|Synonym(s)||ASP, As, agouti, agouti signal protein|
|Chromosomal Location||154,791,402-155,051,012 bp (+)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] In mice, the agouti gene encodes a paracrine signaling molecule that causes hair follicle melanocytes to synthesize pheomelanin, a yellow pigment, instead of the black or brown pigment, eumelanin. Pleiotropic effects of constitutive expression of the mouse gene include adult-onset obesity, increased tumor susceptibility, and premature infertility. This gene is highly similar to the mouse gene and encodes a secreted protein that may (1) affect the quality of hair pigmentation, (2) act as a pharmacological antagonist of alpha-melanocyte-stimulating hormone, (3) play a role in neuroendocrine aspects of melanocortin action, and (4) have a functional role in regulating lipid metabolism in adipocytes. [provided by RefSeq, Jul 2008]
PHENOTYPE: Agouti acts in the hair follicles, primarily affecting the relative amount and distribution of yellow pigment (phaeomelanin) and black pigment (eumelanin) in hairs of the coat. Some alleles show lethal effects or are associated with obesity. [provided by MGI curators]
|Amino Acid Change|
|Institutional Source||Beutler Lab|
Ensembl: ENSMUSP00000105319 (fasta)
|Gene Model||not available|
|Meta Mutation Damage Score||Not available|
|Is this an essential gene?||Probably nonessential (E-score: 0.178)|
|Candidate Explorer Status||CE: no linkage results|
Linkage Analysis Data
|Alleles Listed at MGI|
|Mode of Inheritance||Unknown|
|Local Stock||Sperm, gDNA|
|Last Updated||2021-10-06 11:52 AM by Diantha La Vine|
The index yellowbelly mouse was found in the woodrat stock and had the woodrat coat color dorsally and a yellow belly. Crossing this mouse with a wild type C57BL/6J mouse resulted in progeny with a black coat except for yellow hair on the belly, similar to the classic black and tan (at; MGI:1855941) mouse carrying a mutation in the agouti locus (Figure 1).
|Nature of Mutation|
The coat color phenotype of yellowbelly mice strongly suggested a mutation of agouti; this has not been verified by complementation testing and the nature of the mutation is not known.
|Illustration of Mutations in
Gene & Protein
The agouti (a; alternatively, nonagouti) gene encodes the 131-amino acid secreted agouti signaling protein (ASP). ASP has a cleavable signal peptide (amino acids 1-22), a hydrophobic region (amino acids 40-50), a lysine/arginine-rich basic domain (amino acids 57-85), and a cysteine-rich C-terminus (amino acids 92-131) [Figure 2; (1-5)]. Although not a defined domain, a proline-rich stretch of amino acids (85-91) in ASP shares similarity with the binding motif of the growth factor binding protein IGFBP-3, and may be necessary for protein-protein interactions, for example with the melanocortin 1 receptor (MC1R) (1). In addition, these proline residues may form a hinge between the C-terminus and the rest of the protein, facilitating protein flexibility for ASP-mediated protein-protein interactions (6). Amino acids 3-21, 64-71, and 79-82 are predicted to form alpha-helices; residues 40-50 and 123-126 are predicted to form beta-strands (1).
The function of the hydrophobic region is unknown, but it may function in binding to lipids or membrane phospholipids (1). The basic region of ASP is necessary for full biological activity in vivo (7;8), yet its precise function is not known. Deletion of the basic domain in vitro reduced ASP antagonism of the melanocortin receptors (6), suggesting that the basic region directly influences receptor affinity. Proposed functions of the ASP basic region include protecting ASP from degradation, allowing ASP to interact with cell surface acidic glycosaminoglycans on target cells, and promoting ASP biogenesis (i.e., protein folding, post-translational processing, sorting, and secretion) (7;9). ASP interacts with at least four of the five known melanocortin receptors (1;10). ASP has high affinity for and antagonizes MC1R (expressed throughout the body) and MC4R (expressed throughout the brain), but has no antagonistic effect on MC3R (expressed in the hypothalamus and limbic systems in the brain, and in the placenta and gut) or MC5R (expressed ubiquitously) (11); the effect of ASP on MC2R (expressed in the adrenal cortex and adipose tissue) is unknown (12).
