Medicine:PMEL (gene)
 Generic protein structure example |
Melanocyte protein PMEL also known as premelanosome protein (PMEL), silver locus protein homolog (SILV) or Glycoprotein 100 (gp100), is a protein that in humans is encoded by the PMEL gene.[1][2] Its gene product may be referred to as PMEL, silver, ME20, gp100 or Pmel17.
Structure and function
PMEL is a 100 kDa, 661 amino acids long type I transmembrane glycoprotein that is expressed primarily in melanosomes, which are the melanin-producing organelles in melanocytes of pigment cells of the skin and eye, and in most malignant melanomas.
This protein is involved in melanosome maturation, including melanogenesis, melanosome biogenesis, and melanin polymerization (Eisenberg) [1]. The transmembrane form of PMEL is modified in the secretory pathway by elaboration of N-linked oligosaccharides and addition and modification of O-linked oligosaccharides. It is then targeted to precursors of the pigment organelle, the melanosome, where it is proteolytically processed to several small fragments. Some of these fragments form non-pathological amyloid that assemble into sheets and form the striated pattern that underlies melanosomal ultrastructure. PMEL cleavage is mediated by several proteases including a proprotein convertase of the furin family, a "sheddase" that might include members of the a disintegrin and metalloproteinase (ADAM) family, and additional proteases in melanosomes or their precursors. After the amyloidogenic region is cleaved, the small remaining integral membrane fragment is digested by γ-secretase.
The expression of the PMEL gene is regulated by the microphthalmia-associated transcription factor (MITF).[3][4]
Function in cancer and cancer treatment
The gp100 protein is a melanoma antigen i.e. a tumor-associated antigen.
Short fragments of it have been used to develop the gp100 cancer vaccine which is or contains gp100:209-217(210M).[5]
Hydrophilic recombinant gp100 protein (HR-gp100) has been topically applied on human intact skin in vitro, and used as a vaccine in a mouse model. It was demonstrated that HR-gp100 permeates into human skin, and is processed and presented by human dendritic cells. In the mouse model, an HR-gp100-based vaccine triggered antigen-specific T cell responses, as shown by proliferation assays, ELISA and intracellular staining for IFN-γ.
The gp100 protein contains differentiation antigens.[2], and has been widely studied to be used as a target for melanoma immunotherapy. Different sequences of the GP100 peptide could be used for immunization against tumors. According to a case study, modifications of GP100, such as GP100-209 and GP100-208, have shown a greater number of antigen-specific CTL's (cytotoxic T lymphocytes), which can target and kill cancer cells (Eisenberg).[3]
References
- ↑ "Genomic organization and FISH mapping of human Pmel 17, the putative silver locus". Pigment Cell Res 9 (1): 42–8. Oct 1996. doi:10.1111/j.1600-0749.1996.tb00085.x. PMID 8739560.
- ↑ "Entrez Gene: SILV silver homolog (mouse)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6490.
- ↑ "MLANA/MART1 and SILV/PMEL17/GP100 are transcriptionally regulated by MITF in melanocytes and melanoma". Am. J. Pathol. 163 (1): 333–43. 2003. doi:10.1016/S0002-9440(10)63657-7. PMID 12819038.
- ↑ "Novel MITF targets identified using a two-step DNA microarray strategy". Pigment Cell Melanoma Res. 21 (6): 665–76. 2008. doi:10.1111/j.1755-148X.2008.00505.x. PMID 19067971.
- ↑ "NCI Drug Dictionary". https://www.cancer.gov/publications/dictionaries/cancer-drug.
- Eisenberg, G; Machlenkin, A; Frankenburg, S; Mansura, A; Pitcovski, J; Yefenof, E; Peretz, T; Lotem, M.Sharett (2010). "Transcutaneous immunization with hydrophilic recombinant gp100 protein induces antigen-specific cellular immune response". Cell Immunol 266 (1): 98–103. doi:10.1016/j.cellimm.2010.09.003. PMID 20947070.
Further reading
- "Structural characterization of SIL, a gene frequently disrupted in T-cell acute lymphoblastic leukemia.". Mol. Cell. Biol. 11 (11): 5462–9. 1991. doi:10.1128/mcb.11.11.5462. PMID 1922059.
- "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.". Proc. Natl. Acad. Sci. U.S.A. 88 (20): 9228–32. 1991. doi:10.1073/pnas.88.20.9228. PMID 1924386. Bibcode: 1991PNAS...88.9228K.
