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)

Melanin synthesized by epidermal melanocytes protects the skin against UVR-induced DNA damage and skin cancer. Exposure to UVR increases the synthesis of the photoprotective eumelanin on activation of MC1R, a melanoma susceptibility gene. We studied the expression of MC1R under UVR and alpha-MSH stimulation in skin of different ethnic origins and in melanocytes of various pigmentary levels. This study identifies and characterizes a novel MC1R isoform (MC1R350) generated by alternative splicing of the classically known MC1R (MC1R317). We demonstrate that the melanin content of melanocytes shows a significant positive correlation with MC1R317 levels but correlates inversely with the amount of MC1R350, suggesting that this latter isoform could act as a negative regulator of melanin synthesis. We confirmed that hypothesis by showing that while MC1R317 signaling significantly increases the expression of MITF and tyrosinase, two key factors in the melanin synthesis pathway, MC1R350 dramatically hampers their expression. In the skin, we show that UVR does not increase MC1R350 expression but does significantly increase MC1R317. Taken together, our results strongly suggest that MC1R350 acts as a negative regulator of skin pigmentation and demonstrate for the first time that MC1R isoform-specific expression is closely related to skin pigmentation and photoprotection.
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PMID:Regulation of constitutive and UVR-induced skin pigmentation by melanocortin 1 receptor isoforms. 1687 22

Human epidermal keratinocytes and melanocytes express proopiomelanocortins (POMC) and all of the enzymes for POMC processing, i.e. prohormone convertases PC-1 and PC-2 including the regulatory protein 7B2. In melanocytes POMC processing also occurs in the melanosome, a lysosome-derived organelle that specializes in the biosynthesis of melanin. Consequently, the autocrine synthesis and release of the key hormones ACTH, alpha and beta-MSH and beta-endorphin takes also place in melanocytes. All four hormones have been reported to promote the biosynthesis of eumelanin in melanocytes. ACTH and alpha-MSH bind to the melanocortin-1 receptor (MC-1-R) on the plasma membrane and activate the signalling pathway predominantly coupled to production of cAMP, and in some cell lines raising intracellular calcium levels. In the melanocyte this signalling is redundant due to the high expression of alpha1 and beta2-adrenoceptors. Downstream events increase melanocyte this signalling is redundant due to the high expression of a tyrosinase expression / activity to stimulate eumelanogenesis. Studies with rMC-1-R transfected COS cells showed that both ACTH and alpha-MSH bind to the receptor with similar or different affinity depending on the species (human vs mice). We have modelled the MC-1-R based on the X-ray crystal structure of a homologous 7 receptor rhodopsin. Docking studies with ACTH1-39, ACTH1-17 and ACTH11-17 and alpha-MSH1-13 revealed that all 3 ACTH peptides yield thermodynamically stable (key ACTH1-13 in-lock) complexes. Interestingly, alpha-MSH is predicted to only have a kinetic effect on the MC-1-R and beta-MSH has even a weaker affinity for the MC-1-R than alpha-MSH. Based on these results the relative importance of ACTH versus alpha-MSH in the human epidermis has been re-evaluated.
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PMID:Melanocortins in human melanocytes. 1691 90

This article focuses on recent advances in melanocyte biology and physiology. The major function of this neural crest-derived cell is the production of melanins. A "three enzyme theory" in the initiation of pigmentation is put forward and backed up by recent findings. A receptor-independent role for alpha-MSH and the cofactor (6R)-l-erythro-5,6,7,8-terahydrobiopterin (6BH(4)) in the control of tyrosinase is described. The importance of intramelanosomal pH for melanogenesis is covered. Finally, the redundancy of the cAMP and IP3/DAG/calcium signal in melanocytes together with the downstream events are highlighted. The main message of this article is that the intracellular H(2)O(2)- redox-equilibrium controls melanocyte function in a concentration-dependent manner.
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PMID:Advances in melanocyte basic science research. 1766 94

