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)

A hybrid toxin targeted to melanotropin receptors and selectively cytotoxic to melanoma cell lines in vitro has recently been developed. The toxin, a recombinant fusion protein (designated DAB389-MSH), contains the peptide sequences of alpha-melanocyte-stimulating hormone (alpha-MSH) and the catalytic (cytotoxic; Fragment A) and lipophilic (part of Fragment B) domains of diphtheria toxin. In the present study, binding of DAB389-MSH to melanotropin receptors in biopsy specimens of human and mouse melanoma metastases was assessed by measuring its ability to inhibit binding of a radiolabeled, superpotent analogue of alpha-MSH (125I-[Nle4,D-Phe7]-alpha-MSH; 125I-NDP-MSH) and comparing its potency in this system with those of the established ligands NDP-MSH and alpha-MSH. Radioligand binding to tissue sections in vitro was localized and quantified by autoradiography and image analysis. DAB389-MSH inhibited binding of 125I-NDP-MSH to experimental murine B16-F1C23 melanoma metastasis tissue and to melanoma metastases of three patients. In both mouse and human melanoma tissues, concentration-response relationships for DAB389-MSH-mediated inhibition of 125I-NDP-MSH binding were parallel, and its maximal effects were comparable in magnitude, to those of NDP-MSH and alpha-MSH. Half-maximal peptide concentrations for inhibition of 125I-NDP-MSH binding to mouse melanoma tissue sections were: NDP-MSH, 0.63 nM; alpha-MSH, 3.14 nM; and DAB389-MSH, 10.1 nM. In human melanoma tissues, the respective half-maximal peptide concentrations for inhibition of 125I-NDP-MSH binding to mouse melanoma tissue sections were: NDP-MSH, 1.80 nM; alpha-MSH, 2.43 nM; and DAB389-MSH, 11.9 nM. Taken together, these results suggest that NDP-MSH, alpha-MSH, and DAB389-MSH bind to a common melanotropin receptor in human metastatic melanoma cells. Since previous work has shown that melanotropin receptors are detectable in melanoma metastases of about 80% of human patients, malignant melanoma cells of many patients may be susceptible to killing by the melanotropin receptor-targeted cytotoxin DAB389-MSH.
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PMID:Interaction of an alpha-melanocyte-stimulating hormone-diphtheria toxin fusion protein with melanotropin receptors in human melanoma metastases. 131 97

Melanocytes and melanoma cells are known to possess receptors for melanocyte stimulating hormone (MSH). A cDNA clone, designated 11D, has been isolated from human melanoma cells and encodes a MSH receptor. The cloned cDNA encodes a 317 amino acid protein with transmembrane topography characteristics of a G-protein-coupled receptor, but it does not show striking similarity to already published sequences of other G-protein-coupled receptors. When 11D cDNA is expressed in COS-7 cells, it binds an 125I-labelled MSH analogue (NDP-MSH) in a specific manner. The bound ligand could be displaced by melanotropic peptides, alpha-MSH, beta-MSH, gamma-MSH and ACTH (adrenocorticotropic hormone), but not by the non-melanotropic peptide, beta-endorphin. This is the first report of the cloning of the receptor gene of the melanotropin receptor family.
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PMID:Molecular cloning and expression of the human melanocyte stimulating hormone receptor cDNA. 870 68

