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Gene Review

Pmel  -  premelanosome protein

Mus musculus

Synonyms: D10H12S53E, D12S53Eh, Melanocyte protein PMEL, Melanocyte protein Pmel 17, Pmel17, ...
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Disease relevance of Si

  • The product of the Silver gene has since been discovered numerous times in different contexts, including the initial search for the tyrosinase gene, the characterization of major melanosome constituents in various species, and the identification of tumor-associated antigens from melanoma patients [1].
  • Immunization with human and mouse gp100 together [adenovirus type 2 (Ad2)-hgp100 plus recombinant vaccinia virus (rVV)-mgp100], or immunization with human gp100 (Ad2-hgp100) and boosting with heterologous vector (rVV-hgp100 or rVV-mgp100) or homologous vector (Ad2-hgp100), did not significantly enhance the protective response against B16 melanoma [2].
  • In contrast, immunization of mice with human gp100 using recombinant adenoviruses elicited T cells specific for hgp100, but these T cells also cross reacted with B16 tumor in vitro and induced significant but weak protection against B16 challenge [2].
  • Although a recombinant vaccinia virus (rVV) encoding the mouse homologue of gp100 was nonimmunogenic, immunization of normal C57BL/6 mice with the rVV encoding the human gp100 elicited a specific CD8(+) T cell response [3].
  • Full-length Pmel 17 cDNA also produced in insect cells in a baculovirus expression vector to ensure that activity did not originate from a co-precipitated protein [4].

High impact information on Si

  • A deletion in the first coding exon of the agouti gene was found associated with the proposed recessive allele of agouti in the darkly pigmented Standard Silver fox (aa) [5].
  • A constitutively activating C125R mutation in the MC1R was found specifically in darkly pigmented animals carrying the Alaska Silver allele (EA) [5].
  • The ability to induce specific T cells with human but not mouse gp100 resulted from differences within the major histocompatibility complex (MHC) class I-restricted epitope and not from differences elsewhere in the molecule, as was evidenced by experiments in which mice were immunized with rVV containing minigenes encoding these epitopes [3].
  • One way that the activity of such transcription factors is controlled is by the regulation of their movement between the cytosol and nucleus (Vandromme, M., C. Gauthier-Rouviere, N. Lamb, and A. Fernandez, 1996. Trends Biochem.Sci. 21:59-64; Lei, E.P. and P.A. Silver, 2002. Dev. Cell 2:261-272) [6].
  • The human Pmel 17 gene, designated D12S53E, maps to chromosome 12, region 12pter-q21; and the mouse homologue, designated D12S53Eh, maps to the distal region of mouse chromosome 10, a region also known to carry the coat color locus si (silver) [7].

Chemical compound and disease context of Si

  • We immunized the mice with a recombinant vaccinia virus encoding a form of gp100 that had been modified at position 210 (from a threonine to a methionine) to increase epitope binding to the restricting class I molecule [8].

Biological context of Si

  • Also predicted is the extension of the Pmel 17 protein by 12 residues because a new termination signal created downstream from the wild-type reading frame [9].
  • Pmel 17 cDNA clones, isolated from wild-type and si/si murine melanocyte cDNA libraries, were sequenced and compared [9].
  • No effects were observed with empty plasmid controls, DNA encoding the melanoma-associated antigen pmel17/gp100, the granulocyte-macrophage colony-stimulating factor GM-CSF, B7.1, or CpG-containing oligodeoxynucleotides [10].
  • In addition, administration of gp100+IL12/DCs, which were prepared by a relatively low dose of AdRGD-IL12, could induce more potent tumor-specific cellular immunity in the murine B16BL6 melanoma model than vaccination with gp100/DCs [11].
  • Analysis of these data, in conjunction with the results of our earlier study (Magnuson, T., Epstein, C. J., Silver, L. M., and Martin, G. R. (1982), Nature (London) 298, 750-753), suggests that homozygosity for the genes found in the tw5 haplotype does not reduce cell viability [12].

