Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.10.3.1 (tyrosinase)
 9,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A model system is presented to explain how tyrosinase, an enzyme unique to pigmented cells such as normal and malignant melanocytes can oxidize [3H]-estradiol to radiolabeled products which closely resemble the tight binding of [3H]-estradiol to estrogen receptor. In the model system studied, tyrosinase oxidized [2,4,6,7-3H]-estradiol to [3H]-water and [3H]-estradiol metabolites, the latter of which formed ring-substituted conjugates with nucleophiles like monothioglycerol and BSA. Radiolabeled estradiol without tritium in the C-2 position (i.e. [6,7-3H]-estradiol) failed to liberate [3H]-water when exposed to tyrosinase but, nevertheless, did form ring-substituted [3H]-estradiol adducts with nucleophiles. The [3H]-water and the ring-substituted radiolabeled products possessed several characteristics of a genuine estrogen receptor protein in that they were resistant to dextran-coated charcoal (DCC) adsorption and their enzymatic formation was inhibited with non-steroidal estrogens like diethylstilbestrol. Other natural (estradiol) and synthetic (hydroxytamoxifen) estrogens which contain the phenol grouping also inhibited the enzymatic oxidation of [3H]-estradiol. Although it was difficult to differentiate estrogen receptor from tyrosinase using the conventional DCC assay system, several differences in these two proteins permitted a distinction to be made between them. First, tyrosinase oxidation of [3H]-estradiol was markedly inhibited by sulfhydryl reducing agents (monothioglycerol) that stabilize [3H]-estradiol binding to estrogen receptor. Second, estrogen receptor adsorbed by hydroxylapatite whereas tyrosinase did not, thus permitting the separation of these two proteins prior to incubation with [3H]-estradiol. We conclude that the [3H]-estradiol binding components in melanoma previously reported to be estrogen receptor probably represent instead the radiolabeled products of the tyrosinase-catalyzed oxidation of [3H]-estradiol.
Eur J Cancer Clin Oncol 1983 Aug
PMID:Estrogen receptor in malignant melanoma: fact or artefact? 631 60

Cultures of melanocytes and keratocytes were exposed to 15 micrograms ml-1 tyrosinase and 4-hydroxyanisole (4-OHA) 5 X 10(-4) M to 5 X 10(-2) M for 1 to 24 h. No damage was suffered by either cell below 5 X 10(-3) M 4-OHA for 6 h, but higher concentrations and longer exposures extensively damaged both cells. Exposure of cells washed free of culture medium to tyrosinase and 4-OHA 1 X 10(-3) M for 1 h resulted also in extensive damage. This indicates that an early-formed toxic product of the reaction between tyrosinase and 4-OHA is inactivated by constituents of the medium. This was confirmed by Liquid Chromatography and Scanning Spectrophotometry which showed that a toxic 4-OHA quinone immediately reacted with nucleophilic substances in the medium resulting in products which, on accumulation, are probably responsible for the later (6 h plus) damage to melanocytes and keratocytes. A possible effect of allegedly specific melanocytotoxic drugs on keratocytes should always be borne in mind with tissue culture experiments.
Br J Cancer 1983 Jun
PMID:Ultrastructural and biochemical observations on the effect of 4-hydroxyanisole plus tyrosinase on normal human melanocytes and keratocytes in tissue culture. 640 6

The synthetic glucocorticoid, triamcinolone acetonide, was found to increase melanogenesis in the human melanoma cell line NEL. Treatment of NEL cells for 24 hr with triamcinolone acetonide (1 X 10(-7) M) increased the activity of the enzyme tyrosinase by 43% and the incorporation of the melanin precursor, L-3,4-dihydroxyphenylalanine, by 23%. Additional studies revealed no change in cyclic AMP levels over an 18-hr test period. A 2-hr preincubation of NEL cells with actinomycin D (10 micrograms/ml) prevented the increase in tyrosinase activity by triamcinolone acetonide. When triamcinolone acetonide was added to a synchronized population of NEL cells, an increase in tyrosinase activity was observed at 16 hr, coinciding with the late S phase of the cell cycle. These results suggest that glucocorticoids are involved in the regulation of melanogenesis in NEL cells by increasing the activity of the rate-controlling enzyme tyrosinase.
Cancer Res 1984 May
PMID:Effect of triamcinolone acetonide on tyrosinase activity in a human melanoma cell line. 642 29

