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)

H(2)O(2) and other reactive oxygen species are key regulators of many intracellular pathways. Within mammalian skin, H(2)O(2) is formed as a byproduct of melanin synthesis, and following u.v. irradiation. We therefore analyzed its effects on melanin synthesis. The activity of the rate-limiting melanogenic enzyme, tyrosinase, decreased in H(2)O(2)-treated mouse and human melanoma cells. This inhibition was concentration- and time-dependent in the B16 melanoma model. Maximal inhibition (50-75%) occurred 8-16 hours after a 20 minute exposure to 0.5 mM H(2)O(2). B16 cells withstand this treatment adequately, as shown by a small effect on glutathione levels and a rapid recovery of basal lipid peroxidation levels. Enzyme activities also recovered, beginning to increase 16-20 hours after the treatment. Inhibition of enzyme activities reflected decreased protein levels. mRNAs for tyrosinase, tyrosinase-related protein 1, dopachrome tautomerase, silver protein and melanocortin 1 receptor also decreased after H(2)O(2) treatment, and recovered at different rates. Downregulation of melanocyte differentiation markers mRNAs was preceded by a decrease in microphthalmia transcription factor (Mitf) gene expression, which was quantitatively similar to the decrease achieved using 12-O-tetradecanoylphorbol-13-acetate. Recovery of basal Mitf mRNA levels was also observed clearly before that of tyrosinase. Therefore, oxidative stress may lead to hypopigmentation by mechanisms that include a microphthalmia-dependent downregulation of the melanogenic enzymes.
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PMID:Inhibition of melanogenesis in response to oxidative stress: transient downregulation of melanocyte differentiation markers and possible involvement of microphthalmia transcription factor. 1149 72

Melanosome biogenesis and function were studied after purification of early stage melanosomes and characterization of specific proteins sorted to that organelle. Melanosomes were isolated from highly pigmented human MNT1 melanoma cells after disruption and initial separation by sucrose density gradient centrifugation. Low-density sucrose fractions were found by electron microscopy to be enriched in stage I and stage II melanosomes, and these fractions were further separated and purified by free flow electrophoresis. Tyrosinase and dopachrome tautomerase (DCT) activities were found exclusively in stage II melanosomes, even though DCT (and to some extent tyrosinase) proteins were sorted to stage I melanosomes. Western immunoblotting revealed that these catalytic proteins, as well as TYRP1, MART1, and GP100, were cleaved and inactivated in stage I melanosomes. Proteolytic cleavage was critical for the refolding of GP100 within the melanosomal milieu, and subsequent reorganization of amorphous stage I melanosomes into fibrillar, ovoid, and highly organized stage II melanosomes appears to stabilize the catalytic functions of melanosomal enzymes and allows melanin biosynthesis to begin. These results provide a better understanding of the structural features seen during melanosome biogenesis, and they yield further clues as to the physiological regulation of pigmentation.
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PMID:A model for melanosome biogenesis based on the purification and analysis of early melanosomes. 1152 13

The phenolic biopolymer eumelanin is an important skin pigment found throughout the animal kingdom. The enzyme, tyrosinase, initiates melanogenesis in mammals. The biogenesis is assisted by a number of mammalian protein factors including dopachrome tautomerase and 5,6-dihydroxyindole-2-carboxylate oxidase. Invertebrates, such as insects, employ phenoloxidase and dopachrome (decarboxylating) isomerase for melanin biosynthesis. Recently generated molecular biological and biochemical data indicate that tyrosinase and phenoloxidase are distinctly different enzymes in spite of possessing both monophenol monooxygenase activity as well as o-diphenoloxidase activity. Similarly, insect dopachrome isomerase also differs significantly from its mammalian counterpart in several of its properties including the nature of the enzymatic reaction. In addition, there are considerable differences in the eumelanogenic pathways of these two animal groups that include the utility of substrates, use of dihydroxyindoles and the nature of eumelanin pigment. Thus, the biochemistry and molecular biology of melanogenesis in mammals and insects are significantly different. The advantages of generating different eumelanin pigments and intermediates by the insects are discussed.
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PMID:Comparative biochemistry of eumelanogenesis and the protective roles of phenoloxidase and melanin in insects. 1183 52

