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 effect of glucosidase and mannosidase inhibitors on the ER-associated degradation of tyrosinase was assessed in transiently transfected COS-7 cells. We found that the glucosidase inhibitors castanospermine and deoxynojirimycin had very little effect on tyrosinase degradation, whereas the mannosidase inhibitors deoxymannojirimycin and kifunensine significantly delayed the rate of tyrosinase degradation as measured by pulse-chase analysis. In addition, we show that tyrosinase degradation is sensitive to the proteasome inhibitor lactacystin and that tyrosinase associates with endogenous calnexin in COS-7 cells. Our data support a model of tyrosinase degradation that involves mannose trimming, calnexin association, and the retrograde transport of tyrosinase from the ER to the cytosol for proteasomal degradation. The pathways of tyrosinase degradation have important ramifications with regard to the exact types of antigenic epitopes that are presented to the immune system.
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PMID:Oligosaccharide trimming plays a role in the endoplasmic reticulum-associated degradation of tyrosinase. 1077 75

In this study, we used melb-a melanoblasts as a model to study mechanisms involved in stimulating melanocyte function in vitiliginous skin following exposure to 8-methoxypsoralen (8MOP). Melanin content and tyrosinase activity increased 3- and 7-fold, respectively, in melanoblasts treated with 8MOP for 6 d compared with untreated controls. The intracellular signal pathways involved in 8MOP-induced effects on melanoblasts were investigated, particularly the roles of protein kinase A and protein kinase C. Forskolin, a protein kinase A activator, mimicked and enhanced the 8MOP stimulation of melanoblast pigmentation whereas a protein kinase C activator, 1-oleoyl-2-acetylglycerol, had no effect, indicating that the protein kinase A pathway is involved rather than the protein kinase C pathway. Those observations were confirmed using inhibitors of the protein kinase A or protein kinase C pathways. Western blot and semiquantitative reverse transcriptase polymerase chain reaction were performed to assess the protein and mRNA expression levels of microphthalmia-associated transcription factor and tyrosinase in melanoblasts treated with 8MOP for 3 h, 6 h, 1 d, 3 d, or 6 d. Incubation with 8MOP stimulated microphthalmia-associated transcription factor protein and mRNA levels within 3 h, but, in contrast, tyrosinase mRNA and protein levels did not increase following 8MOP treatment until 1 d after treatment. The proteasome inhibitor lactacystin blocked the proteasome-mediated proteolysis of tyrosinase, and its effect on proteasomal function was enhanced by 8MOP. Taken together, these results show that 8MOP functions by initially stimulating levels of microphthalmia-associated transcription factor expression via activation of the protein kinase A pathway, which thereby stimulates tyrosinase expression and function and eventually leads to dramatic increases in melanin production by melanoblasts.
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PMID:Stimulation of melanoblast pigmentation by 8-methoxypsoralen:the involvement of microphthalmia-associated transcription factor, the protein kinase a signal pathway, and proteasome-mediated degradation. 1248 19

Fatty acids are common components of biological membranes that are known to play important roles in intracellular signaling. We report here a novel mechanism by which fatty acids regulate the degradation of tyrosinase, a critical enzyme associated with melanin biosynthesis in melanocytes and melanoma cells. Linoleic acid (unsaturated fatty acid, C18:2) accelerated the spontaneous degradation of tyrosinase, whereas palmitic acid (saturated fatty acid, C16:0) retarded the proteolysis. The linoleic acid-induced acceleration of tyrosinase degradation could be abrogated by inhibitors of proteasomes, the multicatalytic proteinase complexes that selectively degrade intracellular ubiquitinated proteins. Linoleic acid increased the ubiquitination of many cellular proteins, whereas palmitic acid decreased such ubiquitination, as compared with untreated controls, when a proteasome inhibitor was used to stabilize ubiquitinated proteins. Immunoprecipitation analysis also revealed that treatment with fatty acids modulated the ubiquitination of tyrosinase, i.e. linoleic acid increased the amount of ubiquitinated tyrosinase whereas, in contrast, palmitic acid decreased it. Furthermore, confocal immunomicroscopy showed that the colocalization of ubiquitin and tyrosinase was facilitated by linoleic acid and diminished by palmitic acid. Taken together, these data support the view that fatty acids regulate the ubiquitination of tyrosinase and are responsible for modulating the proteasomal degradation of tyrosinase. In broader terms, the function of the ubiquitin-proteasome pathway might be regulated physiologically, at least in part, by fatty acids within cellular membranes.
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PMID:Fatty acids regulate pigmentation via proteasomal degradation of tyrosinase: a new aspect of ubiquitin-proteasome function. 1473 85

