Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proopiomelanocortin (POMC), the precursor for melanotropic, corticotropic, and opioid peptides such as alpha-melanocyte-stimulating hormone (alpha MSH), ACTH, and other related peptides, was originally identified as a product of the pituitary gland. However, recent evidence shows that POMC products can also be produced by nonpituitary tissues. Because keratinocytes, the major constituent of the epidermis exhibit the capacity to release a variety of proinflammatory and immunomodulatory mediators, the present study was performed to investigate whether human keratinocytes are able to produce POMC-derived peptides. Supernatants of human normal keratinocytes and an epidermal carcinoma cell line (A431) contained significant levels of immunoreactive alpha MSH and ACTH. Upon immuneprecipitation and size-exclusion chromatography, keratinocyte-derived alpha MSH exhibited a molecular mass of approximately 1 kD and was biologically active as demonstrated in a tyrosinase bioassay. Northern blot analysis revealed the expression of POMC-specific transcripts (1.3 kb) in both normal keratinocytes and A431 cells. The production of alpha MSH and ACTH could be significantly upregulated both at the protein and mRNA level upon treatment with phorbol myristate acetate, ultraviolet light, or interleukin 1. These data provide first evidence that human keratinocytes produce POMC-derived peptides such as alpha MSH and ACTH. Because POMC-derived peptides recently have been recognized as potent immunomodulatory mediators, their presence in the epidermis may have a major impact on the skin immune system.
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PMID:Proopiomelanocortin-derived peptides are synthesized and released by human keratinocytes. 818 58

Hair is actively pigmented only when it grows: the melanogenic activity of follicular melanocytes (MC) is strictly coupled to the anagen stage of the hair cycle. In catagen, melanin formation is switched off and is absent throughout telogen. The appearance of pigmentation is preceded, and further accompanied by, a time-frame - restricted, differential pattern of tyrosinase transcription, translation, and enzyme activities during the development of anagen follicles. In this speculative review, we argue that signals required for melanin synthesis and pigment transfer to bulb keratinocytes (KC) are intrinsic to the skin, rather than coming from the serum. First, the proopiomelanocortin (POMC) gene is expressed and translated during anagen, but is below the level of detectability in telogen; POMC is a precursor protein for adrenocorticotropin and melanotropins, which are potent regulators of MC proliferation and differentiation. Second, fibroblasts and KC produce factors that affect MC proliferation and differentiation. We suggest that signals regulating follicular MC activity partially derive from cutaneous cells expressing POMC. Vice versa, MC transfer to surrounding KC pigment granules with potent bioregulatory properties. MC also produce and secrete various signal molecules that can regulate mesenchymal and epithelial cell functions. Anagen-associated melanogenesis and the cyclic production of a pigmented hair shaft result from programmed and tightly coordinated epithelial-mesenchymal-neuroectodermal interactions, in which MC may act not only as pigmentary, but also as hair growth-regulatory cells.
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PMID:Melanogenesis is coupled to murine anagen: toward new concepts for the role of melanocytes and the regulation of melanogenesis in hair growth. 832 58

The melanocyte-stimulating hormone (alpha-MSH) used at 10(-6)-5 x 10(-8) M concentrations inhibited the growth of amelanotic cells of human malignant melanoma BRO and influenced cell morphology without any effect on melanization or tyrosinase activity. Inhibition of tumour cell growth was accompanied by marked elevation of intracellular cAMP levels but not that of cGMP. Dibutyryl-cAMP and the cAMP-dependent protein kinase A inhibitor also inhibited the cell growth. alpha-MSH increased mono-, di- and 1.4.5-myoinositol triphosphate concentrations and influenced the activities of phosphatidylinositol kinase and phosphatidylinositol-4-phosphate kinase determining phosphatidylinositol-4-phosphate kinase and phosphatidylinositol-4.5-diphosphate levels. Myoinositol phosphate concentrations changed on a second scale and levelled off by the 3rd-5th min, whereas that of cAMP increased drastically by the 30th min.
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PMID:[Melanocyte-stimulating hormone induces growth of human malignant melanoma amelanotic cells with a change in cAMP, phosphatidylinositols, and inositol phosphate concentration]. 838 47

The possible mechanisms for the reduced melanin content and poor melanogenic response to MSH was investigated in B16-F10DD differentiation deficient melanoma cells. In particular, the MSH receptor status and associated signal transduction pathway linking to tyrosinase activity in these cells was studied for evidence of any defects. F10DD cells contained high-affinity binding sites for alpha-MSH, with KD values similar to those previously reported for other variants of the B16 melanoma. SDS-PAGE analysis after radioactive ligand cross-linking showed no evidence of gross structural alterations of the receptor. The F10DD cells expressed approximately twice as many receptors as the F10 parent cell line, suggesting a possible feedback response attempting to compensate for the amelanotic condition. The functional integrity of the MSH receptors in F10DD cells was confirmed by the presence of increased levels of cAMP in response to MSH stimulation. These results, coupled with the observation that F10 and F10DD cells express similar levels of tyrosinase mRNA and protein, point to a structural defect in tyrosinase or in the post-translational control mechanisms by which the activity of this enzyme is regulated.
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PMID:MSH receptors and function in amelanotic B16 melanoma cells. 839 Aug 76

