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)

In this study, we investigated the effects of lysophosphatidic acid (LPA) on melanogenesis in Mel-Ab cells. We found that LPA significantly attenuates melanin synthesis, and reduces the activity of tyrosinase, the rate-limiting melanogenic enzyme. Interestingly, LPA was also found to induce the activation of a 90 kDa ribosomal S6 kinase (RSK-1), which is known to phosphorylate microphthalmia-associated transcription factor (MITF) at serine 409. Though it has been previously reported that the phosphorylation of MITF is followed by the degradation of MITF, we found that LPA significantly inhibited MITF promoter activity, and that this reduced MITF and tyrosinase protein production. Our results indicate that LPA contributes to reduced melanin synthesis via the down-regulation of MITF.
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PMID:Effects of lysophosphatidic acid on melanogenesis. 1472 2

In this study, the effects of (-)-epigallocatechin-3-gallate (EGCG) and/or hinokitiol (beta-thujaplicin) on melanogenesis were investigated. Our results showed that both EGCG and hinokitiol significantly inhibited melanin synthesis in a concentration-dependent manner, and that their hypopigmenting effects were stronger than that of kojic acid, which is known to inhibit melanin formation in melanocytes and melanoma cells. Interestingly, EGCG did not show any additive hypopigmenting effect in combination with kojic acid, though EGCG did show a synergistic effect in combination with hinokitiol. Several reports indicate that the activation of extracellular signal-regulated kinase (ERK) induces microphthalmia-associated transcription factor (MITF) degradation. Accordingly, the effects of EGCG and hinokitiol on the ERK signaling pathway were examined. EGCG and hinokitiol induced neither ERK activation nor MITF degradation. On the other hand, both EGCG and hinokitiol reduced the protein levels of MITF and of tyrosinase, the rate limiting melanogenic enzyme, whereas kojic acid had no effect. In addition, hinokitiol strongly downregulated the activity of tyrosinase, whereas EGCG or kojic acid had only a little effect. These results show that both EGCG and hinokitiol reduce MITF production, and suggest that reduced tyrosinase activity by hinokitiol explains their synergistic effect on melanogenesis.
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PMID:(-)-Epigallocatechin-3-gallate and hinokitiol reduce melanin synthesis via decreased MITF production. 1508 40

Little is known about the mechanisms involved in the dysfunction of melanocytes in vitiligo epidermis. It is hypothesized that some cytokine/receptor interactions may be affected, resulting in dysfunction and/or loss of melanocytes. This study has compared the expression of endothelin (ET)-1, the ET-1 receptor (ET(B)R), granulocyte macrophage colony stimulating factor (GM-CSF), stem cell factor (SCF), the SCF receptor (KIT protein), tyrosinase, and S100 alpha between lesional and non-lesional vitiligo epidermis. Analysis by reverse transcription-polymerase chain reaction (RT-PCR) and by western blotting for ET-1 and SCF unexpectedly demonstrated up-regulated expression of these cytokines in lesional vitiligo epidermis. Immunohistochemistry with antibodies to melanocyte markers revealed that at the edge of the lesional epidermis, melanocytes remain and express tyrosinase, S100 alpha and ET(B)R, but not KIT protein or melanocyte-specific microphthalmia-associated transcription factor (MITF-M). Quantitation of the staining revealed a slight or moderate decrease in the number of S100 alpha, tyrosinase, and ET(B)R-positive cells at the edge of the lesional epidermis. In contrast, the number of cells expressing KIT protein was markedly decreased at the edge of the lesional epidermis compared with the non-lesional epidermis. At the centre of the lesional epidermis, there was complete loss of melanocytes expressing KIT protein, S100 alpha, ET(B)R, and/or tyrosinase. Western blotting revealed down-regulated expression of c-kit and MITF-M proteins at the edge of the lesional epidermis in vitiligo. These findings suggest that reduction in the expression of KIT protein by melanocytes and its downstream effectors, including MITF-M, may be associated with the dysfunction and/or loss of melanocytes in vitiligo epidermis.
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PMID:Mechanisms underlying the dysfunction of melanocytes in vitiligo epidermis: role of SCF/KIT protein interactions and the downstream effector, MITF-M. 1509 74