Anatomical context of Si

  • In situ hybridization (ISH) analysis of the murine melanosomal gene, Pmel17, demonstrated robust expression in the presumptive retinal pigmented epithelium (RPE) starting at E9.5, and in neural crest-derived melanoblasts starting at E10 [13].
  • Dorsally localized Pmel17-positive cells at the forebrain/midbrain and midbrain/hindbrain boundaries at E10.5 reveal migratory pathways for cranial melanoblasts that have not been previously described in mouse using Dct expression [13].
  • This laboratory has established in previous studies that Pmel 17, a gene expressed specifically in melanocytes, maps near the silver coat color locus (si/si) on mouse chromosome 10 [9].
  • The ability to load irradiated tumor cells was reproduced in two analogous human melanoma models using melanoma cell lines expressing gp100 and CTL clones specific for a gp100 melanoma antigen [14].
  • We suggest that in situ Pmel 17/silver is a component of a postulated premelanosomal/melanosomal complex of membrane-bound melanogenic oxidoreductive enzymes and cofactors, in analogy to the electron transfer chain in mitochondria [4].

Associations of Si with chemical compounds

  • Melan-si extracts are very efficient in catalyzing dihydroxyindole oxidation, in spite of being heterozygous for the TRP1 mutation, consistent with a stablin effect for the wild-type gp87 protein [15].
  • Mice immunized with gp100 DNA-HVJ-AVE liposomes survived longer compared with control mice immunized with HVJ-AVE liposome alone [16].
  • Maturation of gp100 into 150-180-kDa CBI-gp was inhibited if BF were chased in the presence of glucosidase inhibitors castanospermine or deoxynojirimycin [17].
  • Severe cytotoxicity was observed when testing powder extracts of Swedon, Fuji II, and Lining cement, whereas powder extracts of Ketac Silver, Fuji LC, and Super Bond induced slight to non-cytotoxicity [18].
  • Even for Silver Shield, the extent of protection was inadequate as illustrated by a risk assessment of the skin exposure situation [19].

Regulatory relationships of Si

  • Immune cell depletion experiments identified that CD4(+) T cells also played an important role in the priming phase of antitumor immunity and CD8(+) T lymphocytes were the primary effectors. gp100-specific CTL response were induced most markedly in the tumor-bearing mice immunized with IL-18/gp100-DC [20].

Other interactions of Si

  • Pmel17 expression is Mitf-dependent and reveals cranial melanoblast migration during murine development [13].
  • These cells express several pigment cell-specific genes that are thought or have been shown to be activated by MITF, including dautochrome tautomerase, pMel 17/Silver and tyrosinase-related protein-1, but lack expression of the MITF target gene tyrosinase, which encodes the rate-limiting enzyme in melanin synthesis [21].
  • Of these three mRNAs, Pmel17 mRNA is the most sensitive marker for detecting circulating melanoma cells compared with tyrosinase mRNA and TRP-2 mRNA [22].
  • Immunization with IL-18/gp100-DC resulted in tumor resistance in 87.5% of the mice challenged with B16 cells; however, 12.5% and 25% of mice immunized with gp100 gene-modified DC (gp100-DC) or IL-18 gene-modified DC (IL-18-DC) were tumor free, respectively [20].
  • Activation of tumor-specific CD8(+) pmel-1 T cells with IL-2 and vaccination with an altered peptide ligand caused regression of gp100-positive tumors (B16), but not gp100-negative tumors (methylcholanthrene 205), implanted on opposing flanks of the same mouse [23].

Analytical, diagnostic and therapeutic context of Si

  • Finally, the gp100-specific immune response measured in the peripheral blood of individual animals by real-time RT-PCR or ELISPOT showed a significant correlation with the response measured in the spleen (P=0.001) [24].
  • Induction of antigen-specific immune responses against malignant brain tumors by intramuscular injection of sindbis DNA encoding gp100 and IL-18 [25].
  • Immunogene therapy with the improved Sindbis virus vector expressing xenogeneic gp100 and syngeneic IL-18 may be an excellent approach for developing a new treatment protocol [25].
  • Adoptive T cell immunotherapy of human uveal melanoma targeting gp100 [26].
  • In ELISA all MAbs reacted with purified SDS-disrupted FIV and in flow cytometry all MAbs stained permeated, persistently infected FL4 cells but not unfixed FL4 cells; this indicated that the MAbs recognize essentially cryptic epitopes of the gp100 V3 loop [27].


