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)

The significance of melanotropic hormones as physiologic regulators of cutaneous pigmentation in humans is still controversial. Until recently, no direct effect for melanotropins could be demonstrated on human melanocytes. Here we present conclusive evidence that alpha-melanotropin (alpha-melanocyte-stimulating hormone, alpha-MSH) and the related hormone corticotropin (adrenocorticotropic hormone, ACTH) stimulate the proliferation and melanogenesis of human melanocytes maintained in culture in a growth medium lacking any AMP inducer. The minimal effective dose of either hormone is 0.1 nM. In time-course experiments, the increase in cell number and tyrosinase activity became evident after one treatment of the melanocytes with 100 nM alpha-MSH for 48 hr. The mitogenic effect gradually increased to 50-270% above control, depending on the individual melanocyte strain, with continuous treatment with 100 nM alpha-MSH for 8 days, whereas the melanogenic effect became maximal (70-450% increase above control) after 4 days of treatment. Western blot analysis of tyrosinase and the tyrosinase-related proteins TRP-1 and TRP-2 revealed that alpha-MSH increased the expression of those three melanogenic proteins. This was not accompanied by any change in their mRNA levels after brief (1.5-24 hr) or prolonged (6 days) treatment with 100 nM alpha-MSH, suggesting that the increased expression of these melanogenic proteins was due to posttranscriptional events. These results demonstrate both mitogenic and melanogenic effects of alpha-MSH and ACTH on human melanocytes. That both hormones are effective at subnanomolar concentrations, combined with the presence of melanotropin receptors on human melanocytes, strongly suggests that these melanotropins play a physiologic role in regulating human cutaneous pigmentation.
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PMID:Mitogenic and melanogenic stimulation of normal human melanocytes by melanotropic peptides. 787 59

In mouse melanoma melanocytes, alpha-melanocyte-stimulating hormone (MSH) stimulates differentiation, melanin synthesis and tyrosinase activity. However, the molecular mechanisms underlying these events have not yet been characterized. We have studied the activation of tyrosinase by MSH. Treatment of B16 melanoma cells with either theophylline, MSH, or its superpotent analog [Ahx4, DPhe7]MSH promotes a larger induction of tyrosine hydroxylase than of dopa oxidase activity in whole cell extracts. This higher activation of tyrosine hydroxylation was found not only in the melanosomal but also in the microsomal fraction; it appears to be dependent on continued transcription and translation since it can be blocked by actinomycin and cycloheximide. The tyrosinase activity of control and theophylline-treated extracts displayed several kinetic differences, including different Km values for both substrates and requirements for the cofactor L-dopa. SDS/PAGE, followed by a sensitive specific activity stain, demonstrated that melanosomes of control cells contain one lower-electrophoretic-mobility form of tyrosinase, whereas melanosomes of cells treated with either theophylline or MSH display, in addition to the lower-mobility form, a faster-migrating activity band. These tyrosinase forms are not interconvertible by proteolysis or deglycosylation. Their nature is discussed as related to the properties of the previously described low- and high-electrophoretic-mobility tyrosinases (LEMT and HEMT), as well as of the proteins encoded by the c and b loci.
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PMID:Tyrosinase isoenzymes in mammalian melanocytes. 2. Differential activation by alpha-melanocyte-stimulating hormone. 790 Oct 10

The effect of melanocyte-stimulating hormone (MSH) on the differentiation of mammalian melanocytes has been widely studied since the early 1950s. There have been many reports about the stimulatory effect of MSH on melanin production and specifically on the activity of tyrosinase, the critical enzyme in the melanogenic pathway. However, few and variable results have been obtained concerning the effect of this hormone on the regulation of DOPAchrome tautomerase (TRP2), another melanogenic enzyme which functions later in the melanogenic pathway, or on other melanogenic activities, such as TRP1. In this study, we show that the MSH-induced stimulation of tyrosinase is accompanied by no significant change in the synthesis or catalytic activities of other melanogenic enzymes such as TRP1 or TRP2. This in turn elicits a dramatic increase in melanin production accompanied by a significant decrease in the incorporation of carboxylated precursors into that melanin biopolymer, although the biological implication of that is still unclear.
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PMID:Melanin biosynthesis patterns following hormonal stimulation. 790 53

