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)

Staurosporine, a protein kinase (PK) inhibitor, phorbol-12-myristate-13-acetate (PMA), a PKC activator and A23187 calcium ionophore were added to human melanocyte cultures with or without dibutyryl cyclic AMP (dbcAMP). After 2 days' incubation, changes in various melanogenic factors were examined such as tyrosinase activity and the amount of tyrosinase-related protein (TRP) as well as the morphology of the melanocytes. dbcAMP stimulated all the melanogenic factors. Staurosporine increased tyrosinase activity and amount of TRP and caused morphological changes with the formation of numerous dendrites, regardless of the presence of dbcAMP. In contrast, PMA did not significantly affect tyrosinase activity, TRP content or dendrite formation, with or without dbcAMP. The effects of staurosporine on tyrosinase activity and TRP content were completely inhibited by PMA, but PMA did not significantly affect the staurosporine-induced morphological changes. A23187 inhibited both tyrosinase activity and TRP content, regardless of the presence of dbcAMP, but did not affect the morphology of melanocytes. These findings suggest that tyrosinase activity and TRP content are regulated by adenylate cyclase and Ca2+ and partly by PKC, while the morphological features of melanocytes are affected by intracellular cAMP accumulation and by the inhibition of PKC.
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PMID:Effects of staurosporine, PMA and A23187 on human melanocyte cultures with dibutyryl cyclic AMP. 131 Nov 91

The following studies have been undertaken to compare and correlate the effects of 12-O-tetradecanoylphorbol acetate (TPA), basic fibroblast growth factor (bFGF), cholera toxin (CT), and isobutyl methylxanthine (IBMX) on neonatal human melanocyte (NHM) proliferation, tyrosinase activity, and cyclic adenosine monophosphate (cAMP) concentration. NHM proliferated at a maximal rate in medium containing 8 nM TPA, 200 ng/ml CT, and 10(-4) M IBMX. TPA alone did not result in optimal melanocyte proliferation, and, as previously shown, its mitogenic effect was greatly enhanced by the addition of CT and IBMX individually or concomitantly. Human recombinant (hr) bFGF could replace TPA in the NHM growth medium. Maximal proliferation was achieved using 3 ng/ml hrbFGF, 20 ng/ml CT, and 10(-4) M IBMX. The mitogenic effect of 1.2 ng/ml hrbFGF was potentiated in the concomitant but not individual presence of CT and IBMX. TPA alone in the absence of CT and IBMX caused a dose-dependent stimulation of tyrosinase activity. Maximal tyrosinase activity was obtained in the presence of 0.8 nM TPA, 20 ng/ml CT, and 10(-4) M IBMX. Unlike TPA, hrbFGF alone resulted in inhibition of tyrosinase activity. In the presence of hrbFGF, tyrosinase activity was potentiated by CT and IBMX, but not by CT alone. Neither TPA nor hrbFGF alone could increase intracellular cAMP levels. The effects of CT and IBMX on intracellular cAMP concentration were enhanced to a greater extent by TPA than by hrbFGF. Under our experimental conditions, in the presence of hrbFGF, CT but not IBMX resulted in a dose-dependent increase in cAMP concentration. Further studies on NHM will be aimed at determining the exact role of protein kinase C (PKC) in regulating proliferation and melanogenesis and the mechanism(s) activated by hrbFGF.
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PMID:Mitogenic, melanogenic, and cAMP responses of cultured neonatal human melanocytes to commonly used mitogens. 137 Aug 43

Mouse melanoma cells in culture respond to melanocyte-stimulating hormone (MSH) or to cyclic AMP analogues by demonstrating an increase in tyrosinase activity. In this study the effect of the tumor promoter, 12-O-tetradecanoylphorbol 13-acetate (TPA), on the hormonal induction of tyrosinase was examined. TPA was found to lower basal levels of tyrosinase activity in melanoma cells and to reduce tyrosinase levels in cells treated with either MSH (10(-7) M), dibutyryl cAMP (10(-4) M), isobutylmethylxanthine (IBMX, 10(-4) M), or with the potent MSH analogue, [Nle4,D-phe7]-alpha-MSH. The phorbol ester, phorbol 12,13-dibutyrate was also effective in lowering tyrosinase activity levels, while 4 alpha-phorbol 12,13-didecanoate, which does not bind protein kinase C, was ineffective. In order to determine how TPA may reduce tyrosinase activity in melanoma cells, the levels of tyrosinase mRNA in untreated or TPA-treated cells were determined by Northern blot analysis. A marked down-regulation of constitutive levels of tyrosinase mRNA was observed in cells treated with the tumor promoter. Tyrosinase mRNA levels in cultures exposed to TPA for 48 h were only 7% of control levels. Tyrosinase mRNA levels in cells treated with both MSH and TPA were also lower than in cells treated with MSH alone. Previous studies from this laboratory have shown that insulin both lowers basal tyrosinase activity in melanoma cells and antagonizes the MSH stimulation of the enzyme. We have now determined that this inhibition is also due to reduced levels of tyrosinase mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Down-regulation of tyrosinase mRNA levels in melanoma cells by tumor promoters and by insulin. 170 21