Despite many efforts, regulation of skin and hair pigmentation is still not fully understood. This article focuses mainly on controversial aspects in pigment cell biology which have emerged over the last decade. The central role of tyrosinase as the key enzyme in initiation of melanogenesis has been closely associated with the 6BH4 dependent phenylalanine hydroxylase (PAH) and tyrosine hydroxylase isoform I (THI) providing evidence for an old concept of the three enzyme theory in the initiation of the pigmentation process. In this context, it is noteworthy that intracellular L-phenylalanine uptake and turnover to L-tyrosine via PAH is vital for substrate supply of THI and tyrosinase. While PAH acts in the cytosol of melanocytes, THI and tyrosinase are sitting side by side in the melanosomal membrane. THI at low pH provides L-3,4-hydroxyphenylalanine L-DOPA which in turn is required for activation of met-tyrosinase. After an intramelanosomal pH change, possibly by the p-protein, has taken place, tyrosinase is subject to control by 6/7BH4 and the proopiomelanocortin (POMC) peptides alpha-MSH melanocyte stimulating hormone and beta-MSH in a receptor independent manner. cAMP is required for the activation of microphthalmia-associated transcription factor to induce expression of tyrosinase, for transcription of THI and for activation of PAH. The redundancy of the cAMP signal is discussed. Finally, we propose a novel mechanism involving H2O2 in the regulation of tyrosinase via p53 through transcription of hepatocyte nuclear factor 1alpha which in turn can also affect the POMC response.
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PMID:Regulation of melanogenesis--controversies and new concepts. 1817 48

To examine the possibility of luteolin as a whitening agent, we measured antioxidant activity using DPPH assay, NBT/XO assay and intracellular ROS scavengning assay and depigmenting activity using tyrosinase assay, alpha-MSH-induced melanin production in B-16 cells. Luteolin showed dose-dependent anti-oxidant activity in DPPH, NBT/XO and intracellular ROS assay. Also, luteolin directly inhibited xanthine oxidase activity in a dose-dependent manner. Although luteolin did not directly inhibit tyrosinase activity, it dose-dependently inhibited both tyrosinase activity and melanin production in B16 melanoma cells stimulated by 1 microM alpha-MSH. Luteolin dose-dependently inhibited cAMP levels in B16 melanoma cells stimulated by 1 microM alpha-MSH and 1 microM forskolin, which suggest that luteolin directly inhibits adenyl cyclase in B16 melanoma cells. Therefore, these results suggest that whitening activity of luteolin may be due to the inhibition of adenyl cyclase involved in the signal pathway of alpha-MSH in B16 melanoma cells.
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PMID:Whitening activity of luteolin related to the inhibition of cAMP pathway in alpha-MSH-stimulated B16 melanoma cells. 1880 60

To date, the principal receptor considered to regulate human pigmentation is the melanocortin-1 receptor (MC1-R) via induction of the cAMP/protein kinase A pathway by the melanocortins alpha-MSH and ACTH. In this context, it is noteworthy that beta-MSH can also induce melanogenesis, although it has a low affinity for the MC1-R, whereas the preferred receptor for this melanocortin is the MC4-R. Because beta-MSH is present in the epidermal compartment, it was of interest to ascertain whether functioning MC4-Rs are present in human epidermal keratinocytes and melanocytes. Our results provide evidence that the MC4-R is expressed in situ and in vitro throughout the human epidermis at the mRNA and protein level using RT-PCR, Western blotting, and double immunofluorescence staining. Moreover, radioligand binding studies yielded high-affinity receptors for beta-MSH on epidermal melanocytes (3600 receptors per cell), undifferentiated keratinocytes (7200 receptors per cell), and differentiated keratinocytes (72,700 receptors per cell), indicating that MC4-R expression correlates with epidermal differentiation. Importantly, increased melanogenesis after stimulation of the beta-MSH/cAMP/microphthalmia-associated transcription factor/tyrosinase cascade proved the functionality of this signal in melanocytes, which was attenuated in the presence of the specific MC4-R antagonist HS014. In summary, our results imply an important role for the beta-MSH/MC4-R cascade in human melanocyte biology, although the function and purpose of this signal in keratinocytes needs further elucidation.
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PMID:Regulation of pigmentation in human epidermal melanocytes by functional high-affinity beta-melanocyte-stimulating hormone/melanocortin-4 receptor signaling. 1897 67

The purpose of this study was to evaluate human hair follicle melanogenic activity using the [14C]-2-thiouracil, which was known to incorporate into nascent melanins. Results obtained on pigmented, grey and non-pigmented hair follicles demonstrated that [(14)C]-2-TU incorporation was restricted to the melanogenic compartment with a strong accumulation located around dermal papilla and within the fibre of pigmented hair follicles. Quantitative analysis of [(14)C]-2-TU incorporation showed a significant increase in pigmented hair follicles upon stimulation with 1 microm forskolin concomitant to an increase in tyrosinase levels. A strong significant decrease in [14C]-2-TU incorporation was noted, when hair follicles were incubated with the tyrosinase competitive inhibitor kojic acid (200 microm). Incubation with the MC1-R agonist alpha-MSH (0.2 microm) did not induce a significant stimulation of hair melanogenesis. The present model could thus represent a useful new tool to identify modulators of human hair pigmentation.
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PMID:Human hair follicle pigmentary unit as a direct target for modulators of melanogenesis, as studied by [14C]-2-thiouracil incorporation. 1905 56