In malignant melanoma, melanocyte-stimulating hormone (alpha-MSH) has been found to influence the cellular metabolism of melanoma cells (c-AMP production, protein and RNA synthesis, and tyrosinase activation). In some publications elevated alpha-MSH levels have been described in melanoma patients. In the present study we used a commercially available radioimmunoassay to examine the alpha-MSH levels in patients with malignant melanoma and a control group consisting of apparently healthy volunteers (laboratory assistants) and dermatological patients without malignant tumours. The plasma alpha-MSH levels were (mean +/- SD) 12.2 +/- 12.9 for 37 melanoma patients (17 female, 20 male) and 7.9 +/- 3.5 pmol/l for 38 control persons (18 female, 20 male). The difference is significant according to the distribution-free U-test of Mann and Whitney. In 13 (35%) of the melanoma patients values were above the normal range defined by the 95.5% confidence limit. alpha-MSH cannot be classified as a typical tumour marker. Nonetheless, in our opinion alpha-MSH levels may be useful in monitoring melanoma patients with reference to prognosis and follow up during and after therapy.
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PMID:[The diagnostic significance of alpha-MSH in malignant melanoma of man]. 792 41

The influence of the terminal amino acids of alpha-MSH on its biological action in B16 murine melanoma cells has been systematically studied. Fragments of alpha-MSH lacking various sequences of terminal residues were synthesized by solid-phase peptide synthesis and their binding affinity to melanoma cells was measured using a radioreceptor assay. Biological activity was determined by measuring both tyrosinase activity and melanogenesis. The relative affinities and activities of the fragments generally followed the same pattern as found previously in other assay systems (frog and lizard bioassay and Cloudman S91 mouse melanoma), with the three amino acids at each terminal not being essential for binding and biological activity, although the C-terminal amino acids 11-13 are more important than those in the N-terminus. The differences in biological activity between the fragments can be explained by their relative binding affinities for the receptor.
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PMID:Influence of alpha-MSH terminal amino acids on binding affinity and biological activity in melanoma cells. 793 16

Topical all-trans retinoic acid (RA) modulates growth and differentiation of skin and is used in the treatment of various dermatological disorders. RA is metabolized to 4-hydroxy RA, 4-oxo RA and 5,6-epoxy RA, which are believed to be markedly less active than RA. 3,4-didehydroretinoic acid (ddRA) is a metabolite of 3,4-didehydroretinol which is present in skin. ddRA is biologically active and acts as a morphogen. We have determined the relative biological activity of ddRA, 4-hydroxy RA, 4-oxo RA and 5,6-epoxy RA as assessed by three retinoid responsive systems relevant to skin. RA, ddRA, 4-hydroxy RA, 4-oxo RA and 5,6-epoxy RA (10-100 nM) reduced epidermal transglutaminase activity in human keratinocytes to similar extents, and inhibited alpha-melanocyte-stimulating hormone-isobutylmethylxanthine-inducible tyrosinase activity in Cloudman S-91 mouse melanoma cells by 67, 39, 48, 51 and 19%, respectively, at 100 nM. Daily topical application of the retinoids to hairless mouse skin for 4 days resulted in dose-dependent changes in epidermal thickness and global histological score. The relative potencies of RA, ddRA, 4-hydroxy RA, 4-oxo RA and 5,6-epoxy RA, as calculated by parallel line assay, were 1.0, 0.60, 0.34, 0.29 and 0.18, respectively, for epidermal hyperplasia and 1.0, 0.78, 0.23, 0.14 and 0.08, respectively, for global histological score. Interestingly, the compounds exhibited a similar rank order of potency with respect to induction of cellular retinoic acid binding protein-II mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Retinoic acid metabolites exhibit biological activity in human keratinocytes, mouse melanoma cells and hairless mouse skin in vivo. 810 99