The structure of amino acids 80-132 of the human homolog of ASP (ASIP) has been solved by NMR [Figure 3; PDB: 1Y7K) (13)]. The Cys-rich ASIP C-terminus folds into an inhibitor cysteine knot (ICK) conformation stabilized by five disulfide bridges (Cys93-Cys108, Cys111-Cys132, Cys116-Cys123, Cys100-Cys125, Cys107-Cys114) (1;13-16). Two antiparallel β strands form a small β sheet within the ICK structure. Amino acids 93-108 form an irregular region referred to as the N-terminal loop and residues 128-132 form the C-terminal loop (13). An “active” or “central” loop connecting the two β strands contains an RFF (Arg-Phe-Phe) triplet (aa 117-119) (13). In mouse ASP, the RFF triplet (aa 116-118) is exposed on the surface of the cysteine knot and is a high-affinity MC1-R-binding determinant (16;17). Mutation of the RFF triplet in mouse ASP to alanine, glutamine, histidine, or lysine determined that the positive charge of the Arg residue is essential for MC1-R inhibition (17). ASP exists in two conformations due to a cis versus trans configuration of the peptide bond between Ala104 and Pro105 (13). The trans conformation is the predominant form of ASIP, however, the cis conformation is responsible for its biological activity (13).
Virador et al. designated three bioactive regions in ASP: region 1 (amino acids 26-52; overlaps with the hydrophobic region), region 2 (amino acids 81-87; overlaps with the protein-protein interacting domain and the basic domain), and region 3 (amino acids 107-125; overlaps with the Cys-rich C-terminus) [Figure 2; (1)]. Peptides containing region 1 and 2 regulated the expression of several melanogenic enzymes in cultured melanocytes, including tyrosinase (Tyr; see the record for ghost), Tyrp1 (see the record for chi) and Dct (1). A five-residue motif (KVARP; amino acids 82-86) within region 2 (and the basic domain) was determined to be the minimal functional motif essential for the regulation of Tyr and Tyrp1 mRNA expression in the cultured melanocytes (1). Within the KVARP motif, Val83 was essential for binding of ASP to the melanocortin 1 receptor (MC1R; see the record for deer), while Val83, Arg85, Pro86, and Pro89 were determined to be essential for the binding of ASP to the MC3R, MC4R, and MC5R receptors (6). Region 3 also regulated Tyr expression, but did not affect Tyrp1 or Dct expression or melanin content (1).
Asparagine 39 is predicted to be N-linked glycosylated and this modification, along with the C-terminus and signal peptide, is essential for full ASP activity resulting in yellow pigmentation of mouse fur (8;15).
The a gene is normally expressed in mouse skin throughout early postnatal development, with highest expression during postnatal days 2-7 (3;15;18). In the mouse, the ASP protein is secreted by dermal papilla cells at the base of hair follicles on days 4-7 during the hair growth cycle; after day 7, a expression is turned off (4;19;20). ASP acts in a localized manner within the hair follicle. For a description of aberrant a expression in a mutant mouse models, see the “Background” section, below.
The a gene has three coding exons (exons 2, 3, and 4) that are alternatively spliced to different 5’ untranslated exons (exons 1A, 1A’, 1B, and 1C) [Figure 4; (2;21); reviewed in (22)]. The two ventral-specific exons (exons 1A and 1A’) are 120 kb upstream of exon 2, while the two hair cycle-specific exons, exons 1B and 1C, are 18 kb upstream of exon 2 [(2;3;5;21;23); reviewed in (22)]. The a isoforms encoded by transcripts containing exons 1A or 1A’ are controlled by regulatory elements that direct ventral expression of a so that they are only expressed in the ventral skin of light-bellied mice, while the a isoforms encoded by transcripts containing exons 1B or 1C are controlled by regulatory elements specific for the midphase of the hair growth cycle (between days 3 and 7) so that they are transiently expressed during hair growth in dorsal and ventral skin (3;21;23). Bultman et al. also observed the expression of testis-specific a transcripts in mouse, but the function of these transcripts is unknown (3).
