Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Tyrosinase and tyrosinase-related protein-1 (TRP-1) are two melanogenic enzymes that regulate melanin biosynthesis. Both are glycoproteins and belong to the TRP-1 gene family. They share a significant level of sequence similarity in several regions, including the catalytic domain and the potential N-glycosylation sites. We have recently shown that inhibition of the early steps of N-glycan processing in B16F1 cells dramatically affects tyrosinase activity and melanin synthesis. We present here results on N-glycan processing of TRP-1 and tyrosinase and compare the maturation process and activity of both glycoproteins in the presence of inhibitors of the endoplasmic reticulum stages of N-glycosylation. N-glycan analysis reveals that each of these two glycoproteins contains a mixture of high-mannose and sialylated complex N-glycans. However, in contrast to TRP-1, tyrosinase presents a homogeneous high-mannose glycoform, also. In the presence of alpha-glucosidases inhibitors, the maturation of tyrosinase N-glycans is completely inhibited, whereas TRP-1 is still able to acquire some complex glycans, indicating that endomannosidase acts preferentially on the later glycoprotein. In addition, the dopa-oxidase activity of tyrosinase is totally abolished, whereas for TRP-1 it is only partially affected. The results suggest that despite their structural similarity, tyrosinase is more sensitive than TRP-1 to perturbations of early N-glycan processing, in terms of maturation and catalytical activity.
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PMID:Protein specific N-glycosylation of tyrosinase and tyrosinase-related protein-1 in B16 mouse melanoma cells. 1058 52

Self-antigens, in the form of differentiation antigens, are commonly recognized by the immune system on melanoma and other cancers. We have shown previously that active immunization of mice against the melanocyte differentiation antigen, a tyrosinase-related protein (TRP) gp75(TRP-1) (the brown locus protein) expressed by melanomas, could induce tumor immunity and autoimmunity manifested as depigmentation. In this system, tumor immunity and autoimmunity were mediated by autoantibodies. Here, we characterize immunity against another tyrosinase family glycoprotein TRP-2 (the slaty locus protein), using the same mouse model and method of immunization. As observed previously for gp75(TRP-1), immunity was induced by DNA immunization against a xenogeneic form of TRP-2, but not against the syngeneic gene, and depended on CD4(+) cells. Immunization against TRP-2 induced autoantibodies and autoreactive cytotoxic T cells. In contrast to immunization against gp75(TRP-1), both tumor immunity and autoimmunity required CD8(+) T cells, but not antibodies. Only autoimmunity required perforin, whereas tumor immunity proceeded in the absence of perforin. Thus, immunity induced against two closely related autoantigens that are highly conserved throughout vertebrate evolution involved qualitatively different mechanisms, i.e., antibody versus CD8(+) T cell. However, both pathways led to tumor immunity and identical phenotypic manifestations of autoimmunity.
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PMID:Coupling and uncoupling of tumor immunity and autoimmunity. 1058 62

Several HLA-A*0201-restricted peptide epitopes that can be used as targets for active immunotherapy have been identified within melanocyte differentiation proteins. However, uncertainty exists as to the most effective way to elicit CD8+ T cells with these epitopes in vivo. We report the use of transgenic mice expressing a derivative of HLA-A*0201, and dendritic cells, to enhance the activation of CD8+ T cells that recognize peptide epitopes derived from human tyrosinase and glycoprotein 100. We find that by altering the cell surface density of the immunizing peptide on the dendritic cells, either by pulsing with higher concentrations of peptide, or by changing the MHC-peptide-binding affinity by generating variants of the parent peptides, the size of the activated CD8+ T cell populations can be modulated in vivo. Significantly, the density of peptide that produced the largest response was less than the maximum density achievable through short-term peptide pulsing. We have also found, however, that while some variant peptides are effective at eliciting both primary and recall CD8+ T cell responses that can recognize the parental epitope, other variant epitopes lead to the outgrowth of CD8+ T cells that only recognize the variant. HLA-A*0201 transgenic mice provide an important model to define which peptide variants are most likely to stimulate CD8+ T cell populations that recognize the parental, melanoma-specific peptide.
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PMID:The density of peptides displayed by dendritic cells affects immune responses to human tyrosinase and gp100 in HLA-A2 transgenic mice. 1067 70

Melanin, the phenolic biopolymer that serves as a skin- and hair pigment-protecting agent against harmful solar radiation and a free radical trap, is biosynthesized in animals mainly by the action of tyrosinase also known as phenoloxidase. Regulation of tyrosinase and hence melanogenesis is vital for all animals. In this report, we present the isolation and characterization of a new, heat-labile glycoprotein inhibitor of phenoloxidase from the larvae of Manduca sexta. The inhibitor was isolated from the live larval cuticle by buffer extraction and purified to homogeneity employing ammonium sulfate precipitation, dialysis, and concanavalin A-Sepharose chromatography. It migrated with a molecular weight of 380,000 on SDS-PAGE gels and inhibited the activity of insect and plant as well as fungal phenoloxidases. Inhibitor formed a tight complex with phenoloxidases, which resisted dissociation even by 1% Triton X-100 or SDS. Selective inhibition of phenoloxidase, while acting on certain but not all different substrates, was observed. The physiological importance of this newly discovered high-molecular-weight phenoloxidase inhibitor is discussed.
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PMID:Characterization of a new phenoloxidase inhibitor from the cuticle of Manduca sexta. 1067 12

