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Gregory S Barsh - One of the best experts on this subject based on the ideXlab platform.
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Pigment Cell Melanoma Res. 22; 623–634 ORIGINAL ARTICLE
2013Co-Authors: Tokimasa Hida, Glenn L Millhauser, Kazumasa Wakamatsu, Elena V. Sviderskaya, Andrew J. Donkin, Lluis Montoliu, Lynn M. Lamoreux, Shosuke Ito, Gregory S BarshAbstract:Agouti Protein, mahogunin, and attractin in pheomelanogenesis and melanoblast-like alteration of melanocytes: a cAMP-independent pathwa
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Agouti Protein mahogunin and attractin in pheomelanogenesis and melanoblast like alteration of melanocytes a camp independent pathway
Pigment Cell & Melanoma Research, 2009Co-Authors: Tokimasa Hida, Gregory S Barsh, Glenn L Millhauser, Kazumasa Wakamatsu, Elena V. Sviderskaya, Andrew J. Donkin, Lluis Montoliu, Lynn M. Lamoreux, Shosuke Ito, Kowichi JimbowAbstract:Parts of the research were supported by Wellcome Trust program grants 064583 and 078327 to D.C.B. and E.V.S.; the Japan Society for the Promotion of Science KAKENHI (grants 20790808 to T.H. and 18591262 and 20591357 to K.W. and S.I.); a Grant-in-Aid from the Japanese Ministry of Health, Labour and Welfare (K.J.), the Spanish Ministry of Education and Science BFU2006-12185 (L.M.), the South West Academic Network (A.J.D. and E.V.S.), and NIH grant DK064265 (B.Y. and G.L.M.).
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Agouti Protein mahogunin and attractin in pheomelanogenesis and melanoblast like alteration of melanocytes a camp independent pathway
Pigment Cell & Melanoma Research, 2009Co-Authors: Tokimasa Hida, Gregory S Barsh, Glenn L Millhauser, Kazumasa Wakamatsu, Elena V. Sviderskaya, Andrew J. Donkin, Lluis Montoliu, Lynn M. Lamoreux, Shosuke Ito, Kowichi JimbowAbstract:Melanocortin-1 receptor (MC1R) and its ligands, alpha-melanocyte stimulating hormone (alphaMSH) and Agouti signaling Protein (ASIP), regulate switching between eumelanin and pheomelanin synthesis in melanocytes. Here we investigated biological effects and signaling pathways of ASIP. Melan-a non Agouti (a/a) mouse melanocytes produce mainly eumelanin, but ASIP combined with phenylthiourea and extra cysteine could induce over 200-fold increases in the pheomelanin to eumelanin ratio, and a tan-yellow color in pelletted cells. Moreover, ASIP-treated cells showed reduced proliferation and a melanoblast-like appearance, seen also in melanocyte lines from yellow (A(y)/a and Mc1r(e)/ Mc1r(e)) mice. However ASIP-YY, a C-terminal fragment of ASIP, induced neither biological nor pigmentary changes. As, like ASIP, ASIP-YY inhibited the cAMP rise induced by alphaMSH analog NDP-MSH, and reduced cAMP level without added MSH, the morphological changes and depigmentation seemed independent of cAMP signaling. Melanocytes genetically null for ASIP mediators attractin or mahogunin (Atrn(mg-3J/mg-3J) or Mgrn1(md-nc/md-nc)) also responded to both ASIP and ASIP-YY in cAMP level, while only ASIP altered their proliferation and (in part) shape. Thus, ASIP-MC1R signaling includes a cAMP-independent pathway through attractin and mahogunin, while the known cAMP-dependent component requires neither attractin nor mahogunin.
