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

---

Query: EC:1.10.3.1 (tyrosinase)
9,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In B16 melanocytes, tyrosinase activity and melanin formation are upregulated by alpha-MSH and downregulated by TGF beta1 and TNF alpha. Since TGF beta1 or TNF alpha block the differentiation programs induced by throphic hormones in other cell types, we studied tyrosinase regulation by alpha-MSH in the presence of the hypopigmenting cytokines, as well as the effects of the cytokines on several aspects of alpha-MSH signaling. TGF beta1 and TNF alpha only slightly diminished MC1 receptor gene expression, and had no effect on the intracellular levels of cAMP, or on the alpha-MSH-dependent cAMP rise. The intracellular levels of tyrosinase mRNA, protein and enzymatic activities were also upregulated by alpha-MSH in cells pretreated with TGF beta1 or TNF alpha. Therefore the cytokines do not block the response to alpha-MSH. However, the cytokine-induced inhibition of tyrosinase gene expression, protein levels and the reduction of tyrosinase intracellular half-life also occurred in the presence of alpha-MSH, indicating that the hormone does not override TGF beta1 or TNF alpha inhibition. Thus, tyrosinase activity and the rate of melanin formation in B16 melanocytes might reflect simply the balance between alpha-MSH stimulation and TGF beta1 or TNF alpha inhibition, acting by independent mechanisms.
...
PMID:Independent regulation of tyrosinase by the hypopigmenting cytokines TGF beta1 and TNF alpha and the melanogenic hormone alpha-MSH in B16 mouse melanocytes. 1064 3

Alpha melanocyte-stimulating hormone (MSH) and related proopiomelanocortin-derived (POMC) peptides bind to the melanocortin 1 receptor (MC1-R) of mammalian melanocytes and stimulate proliferation and melanogenesis. POMC transcripts and alpha-MSH-like immunoreactivity have been found in melanoma cells and a possible autocrine loop involving MC1-R and POMC-derived products has been proposed. Therefore, the alpha-MSH/MC1-R system plays a major role in the biology of melanocytes, and provides targets for melanoma diagnosis and therapy. However, the relative levels of MC1-R expression in normal melanocytes (NM) and melanoma cells are unknown, and it is still debated whether or not all human melanomas express the MC1-R. We describe a semiquantitative RT-PCR assay for MC1-R expression, using a competition vector generated by deleting 164 bp of the native gene. The competitor was employed to analyse a panel of human melanoma cells, tumour samples, giant congenital nevus cells (CNM) and normal melanocytes (NM). All samples were positive for MC1-R expression, but expression of the receptor gene did not correlate with that of tyrosinase. Expression levels were about 10 and 20 times higher for surgical specimens and cultured melanoma cells, respectively, than for NM, but comparable for CNM and NM. Thus, high MC1-R expression is a frequent event in malignant melanocytes, and might lead to a higher activity of the alpha-MSH/MC1-R system in melanoma cells as compared to normal melanocytes, for equal local concentrations of the hormone or related melanocortins.
...
PMID:Expression of the MC1 receptor gene in normal and malignant human melanocytes. A semiquantitative RT-PCR study. 1064 13

In the human epidermis both keratinocytes and melanocytes express POMC m-RNA. Immunohistochemical studies of both cell types demonstrate significantly higher levels of alpha-MSH in melanocytes than in keratinocytes. Both cell types also hold the full capacity for de novo synthesis/recycling of the essential cofactor (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (6BH4). 6BH4 is critical for the hydroxylation of the aromatic amino acids L-phenylalanine, L-tyrosine, and L-tryptophan, for nitric oxide production and in various immune modulatory processes. Recently it was shown that tyrosinase activity is regulated by 6BH4 through a specific allosteric inhibition. The tyrosinase/6BH4 inhibition can be activated by 1:1 complex formation between 6BH4 and alpha-MSH, but an excess of alpha-MSH over 6BH4 can inhibit tyrosinase due to complex formation by tyr2 in the alpha-MSH sequence. In both melanocytes and keratinocytes 6BH4 controls the L-tyrosine supply via phenylalanine hydroxylase (PAH). Recently we were able to show that the cellular uptake of L-phenylalanine and its intracellular turnover to L-tyrosine is crucial for melanogenesis. alpha-MSH can promote the production of L-tyrosine via PAH due to activation of the PAH tetramer to the more active dimer by removing 6BH4 from the regulatory binding domain on the enzyme. In conclusion, alpha-MSH can control (1) intracellular L-tyrosine formation from L-phenylalanine in both melanocytes and keratinocytes, and (2) tyrosinase activity, directly, in melanocytes.
...
PMID:alpha-MSH can control the essential cofactor 6-tetrahydrobiopterin in melanogenesis. 1081 64