Tyrosinase, the rate-limiting enzyme of melanin synthesis, is a di-copper metalloprotein that catalyzes the conversion of L-tyrosine to L-DOPAquinone. Phenylthiourea (PTU) is a well-known inhibitor of tyrosinase and melanin synthesis and is known to interact with sweet potato catechol oxidase, an enzyme possessing copper binding domain homology to tyrosinase. While PTU is frequently used to induce hypopigmentation in biological systems, little is known about its effects on tyrosinase and other melanogenic proteins. We have found that PTU induces degradation of tyrosinase but not of other melanogenic proteins including the tyrosinase-related metalloproteins tyrosinase-related protein (Tyrp)1 and Tyrp2. Using pulse-chase analysis coupled with glycosidase digestion, we observed that tyrosinase degradation occurs following complete maturation of the protein and that degradation was reversed by cysteine protease inhibitor E64 but not proteasome inhibitor N-acetyl-L-leucinyl-L-leucinyl-L-norleucinal. We conclude that PTU specifically induces tyrosinse degradation following Golgi maturation. Our data suggest that in addition to well-known ER-directed quality control, tyrosinase is also subject to post-Golgi quality control.
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PMID:Degradation of tyrosinase induced by phenylthiourea occurs following Golgi maturation. 1576 Mar 41

Proteasomes are multicatalytic proteinase complexes within cells that selectively degrade ubiquitinated proteins. We have recently demonstrated that fatty acids, major components of cell membranes, are able to regulate the proteasomal degradation of tyrosinase, a critical enzyme required for melanin biosynthesis, in contrasting manners by relative increases or decreases in the ubiquitinated tyrosinase. In the present study, we show that altering the intracellular composition of fatty acids affects the post-Golgi degradation of tyrosinase. Incubation with linoleic acid (C18:2) dramatically changed the fatty acid composition of cultured B16 melanoma cells, i.e. the remarkable increase in polyunsaturated fatty acids such as linoleic acid and arachidonic acid (C20:4) was compensated by the decrease in monounsaturated fatty acids such as oleic acid (C18:1) and palmitoleic acid (C16:1), with little effect on the proportion of saturated to unsaturated fatty acid. When the composition of intracellular fatty acids was altered, tyrosinase was rapidly processed to the Golgi apparatus from the ER (endoplasmic reticulum) and the degradation of tyrosinase was increased after its maturation in the Golgi. Retention of tyrosinase in the ER was observed when cells were treated with linoleic acid in the presence of proteasome inhibitors, explaining why melanin synthesis was decreased in cells treated with linoleic acid and a proteasome inhibitor despite the abrogation of tyrosinase degradation. These results suggest that the intracellular composition of fatty acid affects the processing and function of tyrosinase in connection with the ubiquitin-proteasome pathway and suggest that this might be a common physiological approach to regulate protein degradation.
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PMID:Intracellular composition of fatty acid affects the processing and function of tyrosinase through the ubiquitin-proteasome pathway. 1623 22

We examined the ability of oxidation products of dopamine, DOPA, and 3,4-dihydroxyphenylacetic acid (DOPAC) to inhibit proteasomal activity. Dopamine, DOPA, and DOPAC underwent tyrosinase-catalyzed oxidation to generate aminochrome, dopachrome, and furanoquinone, respectively. In these studies, the oxidation of dopamine by tyrosinase generated product(s) that inhibited the proteasome, and proteasomal inhibition correlated with the presence of the UV-visible spectrum of aminochrome. The addition of superoxide dismutase and catalase did not prevent proteasomal inhibition. The addition of NADH and the quinone reductase NAD(P)H:quinone oxidoreductase 1 (NQO1) protected against aminochrome-induced proteasome inhibition. Although NQO1 protected against dopamine-induced proteasomal inhibition, the metabolism of aminochrome by NQO1 led to oxygen uptake because of the generation of a redox-labile cyclized hydroquinone, further demonstrating the lack of involvement of oxygen radicals in proteasomal inhibition. DOPA underwent tyrosinase-catalyzed oxidation to form dopachrome, and similar to aminochrome, proteasomal inhibition correlated with the presence of a dopachrome UV-visible spectrum. The inclusion of NQO1 did not protect against proteasomal inhibition induced by dopachrome. Oxidation of DOPAC by tyrosinase generated furanoquinone, which was a poor proteasome inhibitor. These studies demonstrate that oxidation products, including cyclized quinones derived from dopamine and related compounds, rather than oxygen radicals have the ability to inhibit the proteasome. They also suggest an important protective role for NQO1 in protecting against dopamine-induced proteasomal inhibition. The ability of endogenous intermediates formed during dopaminergic metabolism to cause proteasomal inhibition provides a potential basis for the selectivity of dopaminergic neuron damage in Parkinson's disease.
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PMID:A potential role for cyclized quinones derived from dopamine, DOPA, and 3,4-dihydroxyphenylacetic acid in proteasomal inhibition. 1679 May 33