While ACTH is known to induce skin pigmentation in man, its effects on cultured human melanocytes have not been investigated. Using a culture system free of artificial mitogens, we report for the first time that ACTH stimulates melanogenesis in cultured human melanocytes. While ACTH, alpha-MSH and the synthetic alpha-MSH analogue Nle4DPhe7 alpha-MSH all stimulate the activity of tyrosinase, the rate limiting enzyme in melanogenesis, and all produce a 50% increase in the melanin content of the cells at a concentration of 10(-8)-10(-7) mol/l, the shapes of the dose response curves differ: those for the MSH peptides are sigmoidal while those for ACTH are biphasic. In addition, human melanocytes are able to respond to concentrations of ACTH comparable with physiological plasma levels. We suggest that ACTH may be relatively more important than alpha-MSH as a pigmentary hormone in man and could have a physiological role in skin pigmentation.
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PMID:ACTH stimulates melanogenesis in cultured human melanocytes. 813 43

To learn more of the role of calcium in the regulation of melanogenesis, we have used direct manipulation of medium calcium and pharmacological modulation of intracellular calcium to examine the consequences on unstimulated and cyclic AMP elevated tyrosinase activity and melanin synthesis and distribution in B16 melanoma cells. In unstimulated cells, calcium is clearly inhibitory to tyrosinase activity. However, in cells stimulated with cAMP-elevating agents the requirement for extracellular calcium was changed such that cells required a minimum of 0.4-0.6 mmol medium calcium for maximum tyrosinase response to these agents. Paradoxically, pharmacologically increasing intracellular calcium in cAMP-stimulated cells with ionophore inhibited tyrosinase activity, and the calcium-lowering agent TMB8 and the calcium channel blocker verapamil both stimulated tyrosinase activity. When melanin synthesis was measured in cAMP-stimulated cells, TMB8 was found to significantly increase the sensitivity and the maximum melanogenic response to alpha-MSH, suggesting the presence of at least one level of endogenous calcium inhibitory control operative in these cells. In addition, TMB8 changed the distribution of melanin between the cell and the medium such that, in the presence of alpha-MSH and TMB8, significantly more melanin was secreted into the medium. These data suggest that calcium is required for several steps in melanogenesis, having an apparently inhibitory effect on pre-tyrosinase activity in unstimulated cells, but also showing evidence of a positive role in cyclic AMP-stimulated tyrosinase activity, as well as a further possible inhibitory role in melanin movement or secretion.
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PMID:Calcium plays a complex role in the regulation of melanogenesis in murine B16 melanoma cells. 814 88

Although melanocyte stimulating hormone (MSH) peptides are known to stimulate pigmentation in man, previous reports suggest that human melanocytes are relatively unresponsive to these peptides in vitro. This may be related to the conditions under which the melanocytes were cultured. Thus, we have re-investigated the in vitro effects of MSH peptides using human melanocytes cultured in the absence of artificial mitogens. Human melanocytes were incubated with alpha-MSH or its potent analogue Nle4Dphe7 alpha-MSH for 3 days. After 18 hours, melanocyte morphology had evolved from mainly bipolar to dendritic in approximately 66% of cultures. Nle4DPhe7 alpha-MSH produced dose-related increases in both tyrosinase activity and melanin content although the degree of response was variable and tyrosinase activity was the relatively more responsive to the peptide. Similar results were obtained with alpha-MSH, but, although the effect on melanin content was similar to that of Nle4DPhe7 alpha-MSH, the effect on tyrosinase activity was less marked. The preliminary EC50 values for the actions of the MSH peptides suggest that they may be equipotent in their actions on human melanocytes. In addition, we have demonstrated that the common melanocyte mitogens 12-O-tetradecanoyl phorbol-13-acetate (TPA) and cholera toxin affect basal melanogenesis and modulate the effects of the MSH peptides. However, not all melanocyte cultures showed melanogenic responses to the MSH peptides. Ability to respond was unrelated to basal levels of tyrosinase activity or melanin content. In at least some cultures, morphological and melanogenic responses appear to be independent of one another.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Alpha-melanocyte stimulating hormone and its analogue Nle4DPhe7 alpha-MSH affect morphology, tyrosinase activity and melanogenesis in cultured human melanocytes. 817 9

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


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