The effect of Ca2+, Cd2+, Cu2+, Mg2+ and Zn2+ as acetates (10(-3) - 10(-5)M) and of 2% DMSO on the proliferation and differentiation of clone M3 of the Cloudman S91 mouse melanoma was studied and compared with the behaviour of GPK (keratocyte) and MRC5 (fibroblast) cell lines. Whereas neither calcium nor magnesium ions influenced the proliferation of the cells as measured by [3H]-thymidine incorporation, absorbance at 280 nm of NaOH cell digests and cell counts, cadmium, zinc and copper ions selectively inhibited the melanoma line. Cd2+ (10(-5)M) and Zn2+ (10(-4)M) were selectively cytotoxic to melanoma cells in contrast to keratocytes and fibroblasts. No direct effect of the cations on melanogenesis, as estimated from the ratio of absorbance at 350 nm and 280 nm and by tyrosinase assays, was demonstrated. DMSO stimulated melanogenesis in melanoma cells but inhibited their growth. Experiments with ouabain indicate that active transport is involved in the uptake of zinc by melanoma cells.
Eur J Cancer Clin Oncol 1983 Jan
PMID:The effect of divalent cations on Cloudman melanoma cells. 668 80

Levodopa and dopamine are naturally occurring catecholamines with antitumor activity in several experimental tumor systems. Previous studies suggested that their cytotoxic effect was related in part to their inhibitory effect upon DNA polymerase. We have examined the effects of levodopa, dopamine, levodopa methyl ester, norepinephrine, and the analog 3,4-dihydroxybenzylamine upon human and murine melanoma cells. When exponentially growing cells were exposed to these drugs, a characteristic inhibition of thymidine incorporation was observed with much less inhibition of either uridine or leucine incorporation. In order to ascertain that inhibition was occurring at the level of DNA synthesis, we examined the effects of the drugs upon the incorporation of thymidine triphosphate by permeabilized melanoma cells. When melanoma cells were permeabilized by lysolecithin, thereby permitting the direct incorporation of labeled thymidine triphosphate, a similar inhibition of incorporation was observed. Dopamine at a concentration of 4.8 microM caused a 50% reduction in incorporation of label. These results suggested that inhibition did occur at the level of DNA synthesis. In the presence of the melanocyte-specific oxidase, tyrosinase, these derivatives are potent inhibitors of isolated DNA polymerase alpha with 50% inhibitory concentrations between 1 and 10 microM. The inhibition could be completely prevented by the presence of reducing agents such as dithiothreitol (1.0 mM). The quinols themselves were not inhibitors of DNA polymerase. Dopamine analogs represent an interesting class of antitumor agents with inhibitory activity for DNA polymerase.
Cancer Res 1980 May
PMID:Levodopa and dopamine analogs as DNA polymerase inhibitors and antitumor agents in human melanoma. 676 47

Seventy-nine Nigerian oculocutaneous albinos were investigated. Fifty-six had typical tyrosinase-positive albinism (TPA) and 23 had brown albinism (BA), a new oculocutaneous type. The TPA were characterized by localized but no generalized skin pigment, yellow hair, blue to brown irides, nystagmus, and reduced or absent retinal pigment. Localized skin pigment included freckles and lentigines. The iris and skin pigment were the result of the slow accumulation of pigment with age as both were found in older individuals. The most severe skin changes were premalignant keratoses and squamous cell carcinoma of the skin, and the skin malignancies were the major factor in limiting the lifespan for TPA. The BA were characterized by generalized light brown skin pigment, light brown hair, blue to brown irides, nystagmus, and reduced retinal pigment. There was little accumulation or change of pigment in the eyes or skin with age. The generalized light skin pigment was effective in reducing sensitivity to solar radiation and very few BA had premalignant keratoses. Pedigree analysis for BA suggested on autosomal recessive inheritance pattern.
 ...
PMID:Albinism in Nigeria with delineation of new recessive oculocutaneous type. 676 77