Melanocytes produce two types of melanin with distinct chemical compositions and colors. The ratio of the two types, called eumelanin (black to brown) and pheomelanin (yellow to reddish brown), determines the color of hair, skin, and eyes. In mice, eumelanin and pheomelanin produce a black or yellow hair color, respectively. The agouti coat considered “wild type” is composed of black hairs with a yellow band near the tip, which result from a transient switch from eumelanin to pheomelanin production during the hair cycle. This pigment type switching is controlled by signaling from MC1R, a G protein-coupled receptor expressed predominantly in melanocytes of the skin (see the record for deer).
The activity of MC1R is regulated mainly by the opposing effects of two ligands, α-melanocyte-stimulating hormone (α-MSH) and ASP (Figure 5). Binding of α-MSH to MC1R activates the receptor, leading to GDP/GTP exchange on its cognate G-protein. The GTP-bound Gα subunit is released to activate adenylyl cyclase, elevating cAMP, which leads to the activation of PKA, and PKA-induced activation of the CREB family of transcription factors. CREB initiates a transcriptional program for eumelanogenesis. For more information about melanocyte development, please see the record gus-gus; for information about melanin production, please see the records for chi and ghost.
ASP promotes an inactive state of MC1R, thereby inhibiting the eumelanogenic transcriptional program and favoring pheomelanogenesis. Studies have reported that ASP is a competitive antagonist (11) or an inverse agonist of MC1R (10;26-29), or both (19;30). As an antagonist, ASP would compete with α-MSH for binding to the MC1R (3;11). As an inverse agonist, ASP would bind preferentially to the inactive MC1R, stabilizing the inactive conformation of the receptor and reducing the population of the activated receptors (1). Attractin, an accessory receptor for ASP, may function to stabilize ASP at the MC1R or to sequester α-MSH to allow ASP greater access to unoccupied receptors (1). Attractin and mahogunin, an E3 ubiquitin ligase, are essential for ASP to signal pheomelanogenesis (yellow/red pigment production) (19;31). Interestingly, a recent report provided evidence that a reduction in cAMP may be insufficient to downregulate eumelanogenesis and promote pheomelanogenesis; another mechanism may be responsible for downregulating eumelanogenic genes (19).
Activation of MC1R ultimately leads to CREB-dependent transcription of microphthalmia-related transcription factor (MITF), a key positive regulator of eumelanogenesis, melanocyte differentiation, proliferation, and survival (19). MITF transactivates eumelanogenic genes such as Tyr, Tyrp1, and Dct and the matrix protein Pmel (19;30). In contrast, ASP has an inhibitory effect on melanocyte differentiation and eumelanogenesis, manifest by morphological changes, an increase in the ratio of pheomelanin to eumelanin (19), and changes in gene expression (18).
ASP inhibits the differentiation of melanoblasts into melanocytes both in vitro and in vivo (30). Exogenous ASP added to the culture medium of melanoma cell lines inhibited α-MSH-induced eumelanin synthesis, cell proliferation, Tyr activity, and reduced the level of Tyrp1 without altering the level of Tyr (10;26;27;30). Recombinant ASP induced morphological dedifferentiation of cultured melanocytes to a melanoblast-like shape, retarded growth, inhibited eumelanogenesis, and increased the pheomelanin to eumelanin ratio; dedifferentiation was proposed to be due to downregulation of pigment cell-specific genes (18;19;26;32;33). In natural populations of deer mice (Peromyscus) with darker dorsums and light ventrums, increased ventral expression of ASP repressed the terminal differentiation of ventral melanocytes and their colonization in the epidermis (33). However, ASP did not interfere with dorsal-ventral melanocyte migration (33). The level of ASP expression during development correlated with the degree of repression of the terminal step in melanocyte differentiation thereby affecting adult color pattern (33).