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Molecular Pharmacology of Agouti Protein in Vitro and in Vivo
Annals of the New York Academy of Sciences, 2006Co-Authors: Gregory S Barsh, Michael Martin Ollmann, Kimberly A. Miller, Brent D Wilson, Teresa M. GunnAbstract:Agouti Protein and Agouti-related Protein (Agrp) are paracrine signaling molecules that act by antagonizing the effects of melanocortins, and several alternatives have been proposed to explain their mechanisms of action. Genetic crosses in a sensitized background uncover a phenotypic difference between overexpression of Agouti and loss of Mc1r function, demonstrate that a functional Mc1r is required for the pigmentary effects of Agouti, and suggest that Agouti Protein can act as an agonist of the Mc1r in a way that differs from alpha-MSH stimulation. In vitro, Agouti Protein inhibits melanocortin action by two mechanisms: competitive antagonism that depends on the carboxyterminus of the Protein, and downregulation of melanocortin receptor signaling that depends on the aminoterminus. Our findings provide evidence of a novel signaling mechanism whereby alpha-MSH and Agouti Protein function as independent ligands that inhibit each other's binding and transduce opposite signals through a single receptor.
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A biochemical function for attractin in Agouti-induced pigmentation and obesity.
Nature Genetics, 2001Co-Authors: Teresa M. Gunn, Jonathan S. Duke-cohan, Stuart F Schlossman, Donna M. Bouley, Stanley J. Watson, Gregory S BarshAbstract:Agouti Protein, a paracrine signaling molecule normally limited to skin, is ectopically expressed in lethal yellow (A(y)) mice, and causes obesity by mimicking Agouti-related Protein (Agrp), found primarily in the hypothalamus. Mouse attractin (Atrn) is a widely expressed transmembrane Protein whose loss of function in mahogany (Atrn(mg-3J)/ Atrn(mg-3J)) mutant mice blocks the pleiotropic effects of A(y). Here we demonstrate in transgenic, biochemical and genetic-interaction experiments that attractin is a low-affinity receptor for Agouti Protein, but not Agrp, in vitro and in vivo. Additional histopathologic abnormalities in Atrn(mg-3J)/Atrn(mg-3J) mice and cross-species genomic comparisons indicate that Atrn has multiple functions distinct from both a physiologic and an evolutionary perspective.
Richard P. Woychik - One of the best experts on this subject based on the ideXlab platform.
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the effects of calcium channel blockade on Agouti induced obesity
The FASEB Journal, 1996Co-Authors: Jung Han Kim, R. L. Mynatt, Richard P. Woychik, N. Moustaid, Jerry W. Moore, Michael B. ZemelAbstract:We have previously observed that obese viable yellow (Avy/a) mice exhibit increased intracellular Ca2+ ([Ca2+]i) and fatty acid synthase (FAS) gene expression; further, recombinant Agouti Protein increases in cultured adipocytes and these effects are inhibited by Ca2+ channel blockade. Accordingly, we determined the effect of Ca2+ channel blockade (nifedipine for 4 wk) on FAS and obesity in transgenic mice expressing the Agouti gene in a ubiquitous manner. The transgenic mice initially were significantly heavier (30.5+/-0.6 vs. 27.3+/-0.3 g; P<0.001) and exhibited a 0.81 degrees C lower initial core temperature (P<0.0005), an approximately twofold increase in fat pad weights (P=0.002), a sevenfold increase in adipose FAS activity (P=0.009), and a twofold increase in plasma insulin level (P<0.05) compared to control mice. Nifedipine treatment resulted in an 18% decrease in fat pad weights (P<0.007) and a 74% decrease in adipose FAS activity (P=0.03), normalized circulating insulin levels and insulin sensit...
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upregulation of adipocyte metabolism by Agouti Protein possible paracrine actions in yellow mouse obesity
American Journal of Physiology-endocrinology and Metabolism, 1996Co-Authors: Brynn H Jones, Michael B. Zemel, William O. Wilkison, Richard P. Woychik, Edward J Michaud, Jung Han Kim, N. MoustaidAbstract:Mutations leading to ectopic expression of the murine Agouti gene (a) result in progressive obesity. To further characterize this model, we analyzed adipose and hepatic mRNA levels for fatty acid s...