Melanotropinergic neurons in the brain may mediate the known modulatory effects of alpha-melanocyte stimulating hormone (alpha-MSH) and adrenocorticotropic hormone (ACTH) on brain functions including thermoregulation, pituitary regulation, learning and behavior. To determine the distribution of brain melanotropin receptors, we used biologically active [125I]Nle4, D-Phe7-alpha-MSH ([125I]NDP-MSH) for in situ binding and autoradiography in frozen rat brain sections. Specific (alpha-MSH-inhibitable) [125I]NDP-MSH binding sites were distributed in a region-specific pattern, and were present in numerous structures within the septal area, hypothalamus, thalamus, epithalamus, olfactostriatal complex, and midbrain. Each brain structure studied showed a characteristic, reproducible distribution and relative intensity of binding. Receptor peptide selectivity was assessed by comparing the dose-response relationships for inhibition of binding by alpha-MSH, NDP-MSH and ACTH. In all brain structures studied, the 3 peptides gave comparable maximal inhibition of tracer binding, indicating that all detectable binding sites recognized all 3 melanotropins. The respective relative potencies were: NDP-MSH (EC50 = 1.7 +/- 0.6 nM) greater than alpha-MSH (EC50 = 46.9 +/- 11.7 nM) = ACTH. These results provide a preliminary neuroanatomic map of potential target sites for melanotropin actions, and indicate that these sites are capable of recognizing multiple products of the intrinsic melanotropinergic system of the brain.
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PMID:Melanotropin receptors in the brain are differentially distributed and recognize both corticotropin and alpha-melanocyte stimulating hormone. 196 30

Cultured melanoma cells are known targets for the pigment-inducing actions of melanotropins such as alpha-melanocyte-stimulating hormone (alpha-MSH). The objectives of the present studies were to determine the binding properties and functional relevance of MSH binding sites in a mouse melanoma cell line and to determine whether MSH receptors are expressed in situ. The binding properties of MSH receptors in intact cells of a highly metastatic, highly MSH-responsive mouse melanoma cell subline (B16-F10C23) were determined using a radiolabeled, biologically active preparation of the superpotent alpha-MSH analogue, [Nle4,D-Phe7]-alpha-MSH (125I-NDP-MSH). A single high-affinity class of binding site was detected (Kd for NDP-MSH, 5.6 x 10(-11) M; Kd for alpha-MSH, 2.6 x 10(-9) M as determined by Scatchard analysis and heterologous inhibition assays, respectively). alpha-MSH showed nearly identical concentration-response relationships in the radioreceptor assay (inhibition of 125I-NDP-MSH binding) and a bioassay (stimulation of intracellular cyclic AMP accumulation). Furthermore, the respective potencies of three melanotropins, NDP-MSH, alpha-MSH, and adrenocorticotropic hormone, in binding and biological assays were highly correlated. These results indicate that the 125I-NDP-MSH binding site represents the functional MSH receptor. Tumors were induced by inoculation of C57BL/6 mice with B16-F10C23 cells, and the presence of 125I-NDP-MSH binding sites was determined by in situ radiolabeling of frozen tissue sections followed by autoradiography. Specific MSH binding sites were distributed throughout the tumor tissue, but not in associated fibrovascular elements or in neighboring nonmelanoma tissues. As in cultured B16-F10C23 cells, melanotropins inhibited 125I-NDP-MSH binding to tissue sections in a concentration-dependent manner. These results support the hypothesis that functional MSH receptors are expressed in melanoma in situ, suggesting that the activities of melanoma cells in vivo may be subject to modulation by endogenous melanotropins. The methods described will be applicable for studies of the expression and regulation of MSH receptors in human melanoma and other target tissues.
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PMID:Melanotropin receptors of murine melanoma characterized in cultured cells and demonstrated in experimental tumors in situ. 215 54

