UNIPROT:P01189 - FACTA Search

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Query: UNIPROT:P01189 (beta-endorphin)
21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cutaneous pigmentation is determined by the amounts of eumelanin and pheomelanin synthesized by epidermal melanocytes and is known to protect against sun-induced DNA damage. The synthesis of eumelanin is stimulated by the binding of alpha-melanotropin (alpha-melanocyte-stimulating hormone) to the functional melanocortin 1 receptor (MC1R) expressed on melanocytes. The human MC1R gene is highly polymorphic and certain allelic variants of the gene are associated with red hair phenotype, melanoma and non-melanoma skin cancer. The importance of the MC1R gene in determining skin cancer risk led us to examine the impact of specific polymorphisms in this gene on the responses of human melanocytes to alpha-melanotropin and UV radiation. We compared the ability of human melanocyte cultures, each derived from a single donor, to respond to alpha-melanotropin with dose-dependent stimulation of cAMP formation, tyrosinase activity and proliferation. In each of those cultures the MC1R gene was sequenced, and the eumelanin and pheomelanin contents were determined. Human melanocytes homozygous for Arg160Trp, heterozygous for Arg160Trp and Asp294His, or for Arg151Cys and Asp294His substitutions, but not melanocytes homozygous for Val92Met substitution, in the MC1R demonstrated a significantly reduced response to alpha-melanotropin. Additionally, melanocytes with a non-functional MC1R demonstrated a pronounced increase in their sensitivity to the cytotoxic effect of UV radiation compared with melanocytes expressing functional MC1R. We conclude that loss-of-function mutations in the MC1R gene sensitize human melanocytes to the DNA damaging effects of UV radiation, which may increase skin cancer risk.
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PMID:Human melanocortin 1 receptor variants, receptor function and melanocyte response to UV radiation. 1200 19

The characterization of the melanocortin 1 receptor (MC1R) expressed on human melanocytes and the findings that certain mutations in the POMC gene or the MC1R gene result in red hair phenotype underscore the significance of melanocortins and MC1R in regulating human pigmentation. We demonstrated that human melanocytes respond to alpha-melanocortin (alpha-MSH) or ACTH with increased proliferation and melanogenesis, and to agouti signaling protein by abrogation of these effects. alpha-MSH and ACTH were equipotent and more potent than beta-MSH, and gamma-MSH was the least potent in activating the MC1R and stimulating melanogenesis and proliferation of human melanocytes. We characterized the MC1R genotype in a panel of human melanocyte cultures and identified three cultures that were homozygous for Arg160Trp, heterozygous for Arg151Cys and Asp294His, and heterozygous for Arg160Trp and Asp294His substitutions, respectively. Those cultures failed to respond to alpha-MSH with increase in cAMP levels, tyrosinase activity, or proliferation and had an exaggerated response to the cytotoxic effect of ultraviolet (UV) radiation. These loss-of-function mutations have been associated with red hair phenotype and increased risk for skin cancer. Melanocytes homozygous for Val29Met substitution in MC1R responded normally to alpha-MSH and UVB, suggesting that this variant is a polymorphism. We observed that alpha-MSH promotes human melanocyte survival by inhibiting the UV-induced apoptosis independently of melanin synthesis. This effect was absent in human melanocytes with loss of function MC1R mutations. We predict that the survival effect of alpha-MSH is caused by reduction of UV-induced DNA damage and contributes to the prevention of melanoma.
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PMID:Significance of the melanocortin 1 receptor in regulating human melanocyte pigmentation, proliferation, and survival. 1285 36