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Upregulation of adipocyte metabolism by Agouti Protein: possible paracrine actions in yellow mouse obesity
American Journal of Physiology-Endocrinology and Metabolism, 1996Co-Authors: Brynn H Jones, Michael B. Zemel, William O. Wilkison, Richard P. Woychik, Edward J Michaud, Jung Han Kim, N. MoustaidAbstract:Mutations leading to ectopic expression of the murine Agouti gene (a) result in progressive obesity. To further characterize this model, we analyzed adipose and hepatic mRNA levels for fatty acid synthase (FAS) and stearoyl-CoA desaturase (SCD), two key enzymes in de novo fatty acid synthesis and desaturation, respectively. FAS and SCD mRNA in both tissues of obese (Avy) mice were dramatically increased relative to lean (ala) controls. Excessive expression of these genes in this model could be due to direct effects of the Agouti gene product; to test this possibility we treated 3T3-L1 adipocytes in vitro with recombinant Agouti Protein. Agouti treatment increased FAS and SCD mRNA levels by 1.5- and 4-fold, respectively. In addition, FAS activity and triglyceride content were 3-fold higher in Agoutitreated 3T3-L1 cells relative to controls; these effects were attenuated by simultaneous treatment with a calcium channel blocker (nitrendipine). These data demonstrate that the Agouti Protein can directly increase lipogenesis in adipocytes and suggest that these effects are mediated through an intracellular calcium-dependent mechanism.
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ectopic expression of the Agouti gene in transgenic mice causes obesity features of type ii diabetes and yellow fur
Proceedings of the National Academy of Sciences of the United States of America, 1995Co-Authors: Mitchell L. Klebig, John E. Wilkinson, J G Geisler, Richard P. WoychikAbstract:Abstract Mice that carry the lethal yellow (Ay) or viable yellow (Avy) mutation, two dominant mutations of the Agouti (a) gene in mouse chromosome 2, exhibit a phenotype that includes yellow fur, marked obesity, a form of type II diabetes associated with insulin resistance, and an increased susceptibility to tumor development. Molecular analyses of these and several other dominant "obese yellow" a-locus mutations suggested that ectopic expression of the normal Agouti Protein gives rise to this complex pleiotropic phenotype. We have now tested this hypothesis directly by generating transgenic mice that ectopically express an Agouti cDNA clone encoding the normal Agouti Protein in all tissues examined. Transgenic mice of both sexes have yellow fur, become obese, and develop hyperinsulinemia. In addition, male transgenic mice develop hyperglycemia by 12-20 weeks of age. These results demonstrate conclusively that the ectopic Agouti expression is responsible for most, if not all, of the phenotypic traits of the dominant, obese yellow mutants.
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Agouti Protein is an antagonist of the melanocyte stimulating hormone receptor
Nature, 1994Co-Authors: Dongsi Lu, Richard P. Woychik, Derril H. Willard, I R Patel, Sue H Kadwell, Laurie K Overton, Tom Kost, Michael A Luther, Wenbiao Chen, William O. WilkisonAbstract:THE genetic loci Agouti and extension control the relative amounts of eumelanin (brown–black) and phaeomelanin (yellow–red) pigments in mammals1: extension encodes the receptor for melano-cyte-stimulating hormone (MSH)2 and Agouti encodes a novel 131-amino-acid Protein containing a signal sequence3,4. Agouti, which is produced in the hair follicle5, acts on follicular melanocytes6 to inhibit α-MSH-induced eumelanin production, resulting in the subterminal band of phaeomelanin often visible in mammalian fur. Here we use partially purified Agouti Protein to demonstrate that Agouti is a high-affinity antagonist of the MSH receptor and blocks α-MSH stimulation of adenylyl cyclase, the effector through which α-MSH induces eumelanin synthesis. Agouti was also found to be an antagonist of the melanocortin-4 receptor7,8, a related MSH-binding receptor. Consequently, the obesity caused by ectopic expression of Agouti in the lethal yellow (Ay) mouse9 may be due to the inhibition of melanocortin receptor(s) outside the hair follicle.