Previously, we reported that a fungal metabolite, terrein, decreases melanin synthesis via downregulation of microphthalmia-associated transcription factor (MITF). In the present study, we further investigated the long-term hypopigmenting action of terrein in a spontaneously immortalized mouse melanocyte cell line, Mel-Ab. Treatment with terrein at a concentration of 50 mum strongly decreased melanogenesis in a time-dependent manner. Interestingly, the decreased tyrosinase protein levels lasted for at least 7 days, even though the MITF protein levels were restored after 3 days of treatment. In accordance with the results of Western blot analyses, the tyrosinase mRNA levels were found to be continuously decreased for at least 7 days, even though recovery of the MITF mRNA levels began after 3 days of terrein treatment. Therefore, we evaluated tyrosinase downregulation to determine if it is caused by proteasomal degradation. We found that the reduction in tyrosinase levels that was induced by terrein was clearly recovered by MG-132, a proteasome inhibitor. Moreover, ubiquitination of tyrosinase increased following treatment with terrein in the presence of MG-132. Taken together, these results suggest that terrein decreases melanogenesis through ubiquitin-dependent proteasomal degradation as well as via decreased expression of its mRNA.
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PMID:Long-term suppression of tyrosinase by terrein via tyrosinase degradation and its decreased expression. 1949 1

In this study, the decursin derivative dihydropyranocoumarin D2 (1) was selected for its effects on melanogenesis using a spontaneously immortalized mouse melanocyte cell line (Mel-Ab). The results showed that 1 effectively inhibited melanin synthesis in a concentration-dependent manner, but that it did not inhibit tyrosinase in a cell-free system. In addition, the changes in ERK, Akt, and microphthalmia-associated transcription factor (MITF) in response to treatment with 1 were assessed. The results revealed that ERK was dramatically up-regulated and MITF was down-regulated in response to treatment with 1, but that Akt was unchanged. Therefore, the effects of 1 on melanogenesis were examined in the absence or presence of PD98059 (a specific inhibitor of the ERK pathway). PD98059 restored hypopigmentation and the down-regulation of MITF induced by 1. Finally, MITF down-regulation by 1 was clearly restored by both chloroquine, a lysosomal proteolysis inhibitor, and MG132, a proteasome inhibitor.
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PMID:Hypopigmentary action of dihydropyranocoumarin D2, a decursin derivative, as a MITF-degrading agent. 2039 68

How melanosomal proteins such as enzymic proteins (tyrosinase and tyrosinase-related proteins, Tyrps) and structural protein (gp100) are transported from Golgi to melanosomal compartments is not yet fully understood. A number of small GTPases have been found to be associated with melanosomes and we have identified one of them, Rab7, a regulator of vesicular transport, organelle motility, phospholipid signaling and cytosolic degradative machinery, as being involved in the transport of Tyrp1 from Golgi to stage I melanosomes. This study further characterizes the role of Rab7 as a regulator of differential sorting of melanosomal proteins in this process. Murine melanocytes were transiently transfected with a plasmid encoding either wild-type (Rab7WT), constitutively active (Rab7Q67L) or dominant-negative (Rab7N125I and Rab7T22N) Rab7. Through immunocytostaining and confocal laser scanning microscopy, we quantitatively compared the bio-distribution of melanosomal proteins between Rab7WT-expressing cells and mutant Rab7-expressing cells. We also characterized their differential elimination from melanosomal compartments by Rab7 by utilizing a proteasome inhibitor, MG132. Our findings indicate that Rab7 plays an important role in differential sorting of tyrosinase, Tyrp1 and gp100 in early melanogenesis cascade, and that it is more specifically involved with Tyrp1 than tyrosinase and gp100 in the trafficking from Golgi to melanosomes and the specific exit from the degradative process.
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PMID:Rab7 is a critical mediator in vesicular transport of tyrosinase-related protein 1 in melanocytes. 2135 76

(-)-Epigallocatechin-3-gallate (EGCG) has been found to trigger the unfolded protein response (UPR) likely due to the inhibition of glucosidase II, a key enzyme of glycoprotein processing and quality control in the endoplasmic reticulum (ER). These findings strongly suggest that EGCG interferes with glycoprotein maturation and sorting in the ER. This hypothesis was tested in SK-Mel28 human melanoma cells by assessing the effect of EGCG and deoxynojirimycin (DNJ) on the synthesis of two endogenous glycoproteins. Both tyrosinase and vascular endothelial growth factor (VEGF) protein levels were remarkably reduced despite unaltered mRNA expression in EGCG- or DNJ-treated cells compared to control. The hindrance of tyrosinase and VEGF protein synthesis could be prevented by proteasome inhibitor, lactacystine. Collectively, our results support that glucosidase II inhibitor EGCG interferes with protein processing and quality control in the ER, which diverts tyrosinase, VEGF, and likely other glycoproteins towards proteasomal degradation. This mechanism provides a novel therapeutic approach in dermatology and might play an important role in the antitumor effect or hepatotoxicity of EGCG.
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PMID:Inhibition of glycoprotein synthesis in the endoplasmic reticulum as a novel anticancer mechanism of (-)-epigallocatechin-3-gallate. 2216 35


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