Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.10.3.1 (tyrosinase)
 9,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Melanocytes preferentially express an mRNA species, Pmel 17, whose protein product cross-reacts with anti-tyrosinase antibodies and whose expression correlates with the melanin content. We have now analyzed the deduced protein structure and mapped its chromosomal location in mouse and human. The amino acid sequence deduced from the nucleotide sequence of the Pmel 17 cDNA showed that the protein is composed of 645 amino acids with a molecular weight of 68,600. The Pmel 17 protein contains a putative leader sequence and a potential membrane anchor segment, which indicates that this may be a membrane-associated protein in melanocytes. The deduced protein contains five potential N-glycosylation sites and relatively high levels of serine and threonine. Three repeats of a 26-amino acid motif appear in the middle of the molecule. 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).
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PMID: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. 192 86

Two groups of cDNA clones were isolated by screening a lambda gt11 cDNA library of normal human melanocytes with antityrosinase antibodies: one group of 13 was related to the human tyrosinase gene. The properties of the other group of three cDNA clones was investigated by the use of a representative clone, Pmel 17-1. The cDNA hybridized to an mRNA species of approximately 2600 bases from human and murine melanocytes. The transcript of Pmel 17-1 (17-1 mRNA) was expressed preferentially in melanocytes and its abundance paralleled the melanin content. The expression of Pmel 17-1 mRNA increased after stimulation of human and murine melanoma cells with agents that increase the levels of melanization. Immunocompetition assays with monoclonal antibodies to gp75, a known pigmentation-associated antigen of melanocytes, suggested that Pmel 17-1 encodes a 75,000 Mr glycoprotein that is highly abundant in melanotic cells and shares some immunological homology with tyrosinase. The gene for Pmel 17-1 did not map at or near the c-albino locus in mice. The cDNA of Pmel 17-1 detected a single hybridizing restriction fragment in both human and murine DNA, indicating that the gene has been conserved between these two species and exists as a single gene in each.
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PMID:A melanocyte-specific complementary DNA clone whose expression is inducible by melanotropin and isobutylmethyl xanthine. 244 95

Four melanoma proteins, MART-1, gp100, tyrosinase, and tyrosinase-related protein-1 (gp75) were evaluated for recognition by HLA-A2-restricted melanoma-specific cytotoxic T lymphocytes (CTLs) derived from the tumor-infiltrating lymphocytes (TIL) of 10 different patients. 9 of 10 TIL recognized MART-1, 4 recognized gp100 (including 3 that also recognized MART-1), but none of the TIL recognized tyrosinase or gp75. Based on the known HLA-A2.1 peptide binding motifs, 23 peptides from MART-1 were synthesized in an attempt to identify the epitopes recognized by TIL. Three peptides were recognized by TIL when pulsed on T2 target cells. One of the 9-mer peptides, AAGIGILTV, was most effective in sensitizing the T2 cells for TIL lysis. This peptide was recognized by 9 of 10 HLA-A2-restricted melanoma-specific CTLs. Therefore, this peptide appears to be a very common immunogenic epitope for HLA-A2-restricted melanoma-specific TIL and may be useful for the development of immunotherapeutic strategies.
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PMID:Identification of the immunodominant peptides of the MART-1 human melanoma antigen recognized by the majority of HLA-A2-restricted tumor infiltrating lymphocytes. 751 11

MHC class I-restricted CTLs specific for antigens expressed by malignant cells are an important component of immune responses against human cancer. Recently, in melanoma a number of melanocyte differentiation antigens have been identified as potential tumor rejection antigens. In the present study, we show that by applying peptide-loaded dendritic cells, induced by granulocyte-macrophage colony-stimulating factor and interleukin 4 from peripheral blood monocytes of healthy donors, we were able to elicit melanoma-associated antigen-specific CTL in vitro. We demonstrate the induction of CTLs directed against HLA-A2.1 presented epitopes derived from tyrosinase, gp100, and Melan A/MART-1. Apart from lysis of peptide-loaded target cells, these CTLs displayed reactivity with HLA-A2.1+ melanoma tumor cell lines and cultured normal melanocytes endogenously expressing the target antigen. These data indicate that these CTLs recognize naturally processed and presented epitopes and that precursor CTLs against melanocyte differentiation antigens are present in healthy individuals. The ability to generate tumor-specific CTLs in vitro, using granulocyte-macrophage colony-stimulating factor/interleukin 4-induced dendritic cells, illustrates the potential use of this type of antigen-presenting cells for vaccination protocols in human cancer.
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PMID:Generation of antimelanoma cytotoxic T lymphocytes from healthy donors after presentation of melanoma-associated antigen-derived epitopes by dendritic cells in vitro. 758 96