William O. Wilkison - One of the best experts on this subject based on the ideXlab platform.
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MUTATIONS IN THE CARBOXYL TERMINUS OF THE Agouti Protein DECREASE Agouti INHIBITION OF LIGAND BINDING TO THE MELANOCORTIN RECEPTORS
Biochemistry, 1997Co-Authors: Laura L. Kiefer, Derril H. Willard, Kathleen G. Mountjoy, Steven G. Blanchard, Olivia Ittoop, James S. Nichols, Anne T. Truesdale, Keith Bunce, Wen Ji Chen, William O. WilkisonAbstract:Several mutations that cause ectopic expression of the Agouti gene result in obesity, hyperinsulinemia, and yellow coat color. A candidate pathway for Agouti induced obesity and hyperinsulinemia is through altered signaling by melanocortin receptors, as Agouti normally regulates coat coloration through antagonism of melanocortin receptor 1. Furthermore, melanocortin peptides mediate functions including steroidogenesis, lipolysis, and thermoregulation. We report apparent inhibition dissociation constants for mouse and human Agouti Protein inhibition of ligand binding to the melanocortin receptors, to determine which of these receptors might be involved in Agouti induced diabetes. The similarity in the apparent K(I) values for Agouti inhibition of ligand binding to the brain melanocortin receptors 3 and 4 (mouse: K(I) app = 190 +/- 74 and 54 +/- 18 nM; human: K(I) app = 140 +/- 56 and 70 +/- 18 nM, respectively) suggests that the MC3-R is a potential candidate for a receptor mediating the effects of Agouti Protein overexpression. Agouti residues important for melanocortin receptor inhibition were identified through the analysis of deletion constructs and site-specific variants. Val83 is important for inhibition of binding to MC1-R (K(I) app for Val83Ala Agouti increased 13-fold relative to wild-type Protein). Arg85, Pro86, and Pro89 are important for selective inhibition of binding between MC1-R and MC3-R and MC4-R as their apparent K(I) values are essentially unchanged at MC1-R, while they have increased 6-10-fold relative to wild-type Protein at MC3-R and MC4-R.
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upregulation of adipocyte metabolism by Agouti Protein possible paracrine actions in yellow mouse obesity
American Journal of Physiology-endocrinology and Metabolism, 1996Co-Authors: Brynn H Jones, Michael B. Zemel, William O. Wilkison, Richard P. Woychik, Edward J Michaud, Jung Han Kim, N. MoustaidAbstract:Mutations leading to ectopic expression of the murine Agouti gene (a) result in progressive obesity. To further characterize this model, we analyzed adipose and hepatic mRNA levels for fatty acid s...
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Upregulation of adipocyte metabolism by Agouti Protein: possible paracrine actions in yellow mouse obesity
American Journal of Physiology-Endocrinology and Metabolism, 1996Co-Authors: Brynn H Jones, Michael B. Zemel, William O. Wilkison, Richard P. Woychik, Edward J Michaud, Jung Han Kim, N. MoustaidAbstract:Mutations leading to ectopic expression of the murine Agouti gene (a) result in progressive obesity. To further characterize this model, we analyzed adipose and hepatic mRNA levels for fatty acid synthase (FAS) and stearoyl-CoA desaturase (SCD), two key enzymes in de novo fatty acid synthesis and desaturation, respectively. FAS and SCD mRNA in both tissues of obese (Avy) mice were dramatically increased relative to lean (ala) controls. Excessive expression of these genes in this model could be due to direct effects of the Agouti gene product; to test this possibility we treated 3T3-L1 adipocytes in vitro with recombinant Agouti Protein. Agouti treatment increased FAS and SCD mRNA levels by 1.5- and 4-fold, respectively. In addition, FAS activity and triglyceride content were 3-fold higher in Agoutitreated 3T3-L1 cells relative to controls; these effects were attenuated by simultaneous treatment with a calcium channel blocker (nitrendipine). These data demonstrate that the Agouti Protein can directly increase lipogenesis in adipocytes and suggest that these effects are mediated through an intracellular calcium-dependent mechanism.
