition studies. A tyrosine hydroxylase and melanin formation activity with identical properties was found in primary cultures of stria vascularis melanocytes. Immunochemical evidence confirmed the absence of either the tyrosinase encoded for by the albino locus, or the tyrosinase isoenzyme TRP1, encoded for by the brown locus. Conversely, an immunorreactive band of molecular weight 70 kDa was specifically recognized by a tyrosinase polyclonal antiserum in Western blot experiments. These results prove that melanogenesis in the cochlea, and likely in other extracutaneous locations such as the brain, is catalyzed by enzymatic systems different from, but related to tyrosinase.
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PMID:Melanin formation in the inner ear is catalyzed by a new tyrosine hydroxylase kinetically and structurally different from tyrosinase. 927 Dec 51

In the presence of thiols, tyrosine hydroxylase (TH) oxidizes L-dihydroxyphenylalanine (L-DOPA) with a specific activity of up to 140 nmol min(-1) mg(-1) at 37 degrees C and pH 7.0, which is approximately 12-50% of its TH activity under similar experimental conditions. Using assay conditions that are optimal for measuring TH activity, the specific DOPA oxidase activity of human TH is similar to that of mushroom tyrosinase, but the two enzymes are clearly different in terms of substrate specificities, cofactor dependencies, and selectivity with respect to the effects of metal chelators and other inhibitors. In the presence of an excess of dithiothreitol, 2-mercaptoethanol, cysteine, or reduced glutathione, the reaction products of the two enzymes are identical and have been identified tentatively as thioether derivatives of DOPA. Theoretically, the oxidation of L-DOPA by TH may contribute to the formation of neuromelanin (pheomelanin) in catecholaminergic neurons and in the metabolism of DOPA to reactive intermediates that can react with free thiol groups in cellular proteins. The DOPA oxidase activity of TH can lead to errors in the estimation of in vivo or in vitro TH activity, and currently used assay protocols may have to be modified to avoid interference from this activity.
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PMID:L-DOPA is a substrate for tyrosine hydroxylase. 932 1

Mitf (Microphthalmia transcription factor), a basic-helix-loop-helix zipper protein, encoded at the microphthalmia (Mitf) locus, regulates the transcription of the gene encoding tyrosinase, the rate-limiting enzyme in melanin biosynthesis, by binding the DNA sequence CATGTG. This binding site is present also in the genes encoding two tyrosinase related proteins, TRP-1 and TRP-2. To gain insight into the function of Mitf in vivo, we determined whether there was a difference in the levels of these proteins in the RPE/choroid of the vitiligo (Mitfvit) mouse, in which there is a mutation of the Mitf gene. This mouse has alteration of RPE pigmentation and function that presumably leads to slow progressive loss of photoreceptor cells. The RPE/choroid was dissected from eyes of vitiligo and C57BL/6 wild-type mice at postnatal ages 2, 4, 7, 10, 14, 21 and 42 days. Extracts of pooled tissues were subjected to electrophoresis and immunoblotting. The levels of tyrosinase, TRP-1 and TRP-2 were determined densitometrically following immunodetection with rabbit antipeptide antisera. In addition, the tyrosine hydroxylase activity of tyrosinase as assayed radiometrically. Levels of TRP-1 were 3-7 fold greater in control RPE/choroid compared with mutants. This marked difference in protein level was observed at the earliest age examined (P2) and persisted throughout the first two weeks. Tyrosinase levels in mutants were similar to controls at P2 and P4, but were reduced at P10 and beyond. Tyrosinase activity was diminished also in mutants by P10. Levels of TRP-2 were similar between mutants and controls, although the typical decrease seen in controls after P14 was attenuated in the mutant mice. There is a significant reduction in the level of TRP-1 in the RPE/choroid of the Mitfvit mouse. The data suggests that transcription of the gene encoding TRP-1 is extremely dependent upon functional Mitf. It provides in vivo evidence that Mitf regulates the transcription of the gene encoding TRP-1 as well as tyrosinase.
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PMID:Expression of tyrosinase and the tyrosinase related proteins in the Mitfvit (vitiligo) mouse eye: implications for the function of the microphthalmia transcription factor. 959 34

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


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