  1. The Silver locus product Pmel17/gp100/Silv/ME20: controversial in name and in function. Theos, A.C., Truschel, S.T., Raposo, G., Marks, M.S. Pigment Cell Res. (2005) [Pubmed]
  2. Cloning and characterization of the genes encoding the murine homologues of the human melanoma antigens MART1 and gp100. Zhai, Y., Yang, J.C., Spiess, P., Nishimura, M.I., Overwijk, W.W., Roberts, B., Restifo, N.P., Rosenberg, S.A. J. Immunother. (1997) [Pubmed]
  3. gp100/pmel 17 is a murine tumor rejection antigen: induction of "self"-reactive, tumoricidal T cells using high-affinity, altered peptide ligand. Overwijk, W.W., Tsung, A., Irvine, K.R., Parkhurst, M.R., Goletz, T.J., Tsung, K., Carroll, M.W., Liu, C., Moss, B., Rosenberg, S.A., Restifo, N.P. J. Exp. Med. (1998) [Pubmed]
  4. Characterization and subcellular localization of human Pmel 17/silver, a 110-kDa (pre)melanosomal membrane protein associated with 5,6,-dihydroxyindole-2-carboxylic acid (DHICA) converting activity. Lee, Z.H., Hou, L., Moellmann, G., Kuklinska, E., Antol, K., Fraser, M., Halaban, R., Kwon, B.S. J. Invest. Dermatol. (1996) [Pubmed]
  5. A non-epistatic interaction of agouti and extension in the fox, Vulpes vulpes. Våge, D.I., Lu, D., Klungland, H., Lien, S., Adalsteinsson, S., Cone, R.D. Nat. Genet. (1997) [Pubmed]
  6. Nuclear export of OLIG2 in neural stem cells is essential for ciliary neurotrophic factor-induced astrocyte differentiation. Setoguchi, T., Kondo, T. J. Cell Biol. (2004) [Pubmed]
  7. A melanocyte-specific gene, Pmel 17, maps near the silver coat color locus on mouse chromosome 10 and is in a syntenic region on human chromosome 12. Kwon, B.S., Chintamaneni, C., Kozak, C.A., Copeland, N.G., Gilbert, D.J., Jenkins, N., Barton, D., Francke, U., Kobayashi, Y., Kim, K.K. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  8. Recombinant virus vaccination against "self" antigens using anchor-fixed immunogens. Irvine, K.R., Parkhurst, M.R., Shulman, E.P., Tupesis, J.P., Custer, M., Touloukian, C.E., Robbins, P.F., Yafal, A.G., Greenhalgh, P., Sutmuller, R.P., Offringa, R., Rosenberg, S.A., Restifo, N.P. Cancer Res. (1999) [Pubmed]
  9. Mouse silver mutation is caused by a single base insertion in the putative cytoplasmic domain of Pmel 17. Kwon, B.S., Halaban, R., Ponnazhagan, S., Kim, K., Chintamaneni, C., Bennett, D., Pickard, R.T. Nucleic Acids Res. (1995) [Pubmed]
  10. Long-lasting anti-metastatic efficiency of interleukin 12-encoding plasmid DNA. Schultz, J., Pavlovic, J., Strack, B., Nawrath, M., Moelling, K. Hum. Gene Ther. (1999) [Pubmed]
  11. Immunological properties and vaccine efficacy of murine dendritic cells simultaneously expressing melanoma-associated antigen and interleukin-12. Okada, N., Iiyama, S., Okada, Y., Mizuguchi, H., Hayakawa, T., Nakagawa, S., Mayumi, T., Fujita, T., Yamamoto, A. Cancer Gene Ther. (2005) [Pubmed]
  12. Establishment of embryonic stem cell lines from preimplantation mouse embryos homozygous for lethal mutations in the t-complex. Martin, G.R., Silver, L.M., Fox, H.S., Joyner, A.L. Dev. Biol. (1987) [Pubmed]
  13. Pmel17 expression is Mitf-dependent and reveals cranial melanoblast migration during murine development. Baxter, L.L., Pavan, W.J. Gene Expr. Patterns (2003) [Pubmed]