In ultraviolet-induced tanning, the protein levels of various gene products critical for pigmentation (including tyrosinase and tyrosinase-related protein-1) are increased in response to ultraviolet B irradiation, but changes in mRNA levels of these factors have not been investigated in vivo. We have established an in situ hybridization technique to investigate mRNA levels of pro-opiomelanocortin, tyrosinase, tyrosinase-related protein-1, dopachrome tautomerase, P-protein, Pmel-17/gp100, and microphthalmia-associated transcription factor, and have analyzed the changes in mRNA levels in the ultraviolet B-exposed skin in vivo. The right or left forearm of each volunteer was irradiated with ultraviolet B, and skin biopsies were obtained at 2 and 5 d postirradiation. mRNA level of pro- opiomelanocortin was increased 2 d after ultraviolet B irradiation, and returned to a near-basal level after 5 d, whereas the mRNA levels of tyrosinase, tyrosinase-related protein-1, dopachrome tautomerase, P-protein, and Pmel-17/gp100 showed some or no increase at 2 d, but were significantly increased 5 d after ultraviolet B irradiation. Microphthalmia-associated transcription factor mRNA was slightly increased on days 2 and 5 after ultraviolet B irradiation. Our results suggest that the mechanism of the tanning response of human skin may involve the transcriptional regulation of certain pigmentary genes, and that pro-opiomelanocortin-derived melanocortins such as alpha-melanocyte-stimulating hormone and adrenocorticotropic hormone may play a part in regulating these genes in vivo.
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PMID:Increase of pro-opiomelanocortin mRNA prior to tyrosinase, tyrosinase-related protein 1, dopachrome tautomerase, Pmel-17/gp100, and P-protein mRNA in human skin after ultraviolet B irradiation. 1185 78

The tyrosinase gene family encompasses three members, tyrosinase, tyrosinase-related protein 1 (Tyrp1) and dopachrome tautomerase (Dct), which encode for proteins implicated in melanin synthesis. In human and mouse, genomic organization is known for all three genes, revealing common features of regulatory elements and of exon/intron structure. We have set out to identify the complete family from a more primitive vertebrate, the pufferfish Fugu (Takifugu rubripes), which is characterized by a compact genome. We had recently isolated and characterized the Fugu tyrosinase gene (Genesis 28 (2000) 99-105). We now report the isolation and characterization of the two other members of the family, Tyrp1 and Dct. Regulatory sequences from these genes function in mouse pigment cells and are able to mediate reporter gene expression. Our results demonstrate the existence of all three tyrosinase family members in teleosts and underline the evolutionary conservation of the pigmentary system.
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PMID:Genomic structure and evolutionary conservation of the tyrosinase gene family from Fugu. 1203 32

Tyrosinase (TYR), tyrosinase-related protein-1 (TYRP1/gp75) and dopachrome tautomerase (DCT/TYRP2) belong to a family of melanocyte-specific gene products involved in melanin pigmentation. During melanocyte development expression of tyrosinase family genes is thought to be orchestrated in part by the binding of a shared basic helix-loop-helix transcription factor MITF to the M box, a regulatory element conserved among these genes. In transformed melanocytes, expression of tyrosinase and TYRPs is highly variable. Whereas TYR expression in melanoma cells is regulated by both transcriptional and post-translational mechanisms, TYRP1/gp75 transcription is often completely extinguished during melanoma tumor progression. In this study, we investigated the mechanisms of selective repression of TYRP1 transcription. Interestingly, in early stage melanoma cells TYRP1 mRNA could be induced by inhibition of protein synthesis. Transient transfection experiments with a minimal TYRP1 promoter showed that the promoter activity correlates with expression of the endogenous TYRP1 gene. Nucleotide deletion analysis revealed novel regulatory sequences that attenuate the M box-dependent MITF activity, but which are not involved in the repression of TYRP1. Gel mobility shift analysis showed that binding of the transcription factor MITF to the TYRP1 M box is selectively inhibited in TYRP1(-) cells. These data suggest that protein factors that modulate the activity of MITF in melanoma cells repress TYRP1 and presumably other MITF target genes.
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PMID:Selective down-regulation of tyrosinase family gene TYRP1 by inhibition of the activity of melanocyte transcription factor, MITF. 1213 92

The microphthalmia-associated transcription factor is implicated in melanocyte development and in the regulation of melanogenesis. Microphthalmia-associated transcription factor is thought to bind to the M-box promoter elements of tyrosinase, tyrosinase-related protein-1 and dopachrome tautomerase/tyrosinase-related protein-2 and transactivate these genes, resulting in increased pigmentation. Using a luciferase reporter construct driven by the microphthalmia-associated transcription factor promoter, we identified agents that modulate microphthalmia-associated transcription factor promoter activity. Changes in endogenous microphthalmia-associated transcription factor expression levels upon treatment with these agents were confirmed using northern and western blots, and their pigmentary modulating activities were demonstrated. Ultraviolet B irradiation and traditional Chinese medicine-1, a natural extract used in traditional Chinese medicine, upregulated microphthalmia-associated transcription factor gene expression and enhanced tyrosinase activity in vitro. Dihydrolipoic acid, lipoic acid, and resveratrol reduced microphthalmia-associated transcription factor and tyrosinase promoter activities. These agents also inhibited the forskolin- and ultraviolet B-stimulated promoter activities of these genes and significantly reduced tyrosinase activity in melanocyte cultures, resulting in depigmentation. Overexpressed microphthalmia-associated transcription factor was capable of rescuing the repressive effects of these compounds on the cotransfected tyrosinase promoter. Dark-skinned Yucatan swine treated with these agents showed visible skin lightening, which was confirmed histologically, whereas ultraviolet B-induced tanning of light-skinned swine was inhibited using these agents. Our findings suggest that modulation of microphthalmia-associated transcription factor expression can alter skin pigmentation and further confirm the central role of microphthalmia-associated transcription factor in melanogenesis.
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PMID:Modulation of microphthalmia-associated transcription factor gene expression alters skin pigmentation. 1248 19

