Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Six alpha-MSH(4-10) [Nle-Asp-His-D-Phe-Arg-Trp-Lys-amide] derivatives carrying 2 or 1 or no 2,3-dihydroxy-(2S)-propyl (DHP) groups on the Lys10 amino side chain were coupled to diethylene-triaminopentaacetic acid (DTPA, a chelator for 111In) in monomeric and dimeric forms and tested for their binding activity and bioactivity in vitro with mouse and human melanoma cell lines and by receptor autoradiography to tumor sections, as well as in vivo with normal and melanoma-bearing mice: DTPA-[Nle4,Asp5,D-Phe7,Lys(bis-DHP)10]-alpha-MSH(4-10),DTPA-[Nle4, Asp5, D-Phe7,Lys(mono-DHP)10]-alpha-MSH(4-10), DTPA[Nle4,Asp5,D-Phe7,Lys10]-alpha-MSH(4-10), DTPA-bis-([Nle4,Asp5,D-Phe7,Lys(bis-DHP)10]-alpha-MSH(4-10)), DTPA-bis[([Nle4,Asp5,D-Phe7,Lys(mono-DHP)10]-alpha-MSH(4-10)) and DTPA-bis-([Nle4,Asp5,D-Phe7,Lys10]-alpha-MSH(4-10)). In the receptor-binding assays with B16-F1 mouse and D10 human melanoma cells, the KD values ranged between 0.76 and 31.17 nM and in the melanin bioassay the results were similar (EC50 values between 0.15 and 4.40 nM). The tissue distribution of the 111In-labeled compounds in C57Bl/6J mice showed that the dimeric [111In]-DTPA-bis([Nle4,Asp5,D-Phe7,Lys10]-alpha-MSH(4-10)) and the monomeric [111In]-DTPA-[Nle4,Asp5,D-Phe7,Lys(bis-DHP)10]-alpha-MSH(4-10) exhibited the lowest non-specific binding. In mice carrying B16-F1 melanoma tumors, the monomeric compound displayed 2-fold higher 111In uptake by the tumor and a much lower non-specific uptake by the liver (12-fold) and the kidneys (2.5-fold) than the dimeric derivative. This demonstrates that modification of the Lys10 side chain by DHP is a promising lead for new MSH radiopharmaceuticals for melanoma targeting.
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PMID:[111In]-DTPA-labeled analogues of alpha-melanocyte-stimulating hormone for melanoma targeting: receptor binding in vitro and in vivo. 807 62

Specific high-affinity receptors for alpha-melanocyte-stimulating hormone (alpha-MSH) are found in variable abundance on many melanoma cell lines. We have examined melanocortin peptides and other factors for their ability to regulate the number of MSH receptors in eleven human and two mouse melanoma cell lines. MSH induced up-regulation of its own receptors in three human cell lines and down-regulation in six human and two mouse melanoma cell lines. No regulation was observed in two human lines. Scatchard analysis revealed modulation of the number of receptors per cell without any change in affinity. The concentrations inducing half-maximal response for up- and down-regulation were 1.6 nM and 0.23 nM, respectively. ACTH1-17 and [Nle4,D-Phe7]-alpha-MSH were more potent, whereas ACTH1-24, desacetyl-alpha-MSH, and [Nle4]-alpha-MSH were less potent in receptor up-regulation as compared to alpha-MSH. Down-regulation but not up-regulation could be fully mimicked by Gs-protein activation and partially by elevation of cellular cAMP. Combination of different agents which increase cAMP was found to be counterregulatory. TPA and retinoic acid generally down-regulated MSH receptors but had no effect on HBL cells. Several protein kinase inhibitors increased MSH binding in B16 cells. MSH-induced receptor down-regulation and melanin synthesis were most effectively antagonized by selective inhibitors of cAMP-dependent protein kinase in these cells. Taken together, MSH receptors on melanoma cells are both positively and negatively regulated. Whereas cAMP-dependent protein kinase activation seems to be involved in down-regulation, the mechanism responsible for up-regulation remains to be elucidated.
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PMID:Homologous and heterologous regulation of alpha-melanocyte-stimulating hormone receptors in human and mouse melanoma cell lines. 816 86

Receptors for melanotropin (MSH) were found to be expressed by immortalized primary human epidermal keratinocytes (RHEK-1). Using 125I-beta MSH as a probe, the MSH receptors from mouse melanoma cells and human keratinocytes were found to be remarkably similar. In each cell line, there were high and low affinity receptors, with the high affinity classes showing positive cooperativity. Competition of 125I-beta MSH for binding with non-radioactive MSH revealed similar profiles. Cross-linking studies, followed by gel electrophoresis and autoradiography, showed almost identical gel migration patterns. Both cell types expressed internal as well as plasma membrane binding sites. MSH receptors on both cell types were up-regulated by ultraviolet light and by MSH itself. Although the function of MSH receptors expressed by the immortalized keratinocytes is unknown, the results are consistent with recent reports that proliferation of epidermal keratinocytes is stimulated by MSH and that proopiomelanocortin genes are expressed in the epidermis. These results support a model in which keratinocytes and melanocytes, interacting in an "epidermal-melanin unit," each respond to UV light signals with increased MSH receptor activity.
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PMID:MSH receptors in immortalized human epidermal keratinocytes: a potential mechanism for coordinate regulation of the epidermal-melanin unit. 822 66