Melanocyte-stimulating hormone (alpha-MSH) increases cytosolic levels of cAMP as well as tyrosinase activity in murine melanocytes. These activities depend upon the presence of melanin precursors and may differ in human melanocytes. In this study, we demonstrate that high levels of tyrosine (3.7 mM), the chief melanin precursor, reduced the proliferative effect of alpha-MSH and altered human melanocyte morphology as compared to treatment with low (25-30 microM, half-physiological) levels of tyrosine. The anti-proliferative effect of high levels of tyrosine was not restricted to alpha-MSH; tyrosine also reduced proliferation induced by forskolin, a direct activator of the cAMP pathway. Exposure to low tyrosine levels and alpha-MSH induced a dendritic morphology; in the presence of high tyrosine and alpha-MSH, melanocytes displayed large, pigmented cell bodies and less dendricity. Exposure to alpha-MSH in the presence of low tyrosine for up to 9 days did not appreciably increase melanin levels, but culturing the human melanocytes in high levels of tyrosine with alpha-MSH increased melanin levels 10-50-fold, depending on the pigmentation background of the donor. A greater induction of melanin accumulation was observed in melanocytes derived from light-skinned donors than was observed in cells obtained from dark-skinned donors. The poor ability of alpha-MSH to stimulate melanin synthesis was not caused by a lack of induction of melanogenic proteins, as alpha-MSH increased the expression of microphthalmia (MITF), tyrosinase, dopachrome tautomerase (DCT), and Pmel-17, compared to untreated cells or cells stimulated by phorbol ester alone, regardless of tyrosine levels. DCT levels were greatly induced by low tyrosine with alpha-MSH, but were dramatically decreased by high tyrosine with alpha-MSH. Interestingly, in this same medium (high tyrosine), MITF levels also decreased after 2 weeks and were barely detectable by the third week. Despite the absence of MITF at 3 weeks of treatment in high tyrosine medium, tyrosinase levels remained high, thereby suggesting that additional factors must be responsible for tyrosinase transcription in human melanocytes. Our results indicate that tyrosine levels can regulate the proliferative activity induced by alpha-MSH, as well as the extent of melanogenesis in normal human melanocytes. The significance of this work is that tyrosine levels may be part of the mechanism that switches melanocytes out of a proliferative status and into a melanin-synthesizing, terminally differentiated phenotype.
...
PMID:Tyrosine levels regulate the melanogenic response to alpha-melanocyte-stimulating hormone in human melanocytes: implications for pigmentation and proliferation. 1127 92

The synthesis of the visible pigment melanin by the melanocyte cell is the basis of the human pigmentary system, those genes directing the formation, transport and distribution of the specialised melanosome organelle in which melanin accumulates can legitimately be called pigmentation genes. The genes involved in this process have been identified through comparative genomic studies of mouse coat colour mutations and by the molecular characterisation of human hypopigmentary genetic diseases such as OCA1 and OCA2. The melanocyte responds to the peptide hormones alpha-MSH or ACTH through the MC1R G-protein coupled receptor to stimulate melanin production through induced maturation or switching of melanin type. The pheomelanosome, containing the key enzyme of the pathway tyrosinase, produces light red/yellowish melanin, whereas the eumelanosome produces darker melanins via induction of additional TYRP1, TYRP2, SILV enzymes, and the P-protein. Intramelanosomal pH governed by the P-protein may act as a critical determinant of tyrosinase enzyme activity to control the initial step in melanin synthesis or TYRP complex formation to facilitate melanogenesis and melanosomal maturation. The search for genetic variation in these candidate human pigmentation genes in various human populations has revealed high levels of polymorphism in the MC1R locus, with over 30 variant alleles so far identified. Functional correlation of MC1R alleles with skin and hair colour provides evidence that this receptor molecule is a principle component underlying normal human pigment variation.
...
PMID:Human pigmentation genes: identification, structure and consequences of polymorphic variation. 1160 44