The effect of four different retinoids [retinol, 13-cis-retinoic acid (Ro4-3780), beta-all-trans-retinoic acid, and aromatic retinoic acid ethyl ester (Ro10-9359)] on the cellular proliferation (cell number) and biochemical differentiation (tyrosinase activity) of a human melanoma cell line (MIRW) and three subclones was assessed. All four retinoids (10(-6) M) inhibited the cellular proliferation (36 to 42%) and stimulated tyrosinase activity (58 to 72%) in the parent cell line to a similar extent. In contrast, the effects of the different retinoids on three derived melanoma clones was dissimilar. For example, in clone A6, beta-all-transretinoic acid stimulated tyrosinase activity by 48% but caused only a 7% inhibition of cellular proliferation. This retinoid caused a more pronounced effect in the other two subclones, stimulating tyrosinase from 135 to 195% and inhibiting growth 19 to 33%. Al three melanoma clones demonstrated increased tyrosinase activity (110 to 225%) and reduced proliferation (37 to 52%) following exposure to 13-cis-retinoic acid. This retinoid was found overall to be the most effective stimulator of tyrosinase, while retinol was observed to be the least active, stimulating enzyme activity slightly (25%) in only one of three clones. Retinol inhibited proliferation 27 to 33% in two of three melanoma subclones. The aromatic retinoic acid ethyl ester elevated tyrosinase levels in two clones but inhibited the enzyme in one melanoma line. Cellular proliferation, however, was reduced in all three clones. These results suggest that retinoid-induced changes in human melanoma cell growth and differentiation reflect underlying cellular differences and diverse biochemical interactions.
Cancer Res 1980 Jul
PMID:Characterization of the effects of different retinoids on the growth and differentiation of a human melanoma cell line and selected subclones. 677 Sep 95

Melanomas from 20 patients were evaluated for estrogen and progesterone receptors. No restriction as to patient's age, sex, race, or menstrual status was made. Fifteen of the tumors were melanin producing. Of the 20 tumors examined, seven contained more than 3 fm/mg protein of specifically inhibitable estrogen binding. None of the tumors reported here demonstrated either a 4S or 8S binding protein as shown by sucrose density gradient analysis. All tumors in which estradiol binding was observed were melanin producing, whereas none of the amelanotic melanomas (five tumors) bound this steroid. Purified tyrosinase appeared to mimic the estrogen binding detected in melanoma cytosols, as demonstrated with the dextran-coated charcoal technique. Although the binding of estradiol to tyrosinase was inhibited by DOPA, the binding of estradiol to estrogen receptor preparations was not. These studies represent an extensive of previous studies of sex steroid binding in melanomas and suggest that gradient analysis and DOPA inhibition studies should be included in the evaluation of the estrogen binding phenomenon in human melanoma.
Cancer 1980 Sep 15
PMID:Sex steroid receptor analysis in human melanoma. 677 5

A fish melanoma cell line, PSM-1, was established from a hereditary melanoma in an interspecific hybrid of Xiphophorus for cytogenetic studies of this melanoma system. An amelanotic melanoma was obtained from the tail fin of a melanotic F1 hybrid between a spotted platyfish (Xiphophorus maculatus) and an albino swordtail (Xiphophorus helleri). The tumor tissue was dissociated and cultured in Eagle's minimal essential medium supplemented with 10% fetal calf serum. PSM-1 has been maintained for 52 passages and 29 months in vitro since March 3, 1978. This cell line showed considerable variation in cellular morphology. Although no apparent pigment was detectable by light microscopy, melanosomes and premelanosomes could be seen under the electron microscope. The cells grew randomly across each other with an apparent lack of contact inhibition and formed many clumps. The doubling time was approximately 2 days, and the modal chromosome number at the 41st passage was a near triploid 71. A high tyrosinase activity was detected. PSM-1 is similar to some mammalian melanoma cell lines with respect to cytological characteristics and growth patterns.
Cancer Res 1981 Feb
PMID:Establishment of a cell line from the platyfish-swordtail hybrid melanoma. 677 12

Malignant melanomas have been shown to contain high levels of monophenol monooxygenase (tyrosinase) enzyme activity; the enzyme is responsible for melanin synthesis. The melanoma of Sinclair miniature swine has a high incidence of spontaneous regression and thus provides a unique system for analyzing changes in tyrosinase activity at various tumor stages. Three tumor stages (progressively growing tumors, partially regressed tumors, and fully regressed tumors) were analyzed for tyrosinase activity. The progressing tumors were 34-fold higher than were the partially regressed lesions and 400-fold higher than were the fully regressed tumors. Histologically, the decrease in enzyme activity correlated with a loss of tumor cells. Sequential biopsies of tumors during the course of tumor development showed a positive correspondence between tumor volume and tyrosinase activity for the early and late stages of tumor growth and regression. Electrophoretic separation of tyrosinase preparations revealed three major tyrosinase "isoenzymes" whose relative abundance fluctuated during developmental increases and decreases in enzyme activity.
J Natl Cancer Inst 1981 Sep
PMID:Tyrosinase activity and isoenzyme distribution corresponding to growth and regression of melanoma in Sinclair miniature swine. 679 14


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