The combined action of cholera toxin (CT)-dependent activation of the adenylate cyclase signaling pathway, stimulation of protein kinase C, and activation of the tyrosine kinase activity of cell surface receptors and proto-oncogene products, have been shown to stimulate melanocyte proliferation. However, natural factors responsible for the optimal stimulation of normal human melanocyte growth, either isolated or co-cultured with keratinocytes, remain largely unknown. alpha MSH (alpha melanocyte stimulating hormone) has previously been shown to bind to murine and human melanoma cells and to stimulate their adenylate cyclase and tyrosinase activity. In contrast, very little is known about the presence and function of alpha MSH receptors in normal human melanocytes. We now report that alpha MSH: (i) binds to normal human melanocytes through a single class of high-affinity receptors; (ii) does not induce per se melanocytes to enter the S-phase of the cell cycle; (iii) does indeed stimulate melanocyte proliferation in a dose-dependent fashion; but its stimulatory effect requires bFGF and/or the activation of protein kinase C.
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PMID:Alpha melanocyte stimulating hormone (alpha MSH) stimulates normal human melanocyte growth by binding to high-affinity receptors. 822 96

The ACTH/MSH melanocortin core peptide sequence possesses neurotrophic properties in peripheral nerve. During functional neuroanatomical recovery after damage to peripheral nerves, Schwann cells play a significant role in facilitating regeneration. Here we employ a modified super-potent alpha-MSH analogue to solubilise alpha-MSH receptor proteins from cultured primary rat Schwann cells. [125I-Tyr2,Nle4,D-Phe7,ATB-Lys11]-alpha-MSH photoaffinity labelled proteins from Schwann cells were analyzed by SDS-PAGE followed by autoradiography. The results indicate that the alpha-MSH receptor proteins labelled have a molecular weight of 42-45 kDa. These data are the first to demonstrate solubilisation and characterisation of alpha-MSH receptors from non-melanoma cells.
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PMID:Solubilisation partial characterisation of the alpha-MSH receptor on primary rat Schwann cells. 826 90

Four alpha-MSH drug conjugates have been synthesized, 2 C-terminal (Pep 3 and 4) and 2 central fragments (Pep 1 and 2), the latter being the 4-10 sequence known to be the main alpha-MSH-receptor-recognition site. Melphalan was introduced into each sequence at different locations. Their ability to recognize alpha-MSH receptors as well as their cytotoxic effects were compared in 3 cell lines: melanoma, carcinoma and fibroblast cells. Pep 1 and 2 were able to specifically bind to MSH receptors on melanoma cells by displacing labelled alpha-MSH from its binding sites at concentrations similar to the 4-10 heptapeptide sequence known to contain the main receptor-recognition site. They subsequently penetrate the cell, most probably by a receptor internalization mechanism, since about half of their effect could be inhibited by competition at the receptor level. Significant and selective cytotoxic effects to melanoma cells could be observed after only 2 hr exposure to the drug conjugates. Interestingly, these 2 conjugates, differing only in melphalan position, showed completely different cytotoxicity in terms of IC50 values, Pep 1 being 24 times more toxic to all cells; but the 2 were equally specific to melanoma cells. However, they both were less toxic to all cells than melphalan itself. Furthermore, Pep 1 and 2 were able to block the receptor and, unlike Pep 3 and 4, their cytotoxic effect could be significantly inhibited by an alpha-MSH agonist. Pep 3 and 4 were 5 to 10 times less toxic than melphalan to melanoma and carcinoma cells and 50 times less to fibroblast cells, and did not show any cell-type selectivity. They were less toxic than Pep 1 to melanoma and carcinoma cells by a factor of 2, but equally toxic to fibroblasts. In contrast, they were more toxic than Pep 2 to fibroblasts, melanoma and carcinoma by a factor of 3, 10 and 24 respectively. Our data strongly suggest a receptor-mediated cytotoxicity mechanism occurring with alpha-MSH central fragments in human melanoma cells due to the presence of alpha-MSH-specific receptors. This mechanism appeared to be both peptide- and cell-type-specific.
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PMID:Receptor-mediated cytotoxicity of alpha-MSH fragments containing melphalan in a human melanoma cell line. 826 69