Tyrosinase (EC 1.14.18.1), the key enzyme in melanin synthesis, has been shown to be one of the targets for cytotoxic T-cell recognition in melanoma patients. To develop serological reagents useful for immunophenotyping melanoma for tyrosinase, human tyrosinase cDNA was expressed in an Escherichia coli expression vector. The purified recombinant tyrosinase was used to generate mouse monoclonal and rabbit polyclonal antibodies. The prototype monoclonal antibody, T311, recognized a cluster of protein moieties ranging from 70 to 80 kDa in tyrosinase mRNA-positive melanoma cell lines and melanoma specimens as well as in L cells transfected with tyrosinase cDNA. Untransfected L cells and L cells transfected with tyrosinase-related protein 1, TRP-1(gp75), were nonreactive. Immunohistochemical analysis of melanomas with T311 showed tyrosinase in melanotic and amelanotic variants, and tyrosinase expression correlated with the presence of tyrosinase mRNA. Melanocytes in skin stained with T311, whereas other normal tissues tested were negative. The expression pattern of three melanosome-associated proteins--tyrosinase, TRP-1(gp75), and gp100--in melanoma was also compared. Tyrosinase and gp100 are expressed in a higher percentage of melanomas than TRP-1(gp75), and the expression of these three antigens was discordant. Tyrosinase expression within individual tumor specimen is usually homogenous, distinctly different from the commonly observed heterogeneous pattern of gp100 expression.
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PMID:Immunophenotyping of melanomas for tyrosinase: implications for vaccine development. 766 56

Four of ten HLA-A2-restricted melanoma specific CTL that were derived from tumor-infiltrating lymphocytes (TIL) and administered to patients recognized the gp100 melanoma Ag and nine of ten recognized the MART-1 Ag. Adoptive transfer of the four gp100-reactive CTL, but not the other TIL, resulted in tumor regression when infused into autologous patients along with IL-2. Tumor regression was thus correlated with the recognition of gp100 by the administered T cells (p = 0.0048). To identify the epitopes recognized by these four gp100-reactive CTL, 169 peptides containing HLA-A2.1 binding motifs were synthesized and screened for their recognition by TIL using cytotoxicity and IFN-gamma release assays. Five gp100 epitopes (two for TIL620, three for TIL660, one for TIL1143, and two for TIL1200) were recognized by CTL derived from different patients. Five of eight HLA-A2 binding melanoma epitopes (five gp100, one MART-1/Melan-A, two tyrosinase) had intermediate binding affinity to HLA-A2.1. These gp100 epitopes may be responsible for mediating tumor rejection in vivo and thus may be useful for the development of immunotherapies for patients with melanoma.
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PMID:Recognition of multiple epitopes in the human melanoma antigen gp100 by tumor-infiltrating T lymphocytes associated with in vivo tumor regression. 770 34

The silver mutation in mice causes progressive graying of hair due to the loss of functional follicular melanocytes. Recently the silver locus gene (called Pmel 17) has been cloned; its encoded product shares homology with a chick melanosomal matrix protein and a bovine retinal pigment epithelial protein. Although the sequence of the silver gene and the correlation of its expression with pigment production have been reported, its function in melanogenesis is still unknown. In an effort to characterize that function, we have synthesized the predicted carboxyl-terminal peptide of the mouse Pmel 17 protein and generated a rabbit polyclonal antibody (alpha PEP13) to it; that antibody recognized the silver protein specifically. The immunoaffinity-purified silver protein lacked all of the known melanogenic catalytic activities which other tyrosinase-related proteins (TRP) have, nor did it appear to modulate any of those TRP activities. Metabolic labeling experiments demonstrated that the silver protein disappears in vivo within a few hours, indicating that it is rapidly degraded, or quickly processed to lose its carboxyl terminus. Cross-reactivity experiments showed that a recently reported anti-melanosomal matrix protein antibody (alpha MX) also recognizes the silver protein, although at a different epitope from that of alpha PEP13. Using Western immunoblotting, we analyzed subcellular fractions isolated from B16 F10 melanoma cells and found that the silver protein was rich in the melanosome fraction but was absent from coated vesicles which deliver TRPs to melanosomes. These results suggest that the silver locus product is a melanosomal matrix protein which may contribute to melanogenesis as a structural protein, although the possibility remains that it also has a novel catalytic function in melanogenesis.
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PMID:The Pmel 17/silver locus protein. Characterization and investigation of its melanogenic function. 796 86