Two different melanocyte-specific mRNAs are studied as markers for circulating melanoma cells in vitro using the human melanoma cell line G361 and in vivo using blood samples from Japanese melanoma patients at different clinical stages. These mRNAs encode tyrosinase, the most essential enzyme for melanin synthesis, and gp100, a melanosomal matrix glycoprotein recognized by monoclonal antibody HMB-45. We used reverse-transcription polymerase chain reaction (RT-PCR) to detect tyrosinase mRNA and gp100 mRNA in peripheral blood. Since melanocytes would not normally be present in peripheral blood, the detection of those transcripts should indicate the presence of circulating melanoma cells. RT-PCR detection of these two mRNAs was highly sensitive and specific. Our in vitro study showed that as few as 10 melanoma cells in 0.125 ml normal blood could be detected. In in vivo study, 130 blood samples from 55 melanoma patients gave positive and variably sensitive results, whereas no samples from healthy controls or patients with other cancers gave positive results. Tyrosinase mRNA was not detected in any of the melanoma patients. gp100 mRNA was detected in 12 of 55 melanoma patients, in none of five stage I patients (0%), in four of 26 stage II patients (15.4%), in one of six stage III patients (16. 7%) and in seven of 18 stage IV patients (38.9%). Thus gp100 mRNA is a more sensitive marker for detecting circulating melanoma cells compared with tyrosinase mRNA.
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PMID:gp100 mRNA is more sensitive than tyrosinase mRNA for RT-PCR amplification to detect circulating melanoma cells in peripheral blood of melanoma patients. 1080 30

The intracellular vesicular trafficking in the melanosome biogenesis (melanogenesis) is reviewed with the incorporation of our own experimental findings. The melanosome biogenesis involves four stages of melanosome maturation, which reflect the transport of structural and enzymatic proteins from Golgi (trans-Golgi network: TGN) to the melanosomal compartment and their organization therein. The major melanosomal proteins include tyrosinase gene family protein (tyrosinase and tyrosinase-related protein; TRP), lysosome-associated membrane protein (Lamp) and gp100 (pmel 17). They are glycosylated in the endoplasmic reticulum, and transported by vesicles from the TGN to the melanosomal compartment. During the formation of transport vesicles, they assemble on the cytoplasmic face of the TGN to select cargo by interacting directly or indirectly with coat proteins. Tyrosinase and TRP-1 possess the dileucine motifs at the cytoplasmic domain, to which adapter protein-3 binds to transport them from the TGN to stage I melanosomes (related to late endosomes) and then to stage II melanosomes. A number of small guanosine triphosphate-binding proteins, including rab 7, appear to be involved in this vesicular transport. Phosphatidyl inositol 3 kinase also regulates this membrane trafficking of melanosomal glycoprotein. Eumelanogenesis is controlled by melanocyte-stimulating hormone, and all three tyrosinase gene family proteins are transported from the TGN to stage II melanosomes that are elliposoidal and contain the structural matrix of filaments/lamellae. In contrast, pheomelanogenesis is primarily regulated by agouti signal protein, and only tyrosinase is transported from stage I melanosomes to stage II melanosomes that are spherical and related to lysosomes. Because of the absence of TRP-1 and TRP-2 in pheomelanogenesis, it may be suggested that tyrosinase is involved in lysosomal degradation after forming dopaquinone, to which the cysteine present in the lysosomal granule binds to form cysteinyldopas that will then be auto-oxidized to become pheomelanin.
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PMID:Intracellular vesicular trafficking of tyrosinase gene family protein in eu- and pheomelanosome biogenesis. 1104 67

Aurones are plant flavonoids that provide yellow color to the flowers of some popular ornamental plants, such as snapdragon and cosmos. In this study, we have identified an enzyme responsible for the synthesis of aurone from chalcones in the yellow snapdragon flower. The enzyme (aureusidin synthase) is a 39-kilodalton, copper-containing glycoprotein catalyzing the hydroxylation and/or oxidative cyclization of the precursor chalcones, 2',4',6',4-tetrahydroxychalcone and 2',4',6',3,4-pentahydroxychalcone. The complementary DNA encoding aureusidin synthase is expressed in the petals of aurone-containing varieties. DNA sequence analysis revealed that aureusidin synthase belongs to the plant polyphenol oxidase family, providing an unequivocal example of the function of the polyphenol oxidase homolog in plants, i.e., flower coloration.
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PMID:Aureusidin synthase: a polyphenol oxidase homolog responsible for flower coloration. 1107 55