Transforming growth factor-beta1 (TGF-beta1) plays a pivotal role in cell proliferation, differentiation, and apoptosis. In this study, we investigated the effects of TGF-beta1 on melanogenesis using a spontaneously immortalized mouse melanocyte cell line, Mel-Ab. Our results show that TGF-beta1 significantly inhibits melanin synthesis in a concentration-dependent manner and that it reduces the activity of tyrosinase, the rate-limiting melanogenic enzyme. We also found that TGF-beta1 reduces microphthalmia-associated transcription factor (MITF) promoter activity and decreased MITF, tyrosinase, tyrosinase-related protein-1 (TRP-1), and TRP-2 protein production. In addition, TGF-beta1 was found to induce a delay in the activation of extracellular signal-regulated kinase (ERK) at 6h, whereas many growth factors activate ERK transiently in minutes. Moreover, the specific ERK pathway inhibitor, PD98059 blocked the hypopigmenting effects induced by TGF-beta1. PD98059 was also found to abrogate the TGF-beta1-mediated down-regulation of MITF, tyrosinase, TRP-1, and TRP-2 production. These results suggest that the ERK pathway may be involved in the melanogenic signaling cascade, and that delayed ERK activation by TGF-beta1 contributes to reduced melanin synthesis via MITF down-regulation.
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PMID:Transforming growth factor-beta1 decreases melanin synthesis via delayed extracellular signal-regulated kinase activation. 1514 27

Terrein is a bioactive fungal metabolite whose effects are almost unknown. In this study, we found for the first time that terrein has a strong hypopigmentary effect in a spontaneously immortalized mouse melanocyte cell line, Mel-Ab. Treatment of Mel-Ab cells with terrein (10-100 microM) for 4 days significantly reduced melanin levels in a dose-dependent manner. In addition, terrein at the same concentration also reduced tyrosinase activity. We then investigated whether terrein influences the extracellular signal-regulated protein kinase (ERK) pathway and the expression of microphthalmia-associated transcription factor (MITF), which is required for tyrosinase expression. Terrein was found to induce sustained ERK activation and MITF down-regulation, and luciferase assays showed that terrein inhibits MITF promoter activity in a dose-dependent manner. To elucidate the correlation between ERK pathway activation and a decreased MITF transcriptional level, PD98059, a specific inhibitor of the ERK pathway, was applied before terrein treatment and found to abrogate the terrein-induced MITF attenuation. Terrein also reduced the tyrosinase protein level for at least 72 h. These results suggest that terrein reduces melanin synthesis by reducing tyrosinase production via ERK activation, and that this is followed by MITF down-regulation.
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PMID:Terrein: a new melanogenesis inhibitor and its mechanism. 1555 16

Activating BRAF mutations and loss of wild-type INK4A expression both occur at high frequencies in melanomas. Here, we present evidence that BRAF and INK4A have different effects on melanogenesis, a marker of melanocytic differentiation. Human melanoma cell line 624Mel harbors mutations in both BRAF and INK4A. The in vitro and in vivo growth of these cells was inhibited by either reduced expression of mutant BRAF using stable retroviral RNA interference (RNAi) or retrovirus-mediated stable expression of wild-type INK4A cDNA. Consistent with the observed growth inhibition, phosphorylation of S780 and S795 in pRB, both CDK4/6 targets, was suppressed in cells expressing either mutant BRAF RNAi or wild-type INK4A. Interestingly, melanoma cells expressing mutant BRAF RNAi had increased pigmentation, produced more mature melanosomes and melanin and expressed higher levels of tyrosinase and tyrosinase-related protein-1, whereas melanogenesis was not induced by wild-type INK4A. We found that the melanocyte lineage-specific master control protein microphthalmia-associated transcription factor was upregulated by inhibition of mutant BRAF, which may be the cause for the melanogenic effect of BRAF RNAi. The results suggest that, although both BRAF and INK4A lesions promote cell growth and tumor formation, mutant BRAF may also induce dedifferentiation in melanoma cells.
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PMID:Effects on proliferation and melanogenesis by inhibition of mutant BRAF and expression of wild-type INK4A in melanoma cells. 1565 97

We previously established a mouse neural crest cell line named NCCmelb4, which is positive for Kit and negative for tyrosinase. NCCmelb4 cells were useful to study the effects of extrinsic factors such as retinoic acids and vitamin D(3) on melanocyte differentiation, but in order to study the development of melanocytes from multipotent neural crest cells, cell lines of melanocyte progenitors in earlier developmental stages are needed. In the present study, we established an immortal cell line named NCCmelb4M5 that was derived from NCCmelb4 cells. NCCmelb4M5 cells do not express Kit and are immortal and stable in the absence of Kit ligand. They are positive for melanocyte markers such as tyrosinase-related protein 1 and DOPAchrome tautomerase and they contain stage I melanosomes. Interestingly, glial fibrillary acidic protein, which is a marker for glial cells, is also positive in NCCmelb4M5 cells, while NCCmelb4 cells are negative for this protein. Immunostaining and a cell ELISA assay revealed that 12-O-tetradecanoylphorbol 13-acetate (TPA) and cholera toxin (CT) induce Kit expression in NCCmelb4M5 cells. Real-time polymerase chain reaction analysis also demonstrated the induction of Kit mRNA by TPA and CT. Microphthalmia-associated transcription factor mRNA is simultaneously enhanced by the same treatment. Kit induced by TPA/CT in NCCmelb4M5 cells disappeared after the cells were subcultured and incubated without TPA/CT. These findings show that NCCmelb4M5 cells have the potential to differentiate into Kit-positive melanocyte precursors and may be useful to study mechanisms of development and differentiation of melanocytes in mouse neural crest cells.
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PMID:Establishment of a kit-negative cell line of melanocyte precursors from mouse neural crest cells. 1589 15