Microarray analysis determined that ASP downregulates several pigment-related genes that function in melanogenesis, melanosome maturation and function, as well as melanosome transport, including Mitf, Tyr (see the record for ghost), Tyrp1 (see the record for chi), Dct, Rab27a (see the record for concrete), Rab38 (see the record for fenrir), and Hps3 (see the record for pam gray) (18). Microarray analysis also determined that several genes upregulated by ASP are intermediates in the MAPK pathway; inhibitors of the MAPK pathway were often downregulated (18). Upregulation of MAPK signaling influences the coordinated loss of expression of several melanocytic antigens in melanoma cells (34). Surprisingly, several genes in the Wnt signaling pathway (e.g., Tcf4, Lef-1, and cyclin D) known to promote melanocytic differentiation were also upregulated in response to ASP (18). However, in the context of ASP signaling Tcf4 may act as a negative transcriptional regulator of Mitf, Tyr, Tyrp1, and Dct (35). Genes that function in the regulation of oxidative stress, including Atf4, were also altered upon treatment with ASP (18). Twelve transcripts that encode proteins that function in DNA damage repair were also regulated by ASP (18). Several genes involved in the development of the nervous system as well as genes involved in skeletal, bone, cartilage, and muscle development were increased by ASP treatment (18).
Due to transient expression of a during the mouse hair growth cycle, follicular melanocytes first produce eulmelanin, then pheomelanin, then eumelanin again over a 3-day period, resulting in the wild-type agouti phenotype: dorsal coat hairs that are black with a single subapical band of yellow and lighter-colored ventral hairs [(1;7;19;36); reviewed in (22)]. The Mouse Genome Informatics (MGI) database lists over 100 targeted, spontaneous, chemically-induced, or radiation-induced a alleles in mice. Mutations in a can lead to a range of coat color phenotypes, from the production of all yellow to all black hair, depending on whether the mutation is a gain-of-function (usually dominant) or loss-of-function (usually recessive) mutation, respectively [(8;21;37); reviewed in (38)].
Strains with dominant a mutations (e.g., Ay (lethal yellow; MGI:18569798), Avy (viable yellow; MGI:1855930), Asy (sienna yellow; MGI:1855935), and Aiy (intermediate yellow; MGI:1855933)) exhibit yellow fur, adult-onset obesity due to hypertrophy (not hyperplasia) of the adipocytes, pancreatic islet hypertrophy and hyperplasia, hyperinsulinemia, noninsulin-dependent diabetes, impaired glucose tolerance, an increased susceptibility to a variety of spontaneous and/or induced solid tumors including those of the lung, liver, and mammary gland, increased linear growth, and premature infertility [(37;39-50); reviewed in (22)]. It was proposed that ASP acts on both the central nervous system (CNS) and tissues in the periphery to induce obesity syndrome (12). In the CNS and hypothalamus, ASP may antagonize the MC4R, resulting in obesity, hyperphagia, and hyperinsulinemia (12;46;51). Transgenic ASP expression in adipose tissue, coupled with insulin treatment, resulted in significant weight gains in mice (12). The higher susceptibility to tumor formation caused by dominant a mutations is proposed to be due to increases in cell division rates observed in the mutant mice [(48;50); reviewed in (37)]. The a gene may increase the pool of precancerous or primary transformed cells, promote a metabolic change in cells from normal to precancerous, and/or increase cell division of precancerous cells [reviewed in (37)]. Some dominant a mutations are described in more detail, below.