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Agouti Protein is an antagonist of the melanocyte stimulating hormone receptor
Nature, 1994Co-Authors: Dongsi Lu, Richard P. Woychik, Derril H. Willard, I R Patel, Sue H Kadwell, Laurie K Overton, Tom Kost, Michael A Luther, Wenbiao Chen, William O. WilkisonAbstract:THE genetic loci Agouti and extension control the relative amounts of eumelanin (brown–black) and phaeomelanin (yellow–red) pigments in mammals1: extension encodes the receptor for melano-cyte-stimulating hormone (MSH)2 and Agouti encodes a novel 131-amino-acid Protein containing a signal sequence3,4. Agouti, which is produced in the hair follicle5, acts on follicular melanocytes6 to inhibit α-MSH-induced eumelanin production, resulting in the subterminal band of phaeomelanin often visible in mammalian fur. Here we use partially purified Agouti Protein to demonstrate that Agouti is a high-affinity antagonist of the MSH receptor and blocks α-MSH stimulation of adenylyl cyclase, the effector through which α-MSH induces eumelanin synthesis. Agouti was also found to be an antagonist of the melanocortin-4 receptor7,8, a related MSH-binding receptor. Consequently, the obesity caused by ectopic expression of Agouti in the lethal yellow (Ay) mouse9 may be due to the inhibition of melanocortin receptor(s) outside the hair follicle.
N. Moustaid - One of the best experts on this subject based on the ideXlab platform.
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the effects of calcium channel blockade on Agouti induced obesity
The FASEB Journal, 1996Co-Authors: Jung Han Kim, R. L. Mynatt, Richard P. Woychik, N. Moustaid, Jerry W. Moore, Michael B. ZemelAbstract:We have previously observed that obese viable yellow (Avy/a) mice exhibit increased intracellular Ca2+ ([Ca2+]i) and fatty acid synthase (FAS) gene expression; further, recombinant Agouti Protein increases in cultured adipocytes and these effects are inhibited by Ca2+ channel blockade. Accordingly, we determined the effect of Ca2+ channel blockade (nifedipine for 4 wk) on FAS and obesity in transgenic mice expressing the Agouti gene in a ubiquitous manner. The transgenic mice initially were significantly heavier (30.5+/-0.6 vs. 27.3+/-0.3 g; P<0.001) and exhibited a 0.81 degrees C lower initial core temperature (P<0.0005), an approximately twofold increase in fat pad weights (P=0.002), a sevenfold increase in adipose FAS activity (P=0.009), and a twofold increase in plasma insulin level (P<0.05) compared to control mice. Nifedipine treatment resulted in an 18% decrease in fat pad weights (P<0.007) and a 74% decrease in adipose FAS activity (P=0.03), normalized circulating insulin levels and insulin sensit...
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upregulation of adipocyte metabolism by Agouti Protein possible paracrine actions in yellow mouse obesity
American Journal of Physiology-endocrinology and Metabolism, 1996Co-Authors: Brynn H Jones, Michael B. Zemel, William O. Wilkison, Richard P. Woychik, Edward J Michaud, Jung Han Kim, N. MoustaidAbstract:Mutations leading to ectopic expression of the murine Agouti gene (a) result in progressive obesity. To further characterize this model, we analyzed adipose and hepatic mRNA levels for fatty acid s...