Using antibodies that recognize either tyrosinase, tyrosinase-related protein-1 (TRP1), or tyrosinase-related protein-2 (TRP2, DOPAchrome tautomerase), the quantities of those melanogenic enzymes were analyzed in five melanoma cell lines that possess various degrees of melanin production. All cells except JB/MS-W increased melanin production four to 30 times after 4 d of melanocyte-stimulating hormone (MSH) treatment. Melanin production by JB/MS-W cells was always under background, with or without MSH treatment. There was a positive correlation between quantities and synthetic rates of those melanogenic enzymes and their melanin formation or DOPAchrome tautomerase activities. The activity of a heat-resistant melanogenic inhibitory factor was also analyzed. The results showed, surprisingly, that pigmented cells showed higher levels of melanogenic inhibitors activity. Tyrosinase activity was increased dramatically whereas the level of melanogenic inhibitor was remarkably decreased following MSH treatment. Interestingly, melanogenic inhibitor derived from JB/MS-W cells suppressed not only tyrosinase but also DOPAchrome tautomerase, another enzyme functional in melanin production. These results clearly suggest that melanin production is regulated by a subtle balance between the activities of these enzymes and other factors such as the melanogenic inhibitor.
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PMID:Pigment production in murine melanoma cells is regulated by tyrosinase, tyrosinase-related protein 1 (TRP1), DOPAchrome tautomerase (TRP2), and a melanogenic inhibitor. 842 35

Agouti protein is known to antagonize cAMP formation, tyrosinase activation and melanogenesis in mouse B16-F1 melanoma cells induced by alpha-melanocyte-stimulating hormone (alpha-MSH). We now demonstrate that although agouti binds to the melanocortin receptor MC1-R with an almost identical affinity to that of alpha-MSH, it does not antagonize the inhibitory action of alpha-MSH on the growth of B16-F1 cells. Instead it has a similar antiproliferative action with a half-maximal effective concentration of 13 nM. In G4F cells lacking MC1-R, agouti is without effect. Agouti was also found to induce MC1-R down-regulation with identical kinetics and magnitude as alpha-MSH. Thus, the different effects of agouti on B16-F1 cells proceed via interaction with MC1-R but are not exclusively antagonistic.
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PMID:Agouti protein inhibits growth of B16 melanoma cells in vitro by acting through melanocortin receptors. 857 26

Although the ability of UV irradiation to induce pigmentation in vivo and in vitro is well documented, the intracellular signals that trigger this response are poorly understood. We have recently shown that increasing DNA repair after irradiation enhances UV-induced melanization. Moreover, addition of small DNA fragments, particularly thymine dinucleotides (pTpT), selected to mimic sequences excised during the repair of UV-induced DNA photoproducts, to unirradiated pigment cells in vitro or to guinea pig skin in vivo induces a pigment response indistinguishable from UV-induced tanning. Here we present further evidence that DNA damage and/or the repair of this damage increases melanization. (i) Treatment with the restriction enzyme Pvu II or the DNA-damaging chemical agents methyl methanesulfonate (MMS) or 4-nitroquinoline 1-oxide (4-NQO) produces a 4- to 10-fold increase in melanin content in Cloudman S91 murine melanoma cells and an up to 70% increase in normal human melanocytes, (ii) UV irradiation, MMS, and pTpT all upregulate the mRNA level for tyrosinase, the rate-limiting enzyme in melanin biosynthesis. (iii) Treatment with pTpT or MMS increases the response of S91 cells to melanocyte-stimulating hormone (MSH) and increases the binding of MSH to its cell surface receptor, as has been reported for UV irradiation. Together, these data suggest that UV-induced DNA damage and/or the repair of this damage is an important signal in the pigmentation response to UV irradiation. Because Pvu II acts exclusively on DNA and because MMS and 4-NQO, at the concentrations used, primarily interact with DNA, such a stimulus alone appears sufficient to induce melanogenesis. Of possible practical importance, the dinucleotide pTpT mimics most, if not all, of the effects of UV irradiation on pigmentation, tyrosinase mRNA regulation, and response to MSH without the requirement for antecedent DNA damage.
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PMID:DNA damage enhances melanogenesis. 857 19