Production of the pigment eumelanin is controlled by alpha-melanocyte stimulating hormone (alpha-MSH) stimulation of melanocortin 1 receptor (Mc1r), whereas production of pheomelanin results from agouti antagonism of alpha-MSH signalling through Mc1r. The role of agouti in mouse pigmentation has been extensively investigated but a role for agouti signalling protein (ASIP) in human pigmentation has not been determined. To determine whether ASIP regulates known melanogenic genes in humans, ASIP was over-expressed in a human melanoma cell line. Levels of mRNA and protein were measured in genes known to be up or down-regulated by agouti in the mouse, namely microphthalmia (Mitf), tyrosinase (Tyr), tyrosinase-related protein 1 (Tyrp1), dopachrome tautomerase (Dct), Mc1r, silver, initiation transcription factor 2 (Itf2) and mini chromosome maintenance protein 6 (Mcm6). These melanogenic genes were not found to be significantly up or down-regulated by ASIP at the transcriptional level in human melanoma cells. However, ASIP down-regulation of tyrp1 was observed at the translational level. To identify novel genes that may be regulated by ASIP in melanoma cells, microarrays were used to determine differences in gene expression between the control and ASIP transfected melanoma cells. The expression level of human RNAs were determined by microarray analysis using a 19,200 cDNA and a 19,200 oligonucleotide array representing 13,000 and 18,864 individual genes, respectively. Genes observed to be modulated by ASIP were confirmed by quantitative real-time polymerase chain reaction. Results identify five genes, namely PPARbeta, eIF-4B, RRM2, MINOR and EVI2B that are down-regulated by ASIP, indicating a likely role for ASIP in human melanogenesis.
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PMID:Agouti signal protein regulation in human melanoma cells. 1251 27

For proper melanin production, several specific enzymes such as tyrosinase, tyrosinase-related protein 1 (TRP-1) and dopachrome tautomerase are required. Their expressions are increased after exposure to UVB. However, it is not known how long tyrosinase and TRP-1 activities continue after UV irradiation in vivo. The purpose of this study is to measure the changes in expressions of tyrosinase, TRP1, and MITF after exposure to UV on skin in a Korean population. We established an immunohistochemical staining protocol for specimens which were obtained from UV-irradiated skin in five healthy Korean males on the 2nd, 5th, 7th, 28th, and 56th days after UV irradiation. Tyrosinase, TRP-1, and MITF expressions increased until 7 days after UV irradiation and then dropped to the basal constitutive level 4 and 8 weeks later. Interestingly, tyrosinase increased prior to TRP-1. This study reveals the time-sequence of melanin-synthesized enzymes and provides important information for the clinical evaluation of the effectiveness of whitening agents.
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PMID:The expression of melanogenic proteins in Korean skin after ultraviolet irradiation. 1457 56

This study evaluated the effects of synthetic benzylamide compound I (2,6-dimethoxy-N-phenylbenzamide) on the ultraviolet B (UV B)-induced hyperpigmentation of the skin. UV B-induced hyperpigmentation was elicited on brownish guinea pig skin according to the method reported by Hideya et al. [Arch Dermatol Res 290 (1998) 375] with minor modifications. A lightening effect was observed following the topical application of compound I on UV-stimulated hyperpigmentation. The skin returned to its original color after treatment with compound I. Fontana-Masson staining indicated that melanin level in the hyperpigmented area was significantly decreased in the compound I-treated animals. However, the number of melanocytes were not changed in the compound I-treated groups using the S-100 stain, which is an immunohistochemical method. In vitro experiments using the cultured melanoma cells showed a 31.7% inhibition of melanin production by compound I at 100 microM. In addition, this compound had no effect on the tyrosinase enzyme function. However, it exhibited a catalyzing effect on the dopachrome transformation into 5,6-dihydroxyindole-2-carboxylic acid. Overall, the pigment-lightening effects of the compound I may due to the dopachrome tautomerase stimulation.
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PMID:Benzylamide derivative compound attenuates the ultraviolet B-induced hyperpigmentation in the brownish guinea pig skin. 1475 70


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