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Upregulation of adipocyte metabolism by Agouti Protein: possible paracrine actions in yellow mouse obesity
American Journal of Physiology-Endocrinology and Metabolism, 1996Co-Authors: Brynn H Jones, Michael B. Zemel, William O. Wilkison, Richard P. Woychik, Edward J Michaud, Jung Han Kim, N. MoustaidAbstract:Mutations leading to ectopic expression of the murine Agouti gene (a) result in progressive obesity. To further characterize this model, we analyzed adipose and hepatic mRNA levels for fatty acid synthase (FAS) and stearoyl-CoA desaturase (SCD), two key enzymes in de novo fatty acid synthesis and desaturation, respectively. FAS and SCD mRNA in both tissues of obese (Avy) mice were dramatically increased relative to lean (ala) controls. Excessive expression of these genes in this model could be due to direct effects of the Agouti gene product; to test this possibility we treated 3T3-L1 adipocytes in vitro with recombinant Agouti Protein. Agouti treatment increased FAS and SCD mRNA levels by 1.5- and 4-fold, respectively. In addition, FAS activity and triglyceride content were 3-fold higher in Agoutitreated 3T3-L1 cells relative to controls; these effects were attenuated by simultaneous treatment with a calcium channel blocker (nitrendipine). These data demonstrate that the Agouti Protein can directly increase lipogenesis in adipocytes and suggest that these effects are mediated through an intracellular calcium-dependent mechanism.
Glenn L Millhauser - One of the best experts on this subject based on the ideXlab platform.
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Pigment Cell Melanoma Res. 22; 623–634 ORIGINAL ARTICLE
2013Co-Authors: Tokimasa Hida, Glenn L Millhauser, Kazumasa Wakamatsu, Elena V. Sviderskaya, Andrew J. Donkin, Lluis Montoliu, Lynn M. Lamoreux, Shosuke Ito, Gregory S BarshAbstract:Agouti Protein, mahogunin, and attractin in pheomelanogenesis and melanoblast-like alteration of melanocytes: a cAMP-independent pathwa
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pineal specific Agouti Protein regulates teleost background adaptation
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: Chao Zhang, Youngsup Song, Darren A Thompson, Michael E Madonna, Glenn L Millhauser, Sabrina Toro, Zoltan M Varga, Monte Westerfield, Joshua T Gamse, Wenbiao ChenAbstract:Background adaptation is used by teleosts as one of a variety of camouflage mechanisms for avoidance of predation. Background adaptation is known to involve light sensing by the retina and subsequent regulation of melanophore dispersion or contraction in melanocytes, mediated by α-melanocyte-stimulating hormone and melanin-concentrating hormone, respectively. Here, we demonstrate that an Agouti gene unique to teleosts, agrp2, is specifically expressed in the pineal and is required for up-regulation of hypothalamic pmch and pmchl mRNA and melanosome contraction in dermal melanocytes in response to a white background. floating head, a mutant with defective pineal development, exhibits defective up-regulation of mch mRNAs by white background, whereas nrc, a blind mutant, exhibits a normal response. These studies identify a role for the pineal in background adaptation in teleosts, a unique physiological function for the Agouti family of Proteins, and define a neuroendocrine axis by which environmental background regulates pigmentation.
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Agouti Protein mahogunin and attractin in pheomelanogenesis and melanoblast like alteration of melanocytes a camp independent pathway
Pigment Cell & Melanoma Research, 2009Co-Authors: Tokimasa Hida, Gregory S Barsh, Glenn L Millhauser, Kazumasa Wakamatsu, Elena V. Sviderskaya, Andrew J. Donkin, Lluis Montoliu, Lynn M. Lamoreux, Shosuke Ito, Kowichi JimbowAbstract:Parts of the research were supported by Wellcome Trust program grants 064583 and 078327 to D.C.B. and E.V.S.; the Japan Society for the Promotion of Science KAKENHI (grants 20790808 to T.H. and 18591262 and 20591357 to K.W. and S.I.); a Grant-in-Aid from the Japanese Ministry of Health, Labour and Welfare (K.J.), the Spanish Ministry of Education and Science BFU2006-12185 (L.M.), the South West Academic Network (A.J.D. and E.V.S.), and NIH grant DK064265 (B.Y. and G.L.M.).