- "Site-specific recombination of the tal-1 gene is a common occurrence in human T cell leukemia.". EMBO J. 9 (10): 3343–51. 1990. doi:10.1002/j.1460-2075.1990.tb07535.x. PMID 2209547.
- Guillaume van Niel et al. (2015). "Apolipoprotein E Regulates Amyloid Formation within Endosomes of Pigment Cells". Cell Reports 13 (1): 43–51. doi:10.1016/j.celrep.2015.08.057. PMID 26387950.
- "Molecular characterization of the melanocyte lineage-specific antigen gp100.". J. Biol. Chem. 269 (31): 20126–33. 1994. doi:10.1016/S0021-9258(17)32136-1. PMID 7519602.
- "Identification of a human melanoma antigen recognized by tumor-infiltrating lymphocytes associated with in vivo tumor rejection.". Proc. Natl. Acad. Sci. U.S.A. 91 (14): 6458–62. 1994. doi:10.1073/pnas.91.14.6458. PMID 8022805. Bibcode: 1994PNAS...91.6458K.
- "Cloning and expression of the gene for the melanoma-associated ME20 antigen.". DNA Cell Biol. 13 (2): 87–95. 1994. doi:10.1089/dna.1994.13.87. PMID 8179825.
- "Genomic organization and sequence of D12S53E (Pmel 17), the human homologue of the mouse silver (si) locus.". J. Invest. Dermatol. 106 (1): 24–7. 1996. doi:10.1111/1523-1747.ep12326976. PMID 8592076.
- "Polymerization of 5,6-dihydroxyindole-2-carboxylic acid to melanin by the pmel 17/silver locus protein.". Eur. J. Biochem. 236 (1): 180–8. 1996. doi:10.1111/j.1432-1033.1996.t01-1-00180.x. PMID 8617263.
- "Molecular detection of tumor-associated antigens shared by human cutaneous melanomas and gliomas.". Am. J. Pathol. 150 (6): 2143–52. 1997. PMID 9176405.
- "Analysis of Pmel17/gp100 expression in primary human tissue specimens: implications for melanoma immuno- and gene-therapy.". Cancer Immunol. Immunother. 44 (4): 239–47. 1997. doi:10.1007/s002620050379. PMID 9222283.
- "Polymerase chain reaction detection of melanoma cells in the circulation: relation to clinical stage, surgical treatment, and recurrence from melanoma.". J. Clin. Oncol. 16 (5): 1760–9. 1998. doi:10.1200/JCO.1998.16.5.1760. PMID 9586889.
- "Translation of a retained intron in tyrosinase-related protein (TRP) 2 mRNA generates a new cytotoxic T lymphocyte (CTL)-defined and shared human melanoma antigen not expressed in normal cells of the melanocytic lineage.". J. Exp. Med. 188 (6): 1005–16. 1998. doi:10.1084/jem.188.6.1005. PMID 9743519.
- "Detection of melanoma micrometastases in the sentinel lymph node and in nonsentinel nodes by tyrosinase polymerase chain reaction.". J. Invest. Dermatol. 113 (4): 554–9. 1999. doi:10.1046/j.1523-1747.1999.00719.x. PMID 10504440.
- "Distinct protein sorting and localization to premelanosomes, melanosomes, and lysosomes in pigmented melanocytic cells.". J. Cell Biol. 152 (4): 809–24. 2001. doi:10.1083/jcb.152.4.809. PMID 11266471.
- "Production of melanocyte-specific antibodies to human melanosomal proteins: expression patterns in normal human skin and in cutaneous pigmented lesions.". Pigment Cell Res. 14 (4): 289–97. 2002. doi:10.1034/j.1600-0749.2001.140410.x. PMID 11549113.
- "Pmel17 initiates premelanosome morphogenesis within multivesicular bodies.". Mol. Biol. Cell 12 (11): 3451–64. 2002. doi:10.1091/mbc.12.11.3451. PMID 11694580.
- "Identification of a novel gp100/pMel17 peptide presented by HLA-A*6801 and recognized on human melanoma by cytolytic T cell clones.". Tissue Antigens 59 (4): 273–9. 2003. doi:10.1034/j.1399-0039.2002.590404.x. PMID 12135425.
- "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. 2003. doi:10.1073/pnas.242603899. PMID 12477932. Bibcode: 2002PNAS...9916899M.
External links
- Overview of all the structural information available in the PDB for UniProt: P40967 (Melanocyte protein PMEL) at the PDBe-KB.
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