The role of melanocyte stimulating hormone (MSH) as a mediator of the melanogenic response to ultraviolet radiation (UVR) was examined in C57 BL/6 mice. While exposure to UVR (250-300 nm) for 7, 14 and 27 days increased tyrosinase activity in epidermal melanocytes of the ear MSH had no effect and failed to alter the response to UVR. Plasma alpha-MSH concentrations were unchanged following UVR. Theophylline, a phosphodiesterase inhibitor, also had no effect on epidermal tyrosinase activity in non-irradiated and UV irradiated mice. Prostaglandin E2 and arachidonic acid were also ineffective in non-irradiated and UV irradiated mice and indomethacin, an inhibitor of prostaglandin synthesis, failed to increase epidermal tyrosinase activity after UVR. On the other hand, 12-0-tetradecanoyl phorbol 13 acetate, an activator of protein kinase C, increased epidermal tyrosinase activity in non-irradiated mice and also enhanced the effect of UVR.
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PMID:The effect of ultraviolet radiation and melanocyte-stimulating hormone on tyrosinase activity in epidermal melanocytes of the mouse. 212 69

The nature of the relationship between agonist-stimulated cyclic AMP production and metastatic potential was examined in detail for four B16 melanoma cell lines of varying metastatic potential. Highly metastatic cells (B16 F10C1) appeared to differ from cells of low metastatic potential (B16 F1C29) in the degree to which cyclic AMP production in intact cells was stimulated by protein kinase C activation. No significant difference was found in the adenylate-cyclase enzyme activities of the broken cells, irrespective of the agonist used, or in the distribution of cyclic AMP between the intracellular and extracellular compartment. Although B16F1, F10 and F10C1 cells all produced equally pigmented tumors in vivo, the cells differed in their melanogenic response to cyclic AMP elevating agents in vitro: the least metastatic cells produced least agonist-induced cyclic AMP but this induced greatest tyrosinase activation and melanin production in vitro; conversely, the more metastatic cells produced more cyclic AMP but less tyrosinase activation and melanin production in response to agonist stimulation. Thus, agonist-stimulated cyclic AMP production does not appear to be coupled to the differentiated function of melanogenesis for highly metastatic B16 melanoma cells.
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PMID:The regulation of cyclic AMP production and the role of cyclic AMP in B16 melanoma cells of differing metastatic potential. 216 82

Normal human melanocytes, unlike malignant melanoma cells, required at least three growth-promoting agents, i.e., phorbol ester for protein kinase C activation and the growth factors basic fibroblast growth factor (bFGF) and insulin, for growth in chemically defined W489 medium. Cell growth was further stimulated by addition of agents that increase intracellular levels of cyclic adenosine 3',5'-monophosphate (cAMP) to the medium. Among these agents, the pituitary hormones alpha-melanocyte-stimulating hormone (alpha-MSH) and follicle-stimulating hormone were the most potent, whereas bacterial toxins, including cholera, tetanus, and pertussis toxin and their subunits either were less mitogenic or gave variable results depending on the culture tested. Medium containing phorbol ester PMA, growth factors bFGF and insulin (or insulin-like growth factor-I), and synthetic alpha-MSH supported melanocyte growth for more than 5 months with doubling times between 5 and 8 days. Two copper-binding proteins, ceruloplasmin and tyrosinase, were mitogenic when added to medium and ceruloplasmic induced a long bi- to tripolar-shape of cells. Addition of 1 mM dibutyryl cAMP to the medium led to the formation of dendrites in all cells, with an average of 28 extensions per cell. Although cell growth was inhibited by dibutyryl cAMP, cells were not terminally differentiated and continued to proliferate. Dendritic melanocytes showed a 2.2-fold increase in activity of the tyrosine kinase pp60c-src. The induction of dendritic processes in melanocytes by dibutyryl cAMP or sodium butyrate was reversible and appears to reflect the expression of the mature melanocytic phenotype in situ.
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PMID:Regulatory factors that determine growth and phenotype of normal human melanocytes. 246 9

