Agouti Protein Inhibits Growth of B16 Melanoma Cellsin Vitroby Acting through Melanocortin Receptors

Siegrist, Walter; Willard, Derril H.; Wilkison, William O.; Eberlé, Alex N.

doi:10.1006/bbrc.1996.0030

Cited by 49 publications

(33 citation statements)

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“…Both types of mechanism are likely to be temperature-sensitive and occur over a time course longer than that required for antagonist binding. In this regard, Siegrist et al (27) have reported that treatment of B16 melanoma cells with Agouti protein causes a loss of ␣-MSH binding sites on the cell surface. Regardless of the exact mechanism, the differences we observe between fulllength and carboxyl-terminal Agouti protein demonstrate a unique role for a domain or domains in the amino terminus of Agouti protein.…”

Section: A Unique Role For the Amino Terminus Of Agouti Proteinunlikementioning

confidence: 99%

Down-regulation of Melanocortin Receptor Signaling Mediated by the Amino Terminus of Agouti Protein in XenopusMelanophores

Ollmann¹,

Barsh

1999

Journal of Biological Chemistry

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To investigate the potential role of the amino-terminal residues, we compared the function of full-length and carboxyl-terminal fragments of Agrp and Agouti protein in a sensitive bioassay based on pigment dispersion in Xenopus melanophores. We find that carboxyl-terminal Agouti protein, and all forms of Agrp tested, act solely by competitive antagonism of melanocortin action. However, full-length Agouti protein acts by an additional mechanism that is time-and temperature-dependent, depresses maximal levels of pigment dispersion, and is therefore likely to be mediated by receptor down-regulation. Apparent down-regulation is not observed for a mixture of amino-terminal and carboxyl-terminal fragments. We propose that the phenotypic effects of Agouti in vivo represent a bipartite mechanism: competitive antagonism of agonist binding by the carboxyl-terminal portion of Agouti protein and down-regulation of melanocortin receptor signaling by an unknown mechanism that requires residues in the amino terminus of the Agouti protein.

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Section: A Unique Role For the Amino Terminus Of Agouti Proteinunlikementioning

confidence: 99%

Down-regulation of Melanocortin Receptor Signaling Mediated by the Amino Terminus of Agouti Protein in XenopusMelanophores

Ollmann¹,

Barsh

1999

Journal of Biological Chemistry

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“…Other studies, however, suggest alternative mechanisms of Agouti protein action. Agouti protein will inhibit the effects of forskolin or cholera toxin in cultured pigment cells (Siegrist et al 1997;Suzuki et al 1997), and several groups have observed that Agouti protein has physiologic effects in the absence of added melanocortin peptides (Hunt and Thody 1995;Siegrist et al 1996;Sakai et al 1997). In contrast to laboratory mice, where a constitutively active Mc1r mutation is epistatic to a dominant Agouti allele (for review, see Silvers 1979a), Arctic foxes that carry a constitutively active Mc1r allele still display a coat color response to Agouti (Vage et al 1997), which suggests the existence of an as yet unidentified Agouti receptor whose downstream effectors intersect with those of the Mc1r.…”

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confidence: 99%

Interaction of Agouti protein with the melanocortin 1 receptor in vitro and in vivo

Mm¹,

Ml²,

Bd³

et al. 1998

Genes & Development

199

148

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Agouti protein and Agouti-related protein (Agrp) are paracrine-signaling molecules that normally regulate pigmentation and body weight, respectively. These proteins antagonize the effects of ␣-melanocyte-stimulating hormone (␣-MSH) and other melanocortins, and several alternatives have been proposed to explain their biochemical mechanisms of action. We have used a sensitive bioassay based on Xenopus melanophores to characterize pharmacologic properties of recombinant Agouti protein, and have directly measured its cell-surface binding to mammalian cells by use of an epitope-tagged form (HA-Agouti) that retains biologic activity. In melanophores, Agouti protein has no effect in the absence of ␣-MSH, but its action cannot be explained solely by inhibition of ␣-MSH binding. In

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“…In addition, mice carrying dominant agouti mutations exhibit adult onset obesity, hyperinsulinemia, noninsulin-dependent diabetes, and susceptibility to a variety of spontaneous and͞or induced tumors. Several studies have shown that ASP acts as a competitive antagonist of the melanocortin 1 receptor, and the switch between eumelanogenesis and pheomelanogenesis involves the opposing effects of ASP and MSH as ligands for that receptor (14)(15)(16)(17). Other groups have shown that some effects of ASP might be mediated by an alteration in calcium channels, suggesting that ASP also may function through other, as yet undefined, receptors to elicit its pleiotropic effects (18)(19)(20)(21).…”

mentioning

confidence: 99%

Characterization of genes modulated during pheomelanogenesis using differential display

Furumura

Sakai

Potterf

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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Molecular and biochemical mechanisms that modulate the production of eumelanin or pheomelanin pigments involve the opposing effects of two intercellular signaling molecules, ␣-melanocyte stimulating hormone (MSH) and agouti signal protein (ASP). ASP is an antagonist of MSH signaling through the melanocyte-specific MSH receptor, although its mechanism(s) of action is controversial. We previously have reported significant down-regulation of all known melanogenic genes during the eumelanin to pheomelanin switch in murine hair follicle melanocytes and in cultured melanocytes treated with recombinant ASP. To identify factors that might be involved in the switch to pheomelanogenesis, we screened ASP-treated melanocytes by using differential display and identified three up-regulated genes: a DNA replication control protein, a basic helix-loop-helix transcription factor, and a novel gene. We have simultaneously identified six down-regulated genes in ASP-treated melanocytes; two of those encode tyrosinase and TRP2, melanogenic genes known to be down-regulated during pheomelanogenesis, which provide good internal controls for this approach. These results suggest that there are complex mechanisms involved in the switch to pheomelanin production, and that these modulated genes might be involved in the pleiotropic changes seen in yellow mice, including the change in coat color.

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Agouti Protein Inhibits Growth of B16 Melanoma Cellsin Vitroby Acting through Melanocortin Receptors

Cited by 49 publications

References 0 publications

Down-regulation of Melanocortin Receptor Signaling Mediated by the Amino Terminus of Agouti Protein in XenopusMelanophores

Down-regulation of Melanocortin Receptor Signaling Mediated by the Amino Terminus of Agouti Protein in XenopusMelanophores

Interaction of Agouti protein with the melanocortin 1 receptor in vitro and in vivo

Characterization of genes modulated during pheomelanogenesis using differential display

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