The melanotropic actions of alpha-melanocyte-stimulating hormone (alpha-MSH) and other melanocortins are mediated by activation of the melanocortin 1 receptor (MC1R). This G protein-coupled receptor is positively coupled to Gs and triggers the cyclic adenosine mono-phosphate (cAMP) pathway. Mutations of the MC1R gene are associated with skin type and pigmentation phenotypes, and with increased risk of skin cancers. Genetic studies have demonstrated an heterozygote carrier effect for these associations, suggesting the importance of variant allele dosage. This could be accounted for, at least partially, if the number of MC1R molecules, rather than the Gs protein or the effector enzyme, adenylyl cyclase, is limiting for the activation of the signalling pathway. However, the nature of the limiting factor(s) in MC1R signalling has not been investigated. We addressed this question by comparing the cAMP output of clones of human melanoma cell lines enriched in MC1R by stable transfection. We also analysed heterologous cell systems widely used for functional studies of MC1R. We show that cAMP production in clones of Chinese hamster ovary cells stably expressing the MC1R is a linear function of receptor number up to high, supraphysiological levels of approximately 50,000 alpha-MSH binding sites per cell. Enrichment of human melanoma cell lines with MC1R also results in increased cAMP levels, with a small leftward shift of the agonist dose-response curves. Therefore, at physiological expression levels second-messenger generation is dependent on receptor density. Within melanoma cells and also likely in normal melanocytes, MC1R appears the limiting factor controlling the output of the cAMP signalling pathway.
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PMID:Rate limiting factors in melanocortin 1 receptor signalling through the cAMP pathway. 1295 Jul 34

Malignant pleural mesothelioma is a highly aggressive tumor arising from the mesothelial cells that line the pleural cavities. This tumor is resistant to most conventional anticancer treatments and appears to be very sensitive to growth-promoting influences of cytokines and growth factors. Identification of natural inhibitory pathways that control growth should aid discovery of novel therapeutic approaches. We hypothesized that alpha-melanocyte-stimulating hormone (alpha-MSH), which is produced by many cell types and antagonizes cytokines and growth factors, could be an endogenous inhibitory molecule in mesothelioma. Twelve mesothelioma cell lines were established from pleural effusions of patients with malignant mesothelioma. Mesothelioma cells were found to express mRNA for proopiomelanocortin and its processing enzymes; release alpha-MSH peptide into supernatants; and express melanocortin 1 receptor (MC1R), the high-affinity receptor for alpha-MSH. Immunoneutralization of MC1R in the cell lines enhanced expression of interleukin-8 (IL-8), IL-6, and transforming growth factor-beta. These molecules promote mesothelioma proliferation and are considered therapeutic targets in this tumor. Coincubation of mesothelioma cells with synthetic alpha-MSH significantly reduced cell proliferation. The present research shows an autocrine-inhibitory circuit based on alpha-MSH and its receptor MC1R. Activation of MC1R by selective peptides or peptidomimetics might provide a novel strategy to reduce mesothelioma cell proliferation by taking advantage of this endogenous inhibitory circuit.
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PMID:Autocrine inhibitory influences of alpha-melanocyte-stimulating hormone in malignant pleural mesothelioma. 1457 63

The melanocortins (alpha-melanocyte-stimulating hormone and adrenocorticotropin) act on epidermal melanocytes to increase melanogenesis, the eumelanin/pheomelanin ratio and dendricity. These actions are mediated by the heptahelical melanocortin 1 receptor (MC1R), positively coupled to adenylyl cyclase. Gain-of-function mouse Mc1r alleles are associated with a dark, eumelanic coat. Conversely, loss-of-function variants, or overexpression of agouti, a natural melanocortin antagonist, yield yellow, pheomelanic furs. In humans, loss-of-function MC1R variants are associated with fair skin, poor tanning, propensity to freckle and increased skin cancer risk. Therefore, MC1R is a key regulator of mammalian pigmentation. Several observations such as induction of constitutive pigmentation in amelanotic mouse melanoma cells following expression of MC1R indicate that the receptor might display agonist-independent activity. We report a systematic and comparative study of MC1R and Mc1r constitutive activity. We show that expression of MC1R in heterologous systems leads to an agonist-independent increase in cyclic adenosine monophophate (cAMP). Basal signalling is a function of receptor expression and is two to fourfold higher for MC1R than for Mc1r. Moreover, it is observed in human melanoma cells over-expressing the MC1R. Constitutive signalling is abolished or reduced by point mutations of MC1R impairing the response to agonists, and is only doubled by the Lys94Glu mutation, mimicking the constitutively active mouse E(so-3J) allele. Stable or transient expression of wild-type MC1R, but not of loss-of-function mutants, potently stimulates forskolin activation of adenylyl cyclase, a common feature of constitutively active Gs-coupled receptors. Therefore, human MC1R displays a strong agonist-independent constitutive activity.
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PMID:Agonist-independent, high constitutive activity of the human melanocortin 1 receptor. 1525 Sep 41

