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 combined action of cholera toxin (CT)-dependent activation of the adenylate cyclase signaling pathway, stimulation of protein kinase C, and activation of the tyrosine kinase activity of cell surface receptors and proto-oncogene products, have been shown to stimulate melanocyte proliferation. However, natural factors responsible for the optimal stimulation of normal human melanocyte growth, either isolated or co-cultured with keratinocytes, remain largely unknown. alpha MSH (alpha melanocyte stimulating hormone) has previously been shown to bind to murine and human melanoma cells and to stimulate their adenylate cyclase and tyrosinase activity. In contrast, very little is known about the presence and function of alpha MSH receptors in normal human melanocytes. We now report that alpha MSH: (i) binds to normal human melanocytes through a single class of high-affinity receptors; (ii) does not induce per se melanocytes to enter the S-phase of the cell cycle; (iii) does indeed stimulate melanocyte proliferation in a dose-dependent fashion; but its stimulatory effect requires bFGF and/or the activation of protein kinase C.
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PMID:Alpha melanocyte stimulating hormone (alpha MSH) stimulates normal human melanocyte growth by binding to high-affinity receptors. 822 96

We have used the reverse transcription-polymerase chain reaction to survey the repertoire of protein tyrosine kinases expressed in cultured normal human melanocytes, a differentiated cell type derived from the neural crest. We identified 25 different tyrosine kinase cDNAs among a total of 608 protein tyrosinase kinase-related cDNAs analyzed. Six encode receptor tyrosine kinases for known ligands, several of which have been implicated in controlling melanocyte proliferation in vitro. Two others encode apparent receptor tyrosine kinases for unknown ligands. Four encode known non-receptor tyrosine kinases and five encode previously identified anonymous protein tyrosine kinases. Of the eight other melanocyte-associated protein tyrosine kinases, most or all appear to be novel. These 25 protein tyrosine kinase genes exhibit distinct patterns of expression in cultured human melanocytes, human erythroleukemia cells, and a variety of normal human tissues. We mapped 16 of the corresponding protein tyrosine kinase genes to specific human chromosomes, identifying a total of 19 human genetic loci, some of which may constitute candidate genes for genetic disorders of mammalian development.
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PMID:A survey of protein tyrosine kinase mRNAs expressed in normal human melanocytes. 824 43

The proto-oncogene c-Kit encodes a membrane receptor protein with intrinsic tyrosine kinase activity. Activation of c-Kit induces cell proliferation, differentiation or migration among different cell types. The present study provides evidence that c-Kit plays an important role in the cell differentiation rather than in cell proliferation in pigment cells. We found that normal human melanocytes and a limited number of melanoma cells, e.g. WM35, WM39 and G361 cell lines, expressed the c-Kit gene together with tyrosinase and TRP-1 genes. When exposed to alpha-melanocyte stimulating hormone, these three cell lines also showed an increased tyrosinase (dopa-oxidase) activity. By incubating these cells with 20 ng/ml of stem cell factor (SCF) which is a ligand of c-Kit receptor, we found a transient increase of tyrosinase activity 2-4 h post-incubation, indicating an early response of tyrosinase activation, either by elevating tyrosinase protein expression or by tyrosinase protein modification (e.g. phosphorylation). However, Western blot analysis using anti-tyrosinase antibody suggested that there was no change of tyrosinase protein expression between SCF-treated and non-treated cells. We therefore suggest that protein modulation of tyrosinase (e.g. phosphorylation) plays an important role in c-Kit-induced melanogenesis.
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PMID:Coordinated mRNA expression of c-Kit with tyrosinase and TRP-1 in melanin pigmentation of normal and malignant human melanocytes and transient activation of tyrosinase by Kit/SCF-R. 854 20

The purpose of this study was to investigate factors regulating melanogenesis in cultured human uveal melanocytes. The effects of various substances on the melanin content, tyrosinase activity and growth of cultured uveal melanocytes were tested. 12-O-tetradecanoyl-phorbol-13-acetate (a protein kinase C activator) and various cAMP-elevating agents, including isobutylmethylxanthine, cholera, toxin, and dibutyryl-cAMP increased melanin content per culture, tyrosinase activity and cell numbers of uveal melanocytes in a dose dependent manner. Basic fibroblast growth factor (tyrosine kinase activator) stimulated growth but did not affect melanin content per culture of uveal melanocytes in vitro. These results indicate that cAMP-elevating agents and protein kinase C activator stimulate melanogenesis and growth of cultured uveal melanocytes. Tyrosine kinase activator stimulates growth but not melanogenesis of cultured uveal melanocytes.
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PMID:Regulation of melanogenesis by human uveal melanocytes in vitro. 919 91

Twelve analogues of the antibacterial phenolic peptide 5-S-glutathionyl-beta-alanyl-L-dopa (5-S-GA-L-D: 1) were synthesized via orthoquinones using tyrosinase. Several synthesized compounds inhibited the v-Src autophosphorylation tyrosine kinase reaction with an IC50 value comparable to that of herbimycin. The inhibition of c-Src substrate phosphorylation was much less active than v-Src autophosphorylation inhibition. The analogues showed no effects on substrate phosphorylation by epidermal growth factor receptor (EGFR), and this selectivity is the most characteristic feature of the analogues (1-12).
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PMID:Selective inhibition of Src protein tyrosine kinase by analogues of 5-S-glutathionyl-beta-alanyl-L-dopa. 988 Sep 15