Melanocytes are cells of neural crest origin. In the human epidermis, they form a close association with keratinocytes via their dendrites. Melanocytes are well known for their role in skin pigmentation, and their ability to produce and distribute melanin has been studied extensively. One of the factors that regulates melanocytes and skin pigmentation is the locally produced melanocortin peptide alpha-MSH. The effects of alpha-MSH on melanogenesis are mediated via the MC-1R and tyrosinase, the rate-limiting enzyme in the melanogenesis pathway. Binding of alpha-MSH to its receptor increases tyrosinase activity and eumelanin production, which accounts for the skin-darkening effect of alpha-MSH. Other alpha-MSH-related melanocortin peptides, such as ACTH1-17 and desacetylated alpha-MSH, are also agonists at the MC-1R and could regulate melanocyte function. Recent evidence shows that melanocytes have other functions in the skin in addition to their ability to produce melanin. They are able to secrete a wide range of signal molecules, including cytokines, POMC peptides, catecholamines, and NO in response to UV irradiation and other stimuli. Potential targets of these secretory products are keratinocytes, lymphocytes, fibroblasts, mast cells, and endothelial cells, all of which express receptors for these signal molecules. Melanocytes may therefore act as important local regulators of a range of skin cells. It has been shown that alpha-MSH regulates NO production from melanocytes, and it is possible that the melanocortins regulate the release of other signalling molecules from melanocytes. Therefore, the melanocortin signaling system is one of the important regulators of skin homeostasis.
...
PMID:Melanocyte function and its control by melanocortin peptides. 1179 32

Four diarylheptanoids, (5R-1,7-bis (3,4-dihydroxyphenyl)-heptane-5-O-beta-D-glucoside (1), (5R) 1,7-bis (3,4-dihydroxyphenyl)-heptane-5-ol (2), oregonin (3), hirsutanonol (4), were isolated from the bark of Alnus hirsuta Turcz and its inhibitory effects on melanogenesis by measuring the melanin level and tyrosinase activity in B16 melanoma cell were examined. Melanin level and tyrosinase activity were reduced to 75 to 85% by addition of diarylheptanoids to incubation medium of the melanoma cell. On the other hand, melanin level and tyrosinase activity were reduced to 13 to 43% by the addition of diarylheptanoids to incubation medium of the melanoma cell treated with melanogenesis stimulator, alpha-MSH and forskolin. These melanogenesis inhibitory effects were significantly different compared with control.
...
PMID:Melanogenesis inhibitory activities of diarylheptanoids from Alnus hirsuta Turcz in B16 mouse melanoma cell. 1251 Aug 43