Human melanocytes, maintained on bovine corneal endothelium-derived extracellular matrix for at least 4 days in the absence of phorbol 12-myristate 13-acetate (PMA) and cholera toxin (CT), displayed increased tyrosinase activity when exposed to several pro-opiomelanocortin-derived (POMC) peptides. Melanocytes from 9 of 14 donors showed significantly increased tyrosinase activity after treatment with adrenocorticotropic hormone (ACTH; mean increase 320 +/- 107 (S.E.M.)% of control, P < 0.005), while melanocytes from 8 of 13 donors increased tyrosinase in the presence of diacetyl-melanocyte stimulating hormone (di-MSH; mean increase 223 +/- 31 (S.E.M.)% of control, P < 0.005). Maximal increases in tyrosinase were seen after treatment with 10(-10) M ACTH and with 10(-6) M di-MSH. In two cell cultures which showed tyrosinase stimulation, melanin synthesis was similarly increased in the presence of added POMC peptides. PMA but not CT increased tyrosinase activity in melanocytes cultured under these conditions. In the presence of staurosporine, an inhibitor of protein kinase C (PKC), the magnitude of the increase in tyrosinase due to PMA, ACTH and di-MSH was significantly reduced. These results indicate that tyrosinase activity in melanocytes from most human donors, under appropriate conditions, is susceptible to the stimulatory effects of POMC peptides, that ACTH is considerably more potent than di-MSH in this test system and that in human cells the PKC pathway may be important in modulating melanogenesis.
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PMID:Stimulation of tyrosinase in human melanocytes by pro-opiomelanocortin-derived peptides. 759 39

We have investigated the role of protein kinase C (PKC) in human melanogenesis. The level of PKC activity paralleled the total melanin content in cultured newborn melanocytes. Activation of PKC by treatment with 5 x 10(-7) M phorbol dibutyrate acutely caused a doubling in the activity of tyrosinase, the rate-limiting enzyme in melanogenesis, known to correlate directly with melanin synthesis in these cells. When PKC was depleted to 5-10% of initial levels, there was a 40-50% parallel reduction in tyrosinase activity; and regeneration of PKC activity was associated with the recovery of tyrosinase activity. By Northern blot analysis, the alpha and beta but not the gamma isoforms were detectable in melanocytes. By Western blot analysis, the racially determined pigment level in cultured melanocytes correlated with PKC-beta protein expression. In a pigmented human melanoma line (P-MM4, 20-30 ng melanin/micrograms protein)and its nonpigmented subclone (NP-MM4, undetectable melanin), PKC-alpha mRNA was expressed in both, whereas PKC-beta mRNA was detectable only in P-MM4 cells. Tyrosinase protein level was comparable in both cell lines. When NP-MM4 cell lysate was incubated with melanocyte lysate known to contain PKC-beta, tyrosinase activity per microgram of melanocyte protein in the combined lysate increased, consistent with activation of the previously inactive tyrosinase of NP-MM4 origin. Moreover, NP-MM4 cells transiently transfected with PKC-beta cDNA increased tyrosinase activity from undetectable to detectable levels. These combined data show that PKC-beta regulates human melanogenesis by activating tyrosinase.
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PMID:The beta isoform of protein kinase C stimulates human melanogenesis by activating tyrosinase in pigment cells. 768 20

Melanin is specifically produced in melanocytes. The pathway for melanin biosynthesis is regulated by a number of melanocyte-specific proteins, including tyrosinase and tyrosinase-related protein-1 (TRP-1, b locus protein). To understand the regulation of melanogenesis, we examined tyrosinase activities, mRNA levels of tyrosinase and TRP-1, and eumelanin and pheomelanin contents in mouse B16-F1 melanoma cells after they had been treated with some melanotropic reagents. Cholera toxin, alpha-melanocyte-stimulating hormone, and dibutyryl cyclic AMP increased tyrosinase activity and stimulated eumelanin biosynthesis. These reagents elevated intracellular cAMP levels. In contrast, 12-O-tetradecanoylphorbol 13-acetate reduced tyrosinase activity and eumelanin synthesis. In all cases, the mRNA levels of tyrosinase and TRP-1 changed in parallel with tyrosinase activity and eumelanin content. TRP-1 was induced simultaneously with tyrosinase, although its inducibility was lower than that of tyrosinase. These results suggest that the expressions of tyrosinase and TRP-1 genes are coordinately regulated by melanotropic reagents through cAMP-dependent protein kinase and protein kinase C in mouse B16-F1 cells, and that their coordinate expression causes eumelanin biosynthesis.
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PMID:Eumelanin biosynthesis is regulated by coordinate expression of tyrosinase and tyrosinase-related protein-1 genes. 768 98

All-trans retinoic acid is used topically for treating a variety of dermatologic conditions ranging from acne to photoaged skin. Although the clinical effects of retinoic acid treatment are often considerable, relatively little is known about the basic mechanisms underlying such effects. With the development of an in vivo human assay we have investigated the pleiotypic effects of topical retinoids from the histologic to the molecular. Histologically, retinoic acid induces epidermal proliferation and differentiation coupled with dermal fibroblast production of collagen. Immunologic effects include stimulation of the antigen-presenting capacity of Langerhans cells and induction of keratinocyte ICAM-1 expression. At the biochemical level, retinoic acid regulates transglutaminase and tyrosinase activities and activates protein kinase C. Both polar metabolites and stereoisomers of all-trans retinoic acid are also biologically active. Molecular biologic techniques have revealed that elevation of mRNA for cellular retinoic acid binding protein II is a retinoid-related event and that nuclear receptors such as retinoic acid receptors and retinoid X-receptors may transduce the retinoid response.
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PMID:Human in vivo pharmacology of topical retinoids. 772 37


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