Homozygous Ay mice exhibited premature death as early as embryonic day 5.5-6.5; changes in the embryo can be observed in early cleavage (52). The early mortality was proposed to be due to deletion(s) in neighboring gene(s), and not solely due to a defect of the a gene (37). Indeed, a 170-kb deletion in the Ay allele removes all but the promoter and non-coding first exon of Raly, a gene closely linked to a that encodes a heterogeneous nuclear ribonucleoprotein. As a result, exon 1 of Raly is spliced to the coding exons of the wild-type a gene (37;52;53). The a gene, under the control of the Raly promoter, becomes ectopically expressed with a broad temporal and spatial pattern (14).
In the Avy, Aiy, Aiapy (intracisternal A particle (IAP) yellow; MGI:1856403), and Ahvy (hypervariable yellow; MGI:1855945) strains, an IAP retrotransposon inserted in exon 1A of the a gene causes the ectopic expression of ASP due to the use of a constitutively active cryptic promoter in the 5’ long terminal repeat (LTR) of the IAP (3;5;23;54). Ectopic expression of a in the Avy, Aiy, Aiapy, and Ahvy mice was observed in the skin throughout the hair growth cycle as well as in most tissues including the testis, brain, lung, kidney, liver, and spleen (23;54-56). The mice exhibit variable expressivity of the a gene due to the mosaic activity of the IAP, resulting in coat colors that vary from full yellow, variegated yellow/agouti, to full agouti (54;57). The phenotypes of the Aiapy and Ahvy strains correlate with methylation of the 5’ LTR (long terminal repeat) of the IAP: in yellow mice the LTR is unmethylated, in full agouti mice the LTR is heavily methylated, and in mottled mice the methylation of the LTR is intermediate (23;55;57-60). Immune function is another phenotype apparently influenced by the epigenetic regulation of a: relative to black a/a mice, mottled Avy mice exhibit decreased antibody responses to the T-cell dependent immunogen tetanus toxoid, enhanced antibody response to the T-cell-independent immunogen type III pneumococcal polysaccharide, decreased (unadjusted) rates of carbon clearance, and increased levels of serum IgA (61). In contrast, immune function of full agouti Avy mice was similar to that of black a/a mice.
A maternal epigenetic effect is also observed at the a locus; in the Avy mice, the yellow phenotype of a mother contributing an Avy allele shifted the proportion of phenotypes in the offspring to produce more yellow pups and fewer full agouti pups (62;63). Evidence indicates that the effect is due to incomplete erasure of an epigenetic mark, likely methylation, when a silenced Avy allele is passed through the female germ line, resulting in inheritance of the modification by progeny (57). Interestingly, the somatic activity of the IAP was affected by maternal diet such that pregnant black a/a females given a supplementation of methyl donors (e.g., folate, choline, betaine, and vitamin B12) produced a higher frequency of offspring that exhibited the variegated and full agouti phenotypes relative to non-supplemented females, suggesting that methyl metabolism in mothers and/or embryos can influence DNA methylation and subsequent gene expression in embryos (57-60).
Avy mice exhibit increased skeletal muscle (soleus) calcium influx and intracellular free calcium concentrations that correlate with the ectopic expression of ASP and the degree of obesity in the animals; basal calcium efflux is not impaired nor is there an increase in calcium release from sarco/endoplasmic reticulum stores (64). In cultured L6 myocytes and freshly isolated skeletal muscle myocytes from a/a black mice, ASP is capable of inducing increased intracellular free calcium concentrations through an unknown mechanism, supporting the idea that ASP promotes insulin resistance in mutant animals through its ability to increase intracellular calcium (14;64). Several putative mechanisms by which calcium affects insulin resistance have been proposed. First, calcium can mediate protein kinase C (PKC) activation and the subsequent phosphorylation and inactivation of the insulin receptor β-subunit tyrosine kinase (65). Second, increased calcium levels can promote calcium-calmodulin (CaM) binding and the binding of CaM to IRS-1, although the outcome of CaM binding to IRS-1 is unknown. Third, increased calcium also results in the phosphorylation and activation of inhibitor 1, which binds to phosphoserine phosphatase 1 (PP1) and inactivates it. PP1 inactivation impairs the dephosphorylation of insulin-sensitive substrates including GLUT4 and glycogen synthase. Increased intracellular calcium induced by ASP may also contribute to the obesity of Avy mice. Inhibition of calcium channels in transgenic mice that express a in a ubiquitous manner resulted in a decrease in adipose tissue mass and adipocyte lipogenesis (66). In cultured human adipocytes, ASIP increased fatty acid synthase expression and activity, and stimulated the accumulation of triglycerides in a calcium-dependent manner (49). By directly acting on adipose tissue in humans, ASIP may regulate fatty acid metabolism (12).