Two groups of S-[2-(N,N-dialkylamino)ethyl]isothiourea derivates which depigmented melanoma cells either with inhibition of tyrosinase (group 1, R = methyl, isopropyl) or without inhibition of tyrosinase (group 2, R = benzyl, phenyl) were studied. Treatment of human melanoma cells with non-lethal doses of group 1 drugs led to a reduction in the levels of mRNA for the pigmentation genes tyrosinase, tyrosinase-related protein-1 and Pmel 17. The group 1 drug S-[2-N,N-diisopropylamino)ethyl[isothiourea] (DINOR) (R = isopropyl) produced only moderate inhibition of DNA, RNA and protein synthesis in three cell lines during the first 24 hr of treatment, and there was no correlation between the extent of inhibition and long-term toxicity. A group 2 drug (R = benzyl) rapidly inhibited DNA synthesis in an amelanotic melanoma cell line (MM96E) sensitive to killing by the drug; association of the latter with inhibition of RNA or protein synthesis was less clear. MM96E cells were also sensitive to killing by reactive oxygen species. In pigmented melanoma cells (MM418), incorporation of [125I]thiouracil, a false precursor of melanin, increased during the first 24 hr of treatment with DINOR whereas a group 2 drug (R = phenyl) inhibited incorporation of [125I]thiouracil. Cells depigmented by treatment with drugs from either group suffered the same amount of DNA damage as pigmented cells after UVB irradiation, as judged by inhibition of DNA synthesis, but did not recover as well as pigmented cells, whether or not drug was present during recovery. The results suggested that (1) group 1 agents down-regulated message for several pigmentation genes, possibly at the transcriptional level; (2) the toxicity of group 2 drugs was related to reactive oxygen species; and (3) melanin protected cells from UVB by enhancing cellular recovery.
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PMID:Reduction of DNA synthesis, pigment synthesis, pigmentation gene mRNA and resistance to UVB in human melanoma cells treated with analogues of a histamine (H2) agonist. 804 13

Cell lineage-specific cellular proteins, oncogenes from viral or cellular origin and tumor suppressor genes encode tumor-specific/associated antigens. Such antigens can elicit an major compatibility complex (MHC) class I-restricted cytotoxic T lymphocyte (CTL) response, either naturally in cancer patients or following appropriate immunostimulation (in vitro or in vivo). The reported immune responses in humans to the melanoma-associated MAGE gene products, GP100 and tyrosinase, all self-proteins, support the idea to use wild-type p53 products as targets for T cells. An important step towards this goal is identification of potential p53 CTL epitopes. We identified the wild-type p53 peptides with the highest affinity to the HLA-A*0201 molecule using two assays: the previously described MHC peptide-binding assay and the peptide competition assay. We obtained CTL against four p53 peptides with a high affinity for the HLA-A*0201 molecule. These findings are discussed next to a short review concerning the p53 literature.
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PMID:p53, a potential target for tumor-directed T cells. 808 74

We propose that at least two families of genes regulate the melanin biosynthesis. The first is the tyrosinase gene family, which is comprised of tyrosinase (c locus), gp75 (b locus) and DOPAchrome tautomerase (slt locus). The second is the pmel 17 gene family, which is composed of pmel 17 (putative si locus) and chicken melanosomal matrix protein (MMP) 115. It appears that the tyrosinase gene family regulates melanin synthesis in the proximal steps of the melanin biosynthetic pathway and the pmel 17 gene family might be important at distal steps of the pathway.
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PMID:Pigmentation genes: the tyrosinase gene family and the pmel 17 gene family. 843 98


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