Diagnostic records from 338 canine oral melanomas in 338 dogs received at the Veterinary Medical Diagnostic Laboratory (1992-1999) were reviewed. Of these tumors, 122 plus an additional 7 metastatic melanomas of unknown origin were selected for clinical follow-up, histologic review, and immunohistochemistry. Chow Chow, Golden Retriever, and Pekingese/Poodle mix breeds were overrepresented, whereas Boxer and German Shepherd breeds were underrepresented. There was no gender predisposition and the average age at presentation was 11.4 years. Forty-nine dogs were euthanized due to recurrence or metastasis. The average postsurgical survival time was 173 days. The gingiva and the labial mucosa were the most common sites. Most tumors were composed of either polygonal cells (27 cases, 20.9%), spindle cells (44 cases, 34.1%), or a mixture of the two (polygonal and spindle) (54 cases, 41.9%). Clear cell (3 cases, 2.3%) and adenoid/papillary (1 case, 0.8%) patterns were uncommon. The metastases of 6/6 oral melanomas had morphologic and immunohistochemical features similar to those of the primary tumors. Immunohistochemically, Melan A was detected in 113/122 oral (92.6%) and 5/7 (71.9%) metastatic melanomas. Only 4/163 nonmelanocytic tumors were focally and weakly positive for Melan A. Antibodies against vimentin, S100 protein, and neuron-specific enolase stained 129 (100%), 98 (76%), and 115 (89.1%) of 129 melanomas, respectively. Antibodies against other melanocytic-associated antigens (tyrosinase, glycoprotein 100) did not yield adequate staining. We conclude that Melan A is a specific and sensitive marker for canine melanomas.
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PMID:Retrospective study of 338 canine oral melanomas with clinical, histologic, and immunohistochemical review of 129 cases. 1110 49

Typically, melanocytic nevi "mature" (i.e., exhibit a morphologic shift to smaller or spindle cells with progressive depth in the dermis). In contrast, most malignant melanomas (conventional MMs) lack maturation, and are composed of large pleomorphic cells throughout. The authors describe a series of melanomas with paradoxical maturation mimicking the pattern of nevi. Seventeen primary invasive melanomas with paradoxical maturation (IMPs), two epidermotropic metastatic melanomas with maturation (EMMMs), 13 compound nevi (CN), and 14 conventional MMs without apparent maturation were analyzed by histologic, cytomorphometric, and immunohistochemical techniques. With increasing dermal depth, both CN and IMPs had smaller nuclear and cellular areas, and decreased expression of Ki-67, glycoprotein (gp)100 (with HMB-45), and tyrosinase. IMPs had significant differences from conventional MMs; namely, smaller nuclear and cytoplasmic areas (deep), and decreased expression of Ki-67 (superficial and deep), gp100 (deep), and tyrosinase (deep). IMPs also had notable differences from CN: namely, larger nuclear and cellular areas, more confluence, more mitotic figures, increased Ki-67 and gp100 expression in both the superficial and deep portions, and more melanin (deep). The two EMMMs exhibited histologic and immunohistochemical features similar to the primary IMPs. IMP, because of its mimicry of nevus, can present a diagnostic hazard. The authors propose histologic, morphometric, and immunohistochemical criteria that facilitate recognition and accurate diagnosis of this unusual variant of melanoma.
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PMID:Malignant melanoma with paradoxical maturation. 1111 80

A single polypeptide protein of molecular weight 66kDa (MP 66), purified to homogeneity from melanosomes of normal human cadaver skin epidermal melanocytes, was further characterized. Based on the yield in the present investigation, the intracellular concentration of this protein was calculated to be 4.2 microM. It was shown to be a glycoprotein on gel electrophoresis. Based on its partial N-terminal amino acid sequence, it was shown to be distinct from known melanosomal proteins such as gp 75, tyrosinase-related protein-2 (TRP-2) and Pmel 17. Investigation to purify a similar type of protein from B16 murine melanoma tumours by following the same purification procedure resulted in a partially purified protein with a molecular weight of 66 kDa. However, unlike MP 66, this protein did not show inhibition of the monophenolase activity of tyrosinase at pH 6.8. Finally, the effects of 0.5 mM each of CaCl2, ZnSO4 and FeSO4 together, and of human skin epidermal melanosomal proteins, were studied on melanin polymerization at pH 4.7. The metal cations failed to initiate melanin polymerization, while melanosomal proteins did in a dose-dependent manner.
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PMID:Partial characterization of an abundant human skin melanosomal 66 kDa protein (MP 66) and investigation to purify a similar protein from B16 murine melanoma tumours. 1119 72


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