Loss-of-function a mutations alter ASP activity and/or a mRNA levels leading to a darker, less-yellow coat as a result of reduced pheomelanin banding of individual hairs (67). For example, homozygous nonagouti mice (a; MGI:1855937) have a homogeneous black coat in the absence of other mutations (68). Similarly, homozygous extreme nonagouti (ae; MGI:1855939) radiation-induced null mutants have completely black coat hairs (69).
A polymorphism in the 3’ UTR of human ASIP (8818A>G), 25 bp downstream from the termination codon is significantly associated with having dark hair and brown eyes [OMIM: #611742; (70)]. A two-SNP haplotype (rs1015362[G] and rs4911414[T]) at the ASIP locus is significantly associated with instances of cutaneous melanoma, a malignant tumor of melanocytes, and with basal cell carcinoma, a skin neoplasm, in patients from Iceland, Hungary, Romania, and Slovakia (71).
The phenotype observed in the yellowbelly mice resembles that of the at (black and tan; MGI:1855941) mice in that the at mice exhibit black coloration dorsally and have a yellow ventrum (72). The a mutation in the at mice is a spontaneous 6 kb insertion between exon 1C and exon 2 (~2.1 kb 3’ from exon 1C); the insertion contains a retrovirus-like transposable element VL30 with an internal 526 bp direct repeat (2). As a result of the VL30 insertion, the hair cycle-specific promoter/regulatory elements that control a expression on the dorsum are impaired. In the at mice, most, if not all, expression of a is believed to be controlled by the ventral-specific promoter. In the at mice, yellow pigment is synthesized throughout the hair cycle, leading to a ventrum that is yellow, while the dorsal hairs are black (21).
|Primers||Primers cannot be located by automatic search.|
1. Virador, V. M., Santis, C., Furumura, M., Kalbacher, H., and Hearing, V. J. (2000) Bioactive Motifs of Agouti Signal Protein. Exp Cell Res. 259, 54-63.
2. Bultman, S. J., Klebig, M. L., Michaud, E. J., Sweet, H. O., Davisson, M. T., and Woychik, R. P. (1994) Molecular Analysis of Reverse Mutations from Nonagouti (a) to Black-and-Tan (a(t)) and White-Bellied Agouti (Aw) Reveals Alternative Forms of Agouti Transcripts. Genes Dev. 8, 481-490.
3. Bultman, S. J., Michaud, E. J., and Woychik, R. P. (1992) Molecular Characterization of the Mouse Agouti Locus. Cell. 71, 1195-1204.
4. Millar, S. E., Miller, M. W., Stevens, M. E., and Barsh, G. S. (1995) Expression and Transgenic Studies of the Mouse Agouti Gene Provide Insight into the Mechanisms by which Mammalian Coat Color Patterns are Generated. Development. 121, 3223-3232.
5. Miller, M. W., Duhl, D. M., Vrieling, H., Cordes, S. P., Ollmann, M. M., Winkes, B. M., and Barsh, G. S. (1993) Cloning of the Mouse Agouti Gene Predicts a Secreted Protein Ubiquitously Expressed in Mice Carrying the Lethal Yellow Mutation. Genes Dev. 7, 454-467.