The MSH receptor belongs to a unique class of G-protein-coupled receptors, in which calcium ions control the binding affinity of MSH by a yet unknown mechanism. Possible involvement of a calcium-binding protein [e.g. calmodulin (CaM)] in the regulation of MSH receptor activity has been studied in the M2R mouse melanoma cell line. In this study, we tested the inhibitory effects of a group of calmodulin-binding peptides (CBPs) on MSH receptor activities in intact M2R cells and membrane preparations derived from them. We also report here on stimulatory effects of CBPs on cAMP production in M2R cells that could not be produced in other cell lines lacking MSH receptors. This group of CBPs includes synthetic peptides comprising the CaM-binding domains of Ca2+/CaM-dependent enzymes, cytotoxic venom peptides, and peptide hormones that have been reported to directly interact with CaM. The results show that CBPs, at micromolar concentrations, inhibit MSH binding and consequent adenylate cyclase stimulation in a specific and concentration-dependent manner, but have no effect on adenylate cyclase stimulation by prostaglandin E1. On the other hand, when MSH was omitted and forskolin (0.5-1 microM) was added instead, CBPs had the opposite effect on cAMP production, stimulating it in M2R cells, but not in other cell types tested. Thus, these peptides can be considered as antagonists of MSH receptor and partial agonists of M2R adenylate cyclase. In contrast to MSH, the stimulatory effects of CBPs were unaffected by EGTA, suggesting a Ca(2+)-independent action of these peptides. Using phospholipid vesicles and M2R cells, we recently showed that CBP activity in M2R cells may include direct partition into the lipid bilayer of the cell membrane, permitting interaction with hydrophobic lipid-inserted domains of components of the signal transducing machinery. Based on these findings, we suggest that the mechanism of action of CBPs in the M2R cells includes two major components: 1) interaction with the cell surface membrane and penetration into the lipid milieu, and 2) interaction with exposed or lipid-embedded protein epitopes intrinsically associated with the MSH-receptor system, thereby affecting the MSH receptor cascade.
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PMID:Calmodulin-binding peptides interfere with melanocyte-stimulating hormone receptor activity and stimulate adenosine 3',5'-monophosphate production in M2R mouse melanoma cells. 827 31

We have examined the mechanism of homologous regulation of MSH receptor binding and receptor-mediated adenylate cyclase activation in three human and two mouse melanoma cell lines. Pretreatment with alpha-MSH resulted in a time- and dose-dependent up-regulation of MSH receptors in human D10 and 205 melanoma cells whereas in human HBL and in mouse B16-F1 and Cloudman S91 cells alpha-MSH induced receptor down-regulation. Up-regulation of receptors was maximal after a 24-h incubation period and an alpha-MSH concentration of 100 nM (EC50 = 2.4 nM). The increase in alpha-MSH binding was independent of adenylate cyclase activation and protein synthesis and appeared to be caused by recruitment of spare receptors. The structural requirements of the peptide for triggering this process differed from those found in receptor-binding analyses. Receptor down-regulation was maximal after 12 h and hence more rapid than up-regulation. In B16-F1 cells, 10 nM alpha-MSH caused the disappearance of 85-90% of the MSH receptors, the EC50 of 0.23 nM lying exactly between that for alpha-MSH-induced melanogenesis (0.027 nM) and the dissociation constant of receptor binding (1.31 nM). Down-regulation in B16-F1 cells appears to be the consequence of receptor internalization following MSH binding and seems to be initiated during an early step in MSH signalling, preceding the activation of adenylate cyclase and the cAMP signal. Receptor up- and down-regulation were not accompanied by an alteration in affinity to alpha-MSH, as demonstrated by Scatchard analysis of the binding curves.
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PMID:Homologous regulation of the MSH receptor in melanoma cells. 838 55

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.
Melanoma Res 1993 Apr
PMID:MSH receptors and function in amelanotic B16 melanoma cells. 839 Aug 76

A human genomic clone designated MC-2 is isolated. The cloned DNA codes for a protein of 325 amino acids which possesses seven hydrophobic segments, a characteristic of G-protein coupled receptors. The MC-2 receptor is expressed in brain tissue but not in the melanoma cells. When the MC-2 DNA is expressed in COS-7 cells, it binds [125I]-labelled [Nle4, D-Phe7]- alpha melanocyte stimulating hormone (NDP-MSH) which then could be displaced by melanotropic peptides alpha-MSH, beta-MSH, gamma-MSH and adrenocorticotropic hormone, but not by non-melanotropic peptide beta-endorphin. The highest affinity of 5.18 nM was for the NDP-MSH peptide. The novel MC-2 receptor and the MC-1 receptor, described earlier by us (8) showed identical order of affinity for the melanocortin peptides, but the affinities and the fold differences in the affinities to the melanocortin peptides were different when compared to the earlier described MC-1 receptor. The results suggest that the MC-2 DNA codes for a novel melanocortin receptor.
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PMID:Molecular cloning of a novel human melanocortin receptor. 856 9


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