The constitutive color of our skin plays a dramatic role in our photoprotection from solar ultraviolet radiation (UVR) that reaches the Earth and in minimizing DNA damage that gives rise to skin cancer. More than 120 genes have been identified and shown to regulate pigmentation, one of the key genes being melanocortin 1 receptor (MC1R) that encodes the melanocortin 1 receptor (MC1R), a seven-transmembrane G protein-coupled receptor expressed on the surface of melanocytes. Modulation of MC1R function regulates melanin synthesis by melanocytes qualitatively and quantitatively. The MC1R is regulated by the physiological agonists alpha-melanocyte-stimulating hormone (alphaMSH) and adrenocorticotropic hormone (ACTH), and antagonist agouti signaling protein (ASP). Activation of the MC1R by binding of an agonist stimulates the synthesis of eumelanin primarily via activation of adenylate cyclase. The significance of cutaneous pigmentation lies in the photoprotective effect of melanin, particularly eumelanin, against sun-induced carcinogenesis. Epidermal melanocytes and keratinocytes respond to UVR by increasing their expression of alphaMSH and ACTH, which up-regulate the expression of MC1R, and consequently enhance the response of melanocytes to melanocortins. Constitutive skin pigmentation dramatically affects the incidence of skin cancer. The pigmentary phenotype characterized by red hair, fair complexion, inability to tan and tendency to freckle is an independent risk factor for all skin cancers, including melanoma. The MC1R gene is highly polymorphic in human populations, and allelic variation at this locus accounts, to a large extent, for the variation in pigmentary phenotypes and skin phototypes (SPT) in humans. Several allelic variants of the MC1R gene are associated with the red hair and fair skin (RHC) phenotype, and carrying one of these variants is thought to diminish the ability of the epidermis to respond to DNA damage elicited by UVR. The MC1R gene is considered a melanoma susceptibility gene, and its significance in determining the risk for skin cancer is of tremendous interest.
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PMID:MC1R and the response of melanocytes to ultraviolet radiation. 1574 44

Recent work on the melanocortin 1 receptor (MC1R) suggests that MC1R plays a central role in regulation of eumelanin (brown/black melanins) and phaeomelanin (red/yellow melanins) synthesis within the mammalian melanocyte. In the mouse,genetic studies show that the MC1R appears to be a unique, bifunctionally controlled receptor, activated by alpha-MSH and antagonized by agouti,both of which contribute to the variability seen in mammalian coat color. Variants of this receptor are associated with different animal's coat,human skin and hair colors. In addition, cutaneous pigmentation is a major determinant of the cutaneous response to ultraviolet radiation,and consequently of the risk of developing skin cancer. MC1R variants are a risk factor for melanoma susceptibility.
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PMID:[Genotype, melanocortin 1 receptor and ultraviolet radiation]. 1613 51

Studies in mice indicate that alpha-melanocyte-stimulating hormone (alphaMSH) is immunosuppressive, but it is not known whether alphaMSH suppresses human immune responses to exogenous Ags. Human PBMCs, including monocytes, express the melanocortin 1 receptor (MC1R), and it is thought that the ability of alphaMSH to alter monocyte-costimulatory molecule expression and IL-10 release is mediated by this receptor. However, the MC1R gene is polymorphic, and certain MC1R variants compromise receptor signaling via cAMP, resulting in red hair and fair skin. Here, we have investigated whether alphaMSH can suppress Ag-induced lymphocyte proliferation in humans and whether these effects are dependent on MC1R genotype. alphaMSH suppressed streptokinase-streptodornase-induced lymphocyte proliferation, with maximal inhibition at 10(-13)-10(-11) M alphaMSH. Anti-IL-10 Abs failed to prevent suppression by alphaMSH, indicating that it was not due to MC1R-mediated IL-10 release by monocytes. Despite variability in the degree of suppression between subjects, similar degrees of alphaMSH-induced immunosuppression were seen in individuals with wild-type, heterozygous variant, and homozygous/compound heterozygous variant MC1R alleles. RT-PCR of streptokinase-streptodornase-stimulated PBMCs for all five melanocortin receptors demonstrated MC1R expression by monocytes/macrophages, MC1R and MC3R expression by B lymphocytes, but no melanocortin receptor expression by T lymphocytes. In addition, alphaMSH did not significantly inhibit anti-CD3 Ab-induced lymphocyte proliferation, whereas alphaMSH and related analogs (SHU9119 and MTII) inhibited Ag-induced lymphocyte proliferation in monocyte-depleted and B lymphocyte-depleted assays. These findings demonstrate that alphaMSH, acting probably via MC1R on monocytes and B lymphocytes, and possibly also via MC3R on B lymphocytes, has immunosuppressive effects in humans but that suppression of Ag-induced lymphocyte proliferation by alphaMSH is independent of MC1R gene status.
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PMID:Alpha-melanocyte-stimulating hormone suppresses antigen-induced lymphocyte proliferation in humans independently of melanocortin 1 receptor gene status. 1617 30