The specific melanotropin (MSH) binding sites of rat lacrimal glands were characterized with respect to anatomic distribution, peptide specificity and selectivity, and coupling to a biological response. Tissue distribution of MSH binding sites was determined by autoradiography following in situ binding of a radiolabeled, biologically active preparation of a superpotent alpha-MSH analog, [125I]-[Nle4,D-Phe7]-alpha-MSH ([125I]-NDP-MSH). Intense, specific (i.e., alpha-MSH-displaceable) [125I]-NDP-MSH binding was observed throughout lacrimal acinar tissue, but not in ducts or stroma. In freshly isolated lacrimal acinar cells, specific binding of [125I]-NDP-MSH was maximal within 30 min and rapidly reversible, with a dissociation half-time of about 15 min. A number of melanotropins [alpha-MSH, [N,O-diacetyl-Ser1]-alpha-MSH, [des-acetyl-Ser1]-alpha-MSH, beta-MSH, ACTH(1-24) and ACTH(1-39)] were recognized by these binding sites, as assessed by their inhibition of [125I]-NDP-MSH binding; NDP-MSH was the most potent (IC50 = 1.3 x 10(-9) M). In contrast, other peptides, including ACTH(4-10) and the nonmelanotropic peptides VIP, substance P, somatostatin, and ACTH(18-39) (CLIP), had no effects on tracer binding. In isolated lacrimal acinar cells, alpha-MSH and NDP-MSH stimulated intracellular cyclic AMP accumulation. We conclude that lacrimal acinar cells express functional receptors recognizing melanotropins, suggesting that the lacrimal gland may be a target for physiological regulation by endogenous melanotropins.
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PMID:Characterization of functional melanotropin receptors in lacrimal glands of the rat. 216 77

Although some cultured human melanoma cell lines are responsive to melanotropins (melanocyte-stimulating hormones [MSH]), the prevalence and tissue distribution of MSH receptors in melanoma are unknown. We report here the use of an in situ binding technique to demonstrate specific MSH receptors in surgical specimens of human melanoma. The distribution and binding properties of specific MSH binding sites were determined by autoradiography and image analysis after incubation of frozen tumor tissue sections with a biologically active, radiolabeled analogue of alpha-MSH, [125I]iodo-Nle4, D-Phe7-alpha-MSH ([125I]NDP-MSH). In melanoma specimens from 11 patients, 3 showed high levels of specific binding, 5 showed low levels, and in 3 patients specific binding of [125I]NDP-MSH was not detectable. Specific MSH binding sites were present in melanoma cells, but not in adjacent connective or inflammatory tissues. Melanotropins, including alpha-MSH, NDP-MSH, and ACTH, inhibited [125I]NDP-MSH binding in a concentration-dependent manner, whereas unrelated peptides (somatostatin and substance P) did not. The apparent affinity of alpha-MSH for this binding site was in the nanomolar range (EC50 = 2 X 10(-9) M for inhibition of [125I]NDP-MSH binding in situ), similar to that recently described for the murine melanoma receptor. In one patient, analysis of multiple intratumor samples and tumors excised on three separate occasions revealed high levels of specific MSH binding in all samples. These results suggest that endogenous melanotropins may modulate the activities of human melanoma cells in vivo.
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PMID:Melanotropin receptors demonstrated in situ in human melanoma. 234 15

A toxicology study was performed in mice given a superpotent alpha melanocyte stimulating hormone (MSH) analog. This 13 amino acid derivative, [Nle4, D-Phe7]alpha-MSH or NDP-MSH, is a melanotropin which is very slowly biodegraded in vivo and is active at 1/1,000 the concentration of natural alpha-MSH. Mice were administered up to 2 mg/kg of the analog daily and weekly over 4 or 12 weeks by both topical application (in 90% DMSO) or by IP injections (in physiologic saline). At the end of this period, no toxic effects were observed in various organs, on hematologic indices, or on weight gain. A slight increase in triglyceride and platelet levels were noted in mice given the analog weekly for 12 weeks. There was no evidence of an effect on behavior nor ACTH-like endocrine actions such as elevated serum cortisol levels. Transdermal drug delivery studies performed in vitro showed reproducible diffusion of the NDP-MSH analog through full-thickness mouse skin. Approximately 0.002% to 0.05% of a 10(-4) M preparation was transdermally delivered using a DMSO/water solution or a PEG/alcohol cream base, respectively. This superpotent analog is now entering a Phase I clinical trial with possible therapeutic applications for the treatment of hypomelanotic disorders such as vitiligo and for pharmacologic tanning without the need for sunlight exposure.
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PMID:Toxicologic studies of a superpotent alpha-melanotropin, [Nle4, D-Phe7]alpha-MSH. 285 52