6. Kiefer, L. L., Ittoop, O. R., Bunce, K., Truesdale, A. T., Willard, D. H., Nichols, J. S., Blanchard, S. G., Mountjoy, K., Chen, W. J., and Wilkison, W. O. (1997) Mutations in the Carboxyl Terminus of the Agouti Protein Decrease Agouti Inhibition of Ligand Binding to the Melanocortin Receptors. Biochemistry. 36, 2084-2090.
7. Miltenberger, R. J., Mynatt, R. L., Bruce, B. D., Wilkison, W. O., Woychik, R. P., and Michaud, E. J. (1999) An Agouti Mutation Lacking the Basic Domain Induces Yellow Pigmentation but Not Obesity in Transgenic Mice. Proc Natl Acad Sci U S A. 96, 8579-8584.
8. Perry, W. L., Nakamura, T., Swing, D. A., Secrest, L., Eagleson, B., Hustad, C. M., Copeland, N. G., and Jenkins, N. A. (1996) Coupled Site-Directed mutagenesis/transgenesis Identifies Important Functional Domains of the Mouse Agouti Protein. Genetics. 144, 255-264.
9. Furumura, M., Sakai, C., Abdel-Malek, Z., Barsh, G. S., and Hearing, V. J. (1996) The Interaction of Agouti Signal Protein and Melanocyte Stimulating Hormone to Regulate Melanin Formation in Mammals. Pigment Cell Res. 9, 191-203.
10. Suzuki, I., Tada, A., Ollmann, M. M., Barsh, G. S., Im, S., Lamoreux, M. L., Hearing, V. J., Nordlund, J. J., and Abdel-Malek, Z. A. (1997) Agouti Signaling Protein Inhibits Melanogenesis and the Response of Human Melanocytes to Alpha-Melanotropin. J Invest Dermatol. 108, 838-842.
11. Lu, D., Willard, D., Patel, I. R., Kadwell, S., Overton, L., Kost, T., Luther, M., Chen, W., Woychik, R. P., and Wilkison, W. O. (1994) Agouti Protein is an Antagonist of the Melanocyte-Stimulating-Hormone Receptor. Nature. 371, 799-802.
12. Michaud, E. J., Mynatt, R. L., Miltenberger, R. J., Klebig, M. L., Wilkinson, J. E., Zemel, M. B., Wilkison, W. O., and Woychik, R. P. (1997) Role of the Agouti Gene in Obesity. J Endocrinol. 155, 207-209.
13. McNulty, J. C., Jackson, P. J., Thompson, D. A., Chai, B., Gantz, I., Barsh, G. S., Dawson, P. E., and Millhauser, G. L. (2005) Structures of the Agouti Signaling Protein. J Mol Biol. 346, 1059-1070.
14. Dinulescu, D. M., and Cone, R. D. (2000) Agouti and Agouti-Related Protein: Analogies and Contrasts. J Biol Chem. 275, 6695-6698.
15. Willard, D. H., Bodnar, W., Harris, C., Kiefer, L., Nichols, J. S., Blanchard, S., Hoffman, C., Moyer, M., Burkhart, W., and Weiel, J. (1995) Agouti Structure and Function: Characterization of a Potent Alpha-Melanocyte Stimulating Hormone Receptor Antagonist. Biochemistry. 34, 12341-12346.
16. Pallaghy, P. K., Nielsen, K. J., Craik, D. J., and Norton, R. S. (1994) A Common Structural Motif Incorporating a Cystine Knot and a Triple-Stranded Beta-Sheet in Toxic and Inhibitory Polypeptides. Protein Sci. 3, 1833-1839.
17. Kiefer, L. L., Veal, J. M., Mountjoy, K. G., and Wilkison, W. O. (1998) Melanocortin Receptor Binding Determinants in the Agouti Protein. Biochemistry. 37, 991-997.