We have characterized the biochemical function of the melanocortin 1 receptor (MC1R), a critical regulator of melanin synthesis, from 9 phylogenetically diverse primate species with varying coat colors. There is substantial diversity in melanocyte-stimulating hormone (MSH) binding affinity and basal levels of activity in the cloned MC1Rs. MSH binding was lost independently in lemur and New World monkey lineages, whereas high basal levels of MC1R activity occur in lemurs and some New World monkeys and Old World monkeys. Highest levels of basal activity were found in the MC1R of ruffed lemurs, which have the E94K mutation that leads to constitutive activation in other species. In 3 species (2 lemurs and the howler monkey), we report the novel finding that binding and inhibition of MC1R by agouti signaling protein (ASIP) can occur when MSH binding has been lost, thus enabling continuing regulation of the melanin type via ASIP expression. Together, these findings can explain the previous paradox of a predominantly pheomelanic coat in the red ruffed lemur (Varecia rubra). The presence of a functional, MSH-responsive MC1R in orangutan demonstrates that the mechanism of red hair generation in this ape is different from the prevalent mechanism in European human populations. Overall, we have found unexpected diversity in MC1R function among primates and show that the evolution of the regulatory control of MC1R activity occurs by independent variation of 3 distinct mechanisms: basal MC1R activity, MSH binding and activation, and ASIP binding and inhibition. This diversity of function is broadly associated with primate phylogeny and does not have a simple relation to coat color phenotype within primate clades.
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PMID:High diversity in functional properties of melanocortin 1 receptor (MC1R) in divergent primate species is more strongly associated with phylogeny than coat color. 1760 36

In the course of investigations on anorexia during infection, I found that B6-A(y) mice had significantly increased sensitivity to lipopolysaccharide (LPS)-induced lethality as compared with isogenic B6 mice. I also found that the sensitivity to the lethal effect of LPS dramatically increased in aged mice (age effect), both B6 and B6-A(y). However, the A(y) effect of enhancing sensitivity to LPS-induced lethality was still significant, suggesting that the A(y) effect is independent of age. In the absence of tumor necrosis factor alpha (TNFalpha), the A(y) effect was still significant, suggesting that the A(y) effect is independent of TNFalpha toxicity. A dose of LPS of 100 mug per mouse caused 15% lethality in B6, 65% in B6-A(y) (significantly higher than B6), and 100 % in leptin-deficient B6-ob/ob (significantly higher than B6 and B6-A(y)). The results support the hypothesis that endogenous leptin has a protective role against infection, and that a part of this leptin effect is mediated by alpha-melanocyte-stimulating hormone (alphaMSH). In contrast to the results of simple blockade at the melanocortin 4 receptor (MC4R), B6-A(y) suffered more severe LPS-induced anorexia than did B6; therefore, the pathway involving MC4R is not absolutely required for the LPS-induced anorexia, and the presence of pathways involving other melanocortin receptor types was suggested. Because alphaMSH is suggested to be an endogenous anti-inflammatory peptide, and because melanocortin 1 receptor (MC1R) is expressed in various cutaneous cell types, the A(y) effect might be caused via the pathway involving MC1R. Physiologic significance of alphaMSH-MC1R interaction in host defense against infection is discussed.
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PMID:The A y allele at the agouti locus enhances sensitivity to endotoxin-induced lethality in mice. 1791 78

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