Twelve analogues of the antibacterial phenolic peptide 5-S-glutathionyl-N-beta-alanyl-L-dopa (5-S-GA-L-D, 1) were synthesized via orthoquinone using tyrosinase. Several synthesized compounds inhibited the v-Src autophosphorylation tyrosine kinase reaction with an IC50 value comparable to that of herbimycin A. The inhibition of c-Src substrate phosphorylation was much less active than v-Src autophosphorylation inhibition. 5-S-GA-L-D (1) and its analogous competed with peptide substrate and non-compared with ATP. The analogues showed no effects on substrate phosphorylation by epidermal growth factor receptor (EGFR), and this selectivity is the most characteristic feature of the 5-S-GA-L-D and its analogues (1-12).
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PMID:Inhibition effects of 5-S-glutathionyl-N-beta-alanyl-L-dopa analogues against Src protein tyrosine kinase. 1039 35

UV-induced melanogenesis is a well known physiological response of human skin exposed to solar radiation; however, the signaling molecules involved in the stimulation of melanogenesis in melanocytes following UV exposure remain unclear. In this study we induced melanogenesis in vitro in normal human epidermal melanocytes using a single irradiation with UVA at 1 kJ/m2 and examined the potential involvement of mitogen-activated protein kinases (MAPK) as UVA-responsive signaling molecules in those cells. UVA irradiation did not affect the proliferation of melanocytes, but it did increase tyrosinase mRNA expression, which reached a maximum level 4 hr after UVA irradiation. The amount of tyrosinase protein, as quantitated by immunoblotting, was also increased at 24 hr following UVA irradiation. Among the MAPK examined, extracellular signal-related kinase (ERK) 1/2 was phosphorylated within 15 min of UVA irradiation, but no such phosphorylation was observed for c-Jun N-terminal kinases (JNK) or p38. Accordingly, the activity of ERK1/2 was also increased shortly after UVA irradiation. These responses of ERK1/2 to UVA irradiation were markedly inhibited when cells were pre-treated with N-acetyl-L-cysteine, an antioxidant, or with suramin, a tyrosine kinase receptor inhibitor. The formation of (6-4)photoproducts or cyclobutane pyrimidine dimers was not detected in cellular DNA after UVA irradiation. These findings suggest that a single UVA irradiation-induced melanogenesis is associated with the activation of ERK1/2 by upstream signals that originate from reactive oxygen species or from activated tyrosine kinase receptors, but not from damaged DNA.
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PMID:Possible involvement of ERK 1/2 in UVA-induced melanogenesis in cultured normal human epidermal melanocytes. 1131 Jul 89

Vascular endothelial growth factor (VEGF) is an important mediator of tumor-associated angiogenesis, and consequently it has been associated with metastasis. We report here that the overexpression of VEGF(165) in melanoma xenografts promotes an acceleration of tumor growth and an increase in angiogenesis as well as the spontaneous metastasis formation. In addition, VEGF receptors (VEGFR)1, VEGFR2 and neurophilin-1 are expressed in A375 melanoma cells. Forced overexpression of VEGF in these cells induces cell growth and triggers survival activity in serum-starved cultures, by a mechanism dependent on the mitogen-activating protein kinase signaling pathway. Furthermore, these effects are dependent MEK 1/2 activity. Kinase domain region-specific tyrosine kinase inhibitors dramatically reduced DNA synthesis to 20% with respect to the controls, although they did not completely suppress either the p44 or p42-phosphorylated forms of extracellular signal-regulated protein kinase. These inhibitors also provoked a decrease in Akt phosphorylation. We observed a dramatic reduction in survival after treatment with phosphatidylinositol 3'-kinase (PI3K)-specific inhibitor in the presence of specific tyrosinase inhibitors. We suggest that the overproduction of VEGF(165) concomitantly expressed with its receptors favors cell growth and survival of melanoma cells through MAPK and PI3K signaling pathways. These data support the involvement in melanoma growth and survival of a VEGF-dependent internal autocrine loop mechanism, at least in vitro.
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PMID:Overproduction of VEGF concomitantly expressed with its receptors promotes growth and survival of melanoma cells through MAPK and PI3K signaling. 1561 May 28

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

Cardiotoxicity associated with cancer treatment is an important field of interest especially as the new class of VEGF signaling pathway inhibitors (VSP) continues to grow. Small molecule tyrosine kinase inhibitors such as sorafenib, sunitinib, and pazopanib inhibit the downstream pathways of all three of the vascular endothelial growth factor receptors (VEGFR 1, 2, and 3). Other targets of these agents include kinases involved in vascular and myocardial homoeostasis. These agents are all known to frequently cause hypertension, their most common side-effect. Myocardial ischemia has also been reported, but the frequency and etiology of VSP-related ischemia is poorly characterized. This manuscript describes the first reported case of sorafenib-associated multivessel coronary vasospasm in a 57-year-old patient with hepatocellular carcinoma. He underwent sorafenib treatment, a tyrosinase inhibitor, 400 mg twice a day. The vasospasm was reversible under nitroglycerin. Possible mechanisms are also discussed.
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PMID:Sorafenib-associated multivessel coronary artery vasospasm. 2158 15


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