In a family encompassing three generations, six of 11 evaluated members have two or three elements of a triad comprising adrenocortical micronodular dysplasia, mucocutaneous lentigines, and cardiac myxomas. Evaluation of the adrenals in affected members revealed characteristic pathologic lesions of micronodular adrenal hyperplasia and corticotropin-independent steroidogenesis that correlated with age, suggesting a progressive lesion that begins in early childhood. Since all subjects with micronodular hyperplasia and/or cardiac myxomas also had mucocutaneous lentigines, the skin lesions were markers for affected subjects. This family is one of the larger reported with this syndrome. Of special note was the finding of rare visceral tumors in affected family members, including melanocytic schwannomas and a fibrolamellar hepatoma, signaling another feature of the syndrome. Since 60% of this family encompassing three contiguous generations were affected, the syndrome appears to be inherited as an autosomal or X-linked dominant gene.
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PMID:Adrenocortical micronodular dysplasia, cardiac myxomas, lentigines, and spindle cell tumors. Report of a kindred. 382 21

We investigated the potential influence of opioid and melanotropic peptides on endogenous norepinephrine (NE) release from the A2 noradrenergic cell group of rats using a static, fixed-volume incubation procedure. Norepinephrine release from slices of caudal dorsomedial medulla (CDMM) was evoked by high potassium concentrations (20 and 60 mM) in a Ca(2+)-dependent and dose-related manner. Treatment with the potent melanotropin agonist [Nle4,D-Phe7] alpha-MSH(NDP-MSH) had no effect on K(+)-induced NE release. In contrast, human beta-endorphin1-31 significantly reduced K(+)-stimulated NE release, but not in the presence of naloxone. The highly-selective mu-opioid agonist [D-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin (DAMGO) also significantly reduced evoked NE release. The inhibitory effect of DAMGO was completely blocked by naloxone. Naloxone alone did not alter evoked NE release. The inhibitory effect of DAMGO was not enhanced by reducing the stimulatory concentration of K+. None of the peptides tested influenced basal NE release. These data indicate that melanotropin receptors do not regulate NE release in CDMM. In contrast, the opioid peptides DAMGO and beta-endorphin inhibit K(+)-stimulated release of endogenous NE. These data suggest a role for mu-opioid receptors in controlling NE release from A2 noradrenergic neurons.
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PMID:Opioid peptide inhibition of endogenous norepinephrine release from the A2 noradrenergic cell group in vitro. 759 87

Although the administration of melanocyte-stimulating hormone (MSH) peptides results in skin darkening in man, cultured human melanocytes have been reported to be unresponsive to these peptides. This may be a consequence of the conditions under which the cells were maintained in vitro, particularly the use of phorbol esters and cholera toxin as melanocyte mitogens. By culturing the cells in the absence of these additives, we demonstrate that alpha-MSH and its synthetic analogue Nle4DPhe7 alpha-MSH (NDP-MSH) induce dose-related increases in melanin content and tyrosinase activity and affect cell morphology in the majority of human melanocyte cultures. In addition, NDP-MSH induces increases in tyrosinase mRNA and tyrosinase-related protein-1 (TRP-1) mRNA. The dose-response curves for the MSH peptides are sigmoidal and the two peptides are equipotent in their effects on human melanocytes. Adrenocorticotropic hormone (ACTH) also affects morphology and stimulates melanogenesis and tyrosinase activity in human melanocytes. However, the dose-response curves for ACTH are biphasic, and the melanocytes respond to lower concentrations of ACTH than MSH peptides, similar to those normally present in human plasma. These findings may be important in understanding the role of these pro-opiomelanocortin peptides in human skin pigmentation.
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PMID:Cultured human melanocytes respond to MSH peptides and ACTH. 785 66


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