18. Le Pape, E., Passeron, T., Giubellino, A., Valencia, J. C., Wolber, R., and Hearing, V. J. (2009) Microarray Analysis Sheds Light on the Dedifferentiating Role of Agouti Signal Protein in Murine Melanocytes Via the Mc1r. Proc Natl Acad Sci U S A. 106, 1802-1807.
19. Hida, T., Wakamatsu, K., Sviderskaya, E. V., Donkin, A. J., Montoliu, L., Lynn Lamoreux, M., Yu, B., Millhauser, G. L., Ito, S., Barsh, G. S., Jimbow, K., and Bennett, D. C. (2009) Agouti Protein, Mahogunin, and Attractin in Pheomelanogenesis and Melanoblast-Like Alteration of Melanocytes: A cAMP-Independent Pathway. Pigment Cell Melanoma Res. 22, 623-634.
20. Matsunaga, N., Virador, V., Santis, C., Vieira, W. D., Furumura, M., Matsunaga, J., Kobayashi, N., and Hearing, V. J. (2000) In Situ Localization of Agouti Signal Protein in Murine Skin using Immunohistochemistry with an ASP-Specific Antibody. Biochem Biophys Res Commun. 270, 176-182.
21. Vrieling, H., Duhl, D. M., Millar, S. E., Miller, K. A., and Barsh, G. S. (1994) Differences in Dorsal and Ventral Pigmentation Result from Regional Expression of the Mouse Agouti Gene. Proc Natl Acad Sci U S A. 91, 5667-5671.
22. Manne, J., Argeson, A. C., and Siracusa, L. D. (1995) Mechanisms for the Pleiotropic Effects of the Agouti Gene. Proc Natl Acad Sci U S A. 92, 4721-4724.
23. Argeson, A. C., Nelson, K. K., and Siracusa, L. D. (1996) Molecular Basis of the Pleiotropic Phenotype of Mice Carrying the Hypervariable Yellow (Ahvy) Mutation at the Agouti Locus. Genetics. 142, 557-567.
24. Kwon, H. Y., Bultman, S. J., Loffler, C., Chen, W. J., Furdon, P. J., Powell, J. G., Usala, A. L., Wilkison, W., Hansmann, I., and Woychik, R. P. (1994) Molecular Structure and Chromosomal Mapping of the Human Homolog of the Agouti Gene. Proc Natl Acad Sci U S A. 91, 9760-9764.
25. Wilson, B. D., Ollmann, M. M., Kang, L., Stoffel, M., Bell, G. I., and Barsh, G. S. (1995) Structure and Function of ASP, the Human Homolog of the Mouse Agouti Gene. Hum Mol Genet. 4, 223-230.
26. Sakai, C., Ollmann, M., Kobayashi, T., Abdel-Malek, Z., Muller, J., Vieira, W. D., Imokawa, G., Barsh, G. S., and Hearing, V. J. (1997) Modulation of Murine Melanocyte Function in Vitro by Agouti Signal Protein. EMBO J. 16, 3544-3552.
27. Graham, A., Wakamatsu, K., Hunt, G., Ito, S., and Thody, A. J. (1997) Agouti Protein Inhibits the Production of Eumelanin and Phaeomelanin in the Presence and Absence of Alpha-Melanocyte Stimulating Hormone. Pigment Cell Res. 10, 298-303.
28. Siegrist, W., Drozdz, R., Cotti, R., Willard, D. H., Wilkison, W. O., and Eberle, A. N. (1997) Interactions of Alpha-Melanotropin and Agouti on B16 Melanoma Cells: Evidence for Inverse Agonism of Agouti. J Recept Signal Transduct Res. 17, 75-98.
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|Science Writers||Anne Murray|
|Authors||Sungyong Won, Xin Du, Christine Domingo, Bruce Beutler|