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Agouti Protein mahogunin and attractin in pheomelanogenesis and melanoblast like alteration of melanocytes a camp independent pathway
Pigment Cell & Melanoma Research, 2009Co-Authors: Tokimasa Hida, Gregory S Barsh, Glenn L Millhauser, Kazumasa Wakamatsu, Elena V. Sviderskaya, Andrew J. Donkin, Lluis Montoliu, Lynn M. Lamoreux, Shosuke Ito, Kowichi JimbowAbstract:Melanocortin-1 receptor (MC1R) and its ligands, alpha-melanocyte stimulating hormone (alphaMSH) and Agouti signaling Protein (ASIP), regulate switching between eumelanin and pheomelanin synthesis in melanocytes. Here we investigated biological effects and signaling pathways of ASIP. Melan-a non Agouti (a/a) mouse melanocytes produce mainly eumelanin, but ASIP combined with phenylthiourea and extra cysteine could induce over 200-fold increases in the pheomelanin to eumelanin ratio, and a tan-yellow color in pelletted cells. Moreover, ASIP-treated cells showed reduced proliferation and a melanoblast-like appearance, seen also in melanocyte lines from yellow (A(y)/a and Mc1r(e)/ Mc1r(e)) mice. However ASIP-YY, a C-terminal fragment of ASIP, induced neither biological nor pigmentary changes. As, like ASIP, ASIP-YY inhibited the cAMP rise induced by alphaMSH analog NDP-MSH, and reduced cAMP level without added MSH, the morphological changes and depigmentation seemed independent of cAMP signaling. Melanocytes genetically null for ASIP mediators attractin or mahogunin (Atrn(mg-3J/mg-3J) or Mgrn1(md-nc/md-nc)) also responded to both ASIP and ASIP-YY in cAMP level, while only ASIP altered their proliferation and (in part) shape. Thus, ASIP-MC1R signaling includes a cAMP-independent pathway through attractin and mahogunin, while the known cAMP-dependent component requires neither attractin nor mahogunin.
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NMR structure of a minimized human Agouti related Protein prepared by total chemical synthesis.
FEBS letters, 1999Co-Authors: Kimberly A. Bolin, Ira Gantz, Darren A Thompson, Jill Wilken, Stephen B H Kent, D. Joe Anderson, Julie A. Trulson, Glenn L MillhauserAbstract:The structure of the chemically synthesized C-terminal region of the human Agouti related Protein (AGRP) was determined by 2D 1H NMR. Referred to as minimized Agouti related Protein, MARP is a 46 residue polypeptide containing 10 Cys residues involved in five disulfide bonds that retains the biological activity of full length AGRP. AGRP is a mammalian signaling molecule, involved in weight homeostasis, that causes adult onset obesity when overexpressed in mice. AGRP was originally identified by homology to the Agouti Protein, another potent signaling molecule involved in obesity disorders in mice. While AGRP's exact mechanism of action is unknown, it has been identified as a competitive antagonist of melanocortin receptors 3 and 4 (MC3r, MC4r), and MC4r in particular is implicated in the hypothalamic control of feeding behavior. Full length Agouti and AGRP are only 25% homologous, however, their active C-terminal regions are approximately 40% homologous, with nine out of the 10 Cys residues spatially conserved. Until now, 3D structures have not been available for either Agouti, AGRP or their C-terminal regions. The NMR structure of MARP reported here can be characterized as three major loops, with four of the five disulfide bridges at the base of the structure. Though its fold is well defined, no canonical secondary structure is identified. While previously reported structural models of the C-terminal region of AGRP were attempted based on Cys homology between AGRP and certain toxin Proteins, we find that Cys spacing is not sufficient to correctly determine the 3D fold of the molecule.