We have previously shown that Kupffer cells (KCs) of Rana esculenta L. possess melanogenic ability. The melanogenic enzyme activities in these cells are different from those described in skin melanocytes, and very little is known about their regulation by extracellular signalling molecules. In order to study this regulation, we analysed the effects of NDP-MSH on the levels of expression of the tyrosinase gene and on dopa-oxidase activity, using primary cultures of KCs. Incubation of the cells with NDP-MSH increases tyrosinase gene transcription, within the first 24 h of stimulation. To gain insight into the signalling mechanism involved in the cell response to the hormone, KCs in culture were incubated with IBMX or forskolin. These agents mimic the effects of alpha-MSH on melanocytes by increasing the intracellular level of cAMP. The experimental results showed that while the hormonal treatment always activated the KC tyrosinase system, treatment with IBMX or forskolin never did. Therefore, in KCs the tyrosinase-stimulating action of NDP-MSH was not mimicked by cAMP elevating agents. Assays of cAMP levels in cells stimulated with NDP-MSH demonstrated that the hormone does not produce significant increases in intracellular cAMP. On the contrary, forskolin produced significant increases in cAMP starting from 30 min of incubation. These results suggest that tyrosinase induction by melanocortins in KCs is not mediated by the cAMP pathway, and highlight the existence of substantial differences in the hormone signal transduction mechanisms between amphibian KCs and melanocytes or melanoma cells.
...
PMID:Melanogenic response of the Kupffer cells of Rana esculenta L to melanocyte stimulating hormone. 1501 1

The melanocortin system is involved in the regulation of a diverse number of physiologically important pathways including pigmentation, feeding behavior, weight and energy homeostasis, inflammation, and sexual function. All the endogenous melanocortin agonist ligands possess the conserved His-Phe-Arg-Trp tetrapeptide sequence that is postulated to be important for melanocortin receptor molecular recognition and stimulation. Previous studies by our laboratory resulted in the discovery that increasing alkyl chain length at the N-terminal "capping" region of the His-dPhe-Arg-Trp-NH(2) tetrapeptide resulted in a 100-fold increased melanocortin receptor agonist potency. This study was undertaken to systematically evaluate the pharmacological effects of increasing N-capping alkyl chain length of the CH(3)(CH(2))(n)CO-His-dPhe-Arg-Trp-NH(2) (n = 6-16) tetrapeptide template. Twelve analogues were synthesized and pharmacologically characterized at the mouse melanocortin receptors MC1R and MC3R-MC5R and human melanocytes known to express the MC1R. These peptides demonstrated melanocortin receptor selectivity profiles different from those of previously published tetrapeptides. The most notable results of enhanced ligand potency (20- to 200-fold) and receptor selectivity were observed at the MC1R. Tetrapeptides that possessed greater than nine alkyl groups were superior to alpha-MSH in terms of the stimulation of human melanocyte tyrosinase activity. Additionally, the n-pentadecanoyl derivative had a residual effect on tyrosinase activity that existed for at least 4 days after the peptide was removed from the human melanocyte culture medium. These data demonstrate the utility, potency, and residual effect of melanocortin tetrapeptides by adding N-terminal fatty acid moieties.
...
PMID:N-terminal fatty acylated His-dPhe-Arg-Trp-NH(2) tetrapeptides: influence of fatty acid chain length on potency and selectivity at the mouse melanocortin receptors and human melanocytes. 1585 38

In the current study, the involvement of calpain, a cysteine proteinase in the regulation of melanogenesis was examined using mouse B16 melanoma cells. In response to alpha-melanocyte-stimulating hormone (a-MSH), B16 melanoma cells underwent differentiation characterized by increased melanin biosynthesis. The total calapain activity was decreased within 2 h following alpha-MSH-treatment, and restored to the initial level in 6-12 h. To further investigate the involvement of calpain in the regulation of melanogenesis, the effect of calpain inhibitors on alpha-MSH-induced melanogenesis was examined. Inhibition of calpain by either N-acetyl-Leu-Leu-norleucinal (ALLN) or calpastatin (CS) peptide blocked alpha-MSH-induced melanogenesis. The magnitude of inhibition of melanin biosynthesis was well correlated with a decrease in the activity of tyrosinase, a key regulatory enzyme in melanogenesis. Treatment of B16 cells with ALLN caused marked decrease in both tyrosinase protein and mRNA levels. These results indicate that calpain would be involved in the melanogenic signaling by modulating the expression of tyrosinase in mouse B16 melanoma cells.
...
PMID:Involvement of calpain in melanogenesis of mouse B16 melanoma cells. 1633 89


<< Previous 1 2 3 4 5 6 7 8 9 Next >>

---