In the present study, we investigated the effects of heat treatment on melanogenesis in a mouse melanocyte cell line (Mel-Ab). It has been reported that activated extracellular signal-regulated kinase (ERK) is responsible for microphthalmia-associated transcription factor (MITF) degradation, which leads to a reduction in tyrosinase protein production and melanin synthesis. Here we demonstrate that heat treatment induces sustained ERK activation, which may inhibit melanogenesis. However, the specific ERK pathway inhibitors, PD98059 or U0126 did not restore heat-induced hypopigmentation. Furthermore, PD98059 or U0126 hardly blocked the heat-induced activation of ERK. These results suggest that heat treatment may inactivate protein phosphatase, and thus ERK activation is maintained. To support this hypothesis, we examined the effects of heat treatment on protein phosphatase 2A (PP2A) activity. The results obtained show that heat treatment inactivates PP2A, which may subsequently cause ERK activation and that heat treatment inhibits MITF promoter activity. Overall, our results demonstrate that heat treatment reduces melanin production in a temperature-dependent manner.
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PMID:Heat treatment decreases melanin synthesis via protein phosphatase 2A inactivation. 1589 74

Pigmented neurofibroma (PNF) is a rare variant of neurofibroma showing melanin production. To clarify the clinicopathologic features of PNF and to characterize melanogenesis in PNF, 12 cases of PNF were examined in comparison with schwannoma (SCH, n = 16) and neurofibroma (NF, n = 26). The PNF patients were all Japanese including 7 men and 5 women, and patient age ranged from 11 to 71 years (median, 23.5 years). They showed strong a predisposition for neurofibromatosis type 1. Their tumor size was large, and tumors arose from various sites of skin. Histologically, clusters of epithelioid, dendritic, and spindle melanin-producing cells with faint pigmentation had a tendency to locate in deep dermis and subcutis, which seems to be a characteristic pattern of melanogenesis. There was a transition between melanin-producing cells and Schwann cells. Immunohistochemical examination included known melanogenic markers, microphthalmia-associated transcription factor (MITF), which is a key regulator of melanogenesis, and 2 tyrosine kinase receptors, c-Met and c-Kit, which regulate the development of melanocytes. In PNF, melanin-producing cells were S100 (+), MITF (+), Melan-A (+), tyrosinase (+/-), HMB45 (+/-), c-Met (+), and c-Kit (-). Schwann cells were S100 (+), MITF (-), Melan-A (-), tyrosinase (-), HMB45 (-), c-Met (-), and c-Kit (-), and intermediate spindle cells were S100 (+), MITF (+), Melan-A (+), tyrosinase (-), HMB45 (-), c-Met (+), and c-Kit (-). When compared with SCH and NF, MITF was weakly expressed in a part of tumor cells of SCH, whereas no definite staining was found in NF. c-Met expression was very weak in a scattered manner in SCH (10/15 cases) and NF (10/26 cases). These results suggest that PNF is a unique tumor that shows differentiation toward mature melanin production, but ability of melanin synthesis seems to be impaired. There may be a close relationship between up-regulated MITF and c-Met and the peculiar melanogenic nature of PNF, and both of these are useful diagnostic tools for distinguishing PNFs with less melanin production from NFs.
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PMID:Pigmented neurofibroma: review of Japanese patients with an analysis of melanogenesis demonstrating coexpression of c-met protooncogene and microphthalmia-associated transcription factor. 1611 3

In this study, we investigated the effects of 4-n-butylresorcinol on melanogenesis in a spontaneously immortalized mouse melanocyte cell line, Mel-Ab. Our results show that 4-n-butylresorcinol significantly inhibits melanin synthesis in a concentration-dependent manner. In addition, it was also found to inhibit the activity of tyrosinase, the rate-limiting melanogenic enzyme. Several reports have indicated that the activation of extracellular signal-regulated kinase (ERK) or of Akt reduces melanin synthesis via microphthalmia-associated transcription factor (MITF) down-regulation. Accordingly, we examined the effects of 4-n-butylresorcinol on the ERK and Akt signaling pathways. 4-n-Butylresorcinol did not induce ERK, Akt activation, or MITF degradation, and had no effect on cAMP response element binding protein (CREB) phosphorylation, which stimulates MITF expression. In contrast, 4-n-butylresorcinol strongly reduced tyrosinase activity in a cell-free system. Moreover, 4-n-butylresorcinol showed an additive effect in combination with hinokitiol, which reduces MITF expression. These results show that the hypopigmentary effect of 4-n-butylresorcinol results from its direct inhibition of tyrosinase.
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PMID:Inhibitory effects of 4-n-butylresorcinol on tyrosinase activity and melanin synthesis. 1632 52


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