  14. Strategies for antigen loading of dendritic cells to enhance the antitumor immune response. Strome, S.E., Voss, S., Wilcox, R., Wakefield, T.L., Tamada, K., Flies, D., Chapoval, A., Lu, J., Kasperbauer, J.L., Padley, D., Vile, R., Gastineau, D., Wettstein, P., Chen, L. Cancer Res. (2002) [Pubmed]
  15. New insights on the structure of the mouse silver locus and on the function of the silver protein. Solano, F., Martínez-Esparza, M., Jiménez-Cervantes, C., Hill, S.P., Lozano, J.A., García-Borrón, J.C. Pigment Cell Res. (2000) [Pubmed]
  16. Protective immunization against melanoma by gp100 DNA-HVJ-liposome vaccine. Zhou, W.Z., Kaneda, Y., Huang, S., Morishita, R., Hoon, D. Gene Ther. (1999) [Pubmed]
  17. Processing and transport of a lysosomal membrane glycoprotein is developmentally regulated in African trypanosomes. Kelley, R.J., Brickman, M.J., Balber, A.E. Mol. Biochem. Parasitol. (1995) [Pubmed]
  18. Cytotoxicity of liquids and powders of chemically different dental materials evaluated using dimethylthiazol diphenyltetrazolium and neutral red tests. Lönnroth, E.C., Dahl, J.E. Acta Odontol. Scand. (2003) [Pubmed]
  19. Permeation of Telone EC through protective gloves. Zainal, H., Que Hee, S.S. Journal of hazardous materials. (2005) [Pubmed]
  20. Effective induction of therapeutic antitumor immunity by dendritic cells coexpressing interleukin-18 and tumor antigen. Xia, D., Zheng, S., Zhang, W., He, L., Wang, Q., Pan, J., Zhang, L., Wang, J., Cao, X. J. Mol. Med. (2003) [Pubmed]
  21. Signaling and transcriptional regulation in the neural crest-derived melanocyte lineage: interactions between KIT and MITF. Hou, L., Panthier, J.J., Arnheiter, H. Development (2000) [Pubmed]
  22. Detection of circulating melanoma cells by RT-PCR amplification of three different melanocyte-specific mRNAs in a mouse model. Tsukamoto, K., Hirata, S., Osada, A., Kitamura, R., Shimada, S. Pigment Cell Res. (2000) [Pubmed]
  23. Vaccine-stimulated, adoptively transferred CD8+ T cells traffic indiscriminately and ubiquitously while mediating specific tumor destruction. Palmer, D.C., Balasubramaniam, S., Hanada, K., Wrzesinski, C., Yu, Z., Farid, S., Theoret, M.R., Hwang, L.N., Klebanoff, C.A., Gattinoni, L., Goldstein, A.L., Yang, J.C., Restifo, N.P. J. Immunol. (2004) [Pubmed]
  24. Analysis of cellular immune responses in the peripheral blood of mice using real-time RT-PCR. Hempel, D.M., Smith, K.A., Claussen, K.A., Perricone, M.A. J. Immunol. Methods (2002) [Pubmed]
  25. Induction of antigen-specific immune responses against malignant brain tumors by intramuscular injection of sindbis DNA encoding gp100 and IL-18. Yamanaka, R., Xanthopoulos, K.G. DNA Cell Biol. (2005) [Pubmed]
  26. Adoptive T cell immunotherapy of human uveal melanoma targeting gp100. Sutmuller, R.P., Schurmans, L.R., van Duivenvoorde, L.M., Tine, J.A., van Der Voort, E.I., Toes, R.E., Melief, C.J., Jager, M.J., Offringa, R. J. Immunol. (2000) [Pubmed]
  27. Epitope mapping of the V3 domain of feline immunodeficiency virus envelope glycoprotein by monoclonal antibodies. Lombardi, S., Massi, C., Tozzini, F., Zaccaro, L., Bazzichi, A., Bandecchi, P., La Rosa, C., Bendinelli, M., Garzelli, C. J. Gen. Virol. (1995) [Pubmed]
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