Work in the past 8 years, particularly in the past 1-2 years, has greatly expanded our understanding of the mechanisms by which ultraviolet irradiation stimulates melanogenesis in the skin. A direct effect of UV photons on DNA results in up-regulation of the gene for tyrosinase, the rate-limiting enzyme in melanin synthesis, as well as an increase in cell surface expression of receptors for at least one of the several known keratinocyte-derived melanogenic factors, MSH. Direct effects of UV on melanocyte membranes, releasing DAG and arachidonic acid, may also play a role in the tanning response. Diacylglycerol may activate PKC-beta, which in turn phosphorylates and activates tyrosinase protein; the pathways by which products of other inflammatory mediator cascades may act on melanogenesis are unknown. The tanning response also relies heavily on UV-stimulated increased production and release of numerous keratinocyte-derived factors including bFGF, NGF, endothelin-1 and the POMC-derived peptides MSH, ACTH, beta-LPH and beta-endorphin. These factors variably induce melanocyte mitosis, increase melanogenesis, enhance dendricity and prevent apoptotic cell death following the UV injury. Thus, events within the epidermal melanin unit conspire to maintain or increase melanocyte number, increase melanin pigment throughout the epidermis. Overall, ultraviolet-induced melanogenesis may be one part of a eukaryotic SOS response to damaging ultraviolet irradiation that has evolved over time to provide a protective tan in skin at risk of further injury from sun exposure. These recent insights into the mechanisms underlying ultraviolet-induced melanogenesis offer the opportunity for novel therapeutic approaches to minimizing acute and chronic photodamage in human skin.
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PMID:Mechanisms of ultraviolet light-induced pigmentation. 857 60

alpha-Melanocyte stimulating hormone (alpha-MSH) and ACTH increase the proliferation and melanogenesis of cultured human melanocytes. To further analyze how melanotropins produce these biological effects, we investigated the regulation of the melanocortin receptor MC1R expression by alpha-MSH and ACTH using Northern blot analysis and determine the relative affinity of the receptor for the structurally similar peptides alpha-MSH, ACTH, beta-MSH, and gamma-MSH. We also determined the relative potencies of these hormones to stimulate cAMP formation, tyrosinase activity, and melanocyte proliferation. The order of affinity and potency of the noted melanotropins in these assays were alpha-MSH = ACTH > beta-MSH > gamma-MSH. Because the binding affinity of each of these melanotropins for the MC1R correlated with its ability to stimulate human melanocyte proliferation and melanogenesis, we conclude that these effects are mediated specifically by binding to and activation of the MC1R. gamma-MSH stimulated cAMP formation without affecting proliferation or melanogenesis. However, we found that relative to alpha-MSH, the effect of gamma-MSH on cAMP formation was transient. Our results suggest that alpha-MSH, ACTH, and possibly beta-MSH, but not gamma-MSH, are capable of a physiological role in regulating human pigmentation, and that melanocytes in human skin are a specific target for these hormones.
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PMID:Binding of melanotropic hormones to the melanocortin receptor MC1R on human melanocytes stimulates proliferation and melanogenesis. 861 94

Seventeen human melanoma cell (HMC) lines, both melanotic and amelanotic, were incubated in the continuous presence of a potent melanotropic peptide hormone analog, [Nle4,D-Phe7] alpha-MSH, for 72 hr with daily changes of medium. Only one cell line (HD, melanotic) consistently responded to the hormone analog by increased tyrosinase activity. Three (one melanotic, two amelanotic) of the HMC lines also failed to respond to the peptide by either increased or decreased enzyme activity when incubated continuously in the presence of the peptide for longer periods of time (6,15,27,43 days). The HD cell line, however, again responded with increasingly enhanced basal enzyme activity the longer the cells were incubated in the presence of the melanotropin. One amelanotic cell line (C8161) responded with enhanced enzyme activity when grown to confluency in the continuous presence of the peptide. Basal tyrosinase activity of the C8161 cell line may have increased as cell density in the flasks increased. These results suggest that under conditions of increased cell number, phenotypic expression of tyrosinase activity in so called "amelanotic" (tyrosinase-negative) cells is increased and can be enhanced further by stimulation with a melanotropic peptide. Under conditions of increased cell number, the presence of [Nle4,D-Phe7] alpha-MSH caused morphological differentiation (shape change); the cells became enlarged and very dendritic. The number of cells in monolayer (surface of the flask) and in the medium were drastically reduced in both melanotic and "amelanotic" cell lines incubated with [Nle4,D-Phe7] alpha-MSH. The data support other published reports that melanotropic peptides inhibit human melanoma cell growth (proliferation) in vitro, most likely through a cytostatic mechanism. [Nle4,D-Phe7] alpha-MSH also exhibited a prolonged (residual) inhibitory action on HD cell proliferation. In other words, inhibition of cell growth (proliferation) of the HMCs was evident even several days after removal of the melanotropic peptide from the incubation medium.
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PMID:The melanotropic peptide, [Nle4,D-Phe7] alpha-MSH, stimulates human melanoma tyrosinase activity and inhibits cell proliferation. 878 40


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