Arbutin has been used as a whitening agent in cosmetic products. Melanin, the major pigment that gives color to skin, may be over-produced with sun exposure or in conditions such as melasma or hyperpigmentary diseases. Tyrosinase is a key enzyme that catalyzes melanin synthesis in melanocytes; therefore, inhibitors of the tyrosinase enzyme could be used for cosmetic skin whitening. A recent study has reported that arbutin decreases melanin biosynthesis through the inhibition of tyrosinase activity. However, this inhibitory mechanism of arbutin was not sufficiently demonstrated in skin tissue models. We found that arbutin both inhibits melanin production in B16 cells induced with alpha-MSH and decreases tyrosinase activity in a cell-free system. Furthermore, the hyperpigmentation effects of alpha-MSH were abrogated by the addition of arbutin to brownish guinea pig and human skin tissues. These results suggest that arbutin may be a useful agent for skin whitening.
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PMID:Inhibitory effects of arbutin on melanin biosynthesis of alpha-melanocyte stimulating hormone-induced hyperpigmentation in cultured brownish guinea pig skin tissues. 1938 80

More than 150 genes have been identified that affect skin color either directly or indirectly, and we review current understanding of physiological factors that regulate skin pigmentation. We focus on melanosome biogenesis, transport and transfer, melanogenic regulators in melanocytes, and factors derived from keratinocytes, fibroblasts, endothelial cells, hormones, inflammatory cells, and nerves. Enzymatic components of melanosomes include tyrosinase, tyrosinase-related protein 1, and dopachrome tautomerase, which depend on the functions of OA1, P, MATP, ATP7A, and BLOC-1 to synthesize eumelanins and pheomelanins. The main structural component of melanosomes is Pmel17/gp100/Silv, whose sorting involves adaptor protein 1A (AP1A), AP1B, AP2, and spectrin, as well as a chaperone-like component, MART-1. During their maturation, melanosomes move from the perinuclear area toward the plasma membrane. Microtubules, dynein, kinesin, actin filaments, Rab27a, melanophilin, myosin Va, and Slp2-a are involved in melanosome transport. Foxn1 and p53 up-regulate skin pigmentation via bFGF and POMC derivatives including alpha-MSH and ACTH, respectively. Other critical factors that affect skin pigmentation include MC1R, CREB, ASP, MITF, PAX3, SOX9/10, LEF-1/TCF, PAR-2, DKK1, SCF, HGF, GM-CSF, endothelin-1, prostaglandins, leukotrienes, thromboxanes, neurotrophins, and neuropeptides. UV radiation up-regulates most factors that increase melanogenesis. Further studies will elucidate the currently unknown functions of many other pigment genes/proteins. (c) 2009 International Union of Biochemistry and Molecular Biology, Inc.
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PMID:Physiological factors that regulate skin pigmentation. 1944 48

One skin cancer prevention strategy that we are developing is based on synthesizing and testing melanocortin analogs that reduce and repair DNA damage resulting from exposure to solar ultraviolet (UV) radiation, in addition to stimulating pigmentation. Previously, we reported the effects of tetrapeptide analogs of alpha-melanocortin (alpha-MSH) that were more potent and stable than the physiological alpha-MSH, and mimicked its photoprotective effects against UV-induced DNA damage in human melanocytes. Here, we report on a panel of tripeptide analogs consisting of a modified alpha-MSH core His(6)-d-Phe(7)-Arg(8), which contained different N-capping groups, C-terminal modifications, or arginine mimics. The most potent tripeptides in activating cAMP formation and tyrosinase of human melanocytes were three analogs with C-terminal modifications. The most effective C-terminal tripeptide mimicked alpha-MSH in reducing hydrogen peroxide generation and enhancing nucleotide excision repair following UV irradiation. The effects of these three analogs required functional MC1R, as they were absent in human melanocytes that expressed non-functional receptor. These results demonstrate activation of the MC1R by tripeptide melanocortin analogs. Designing small analogs for topical delivery should prove practical and efficacious for skin cancer prevention.
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PMID:alpha-MSH tripeptide analogs activate the melanocortin 1 receptor and reduce UV-induced DNA damage in human melanocytes. 1971 49


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