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)

Antigen expression in melanoma is heterogeneous. Immunophenotyping using a panel of monoclonal antibodies may facilitate immunotherapy. An immunoblot procedure was developed to detect antigens in melanoma cells. Numerous monoclonal antibodies were tested to determine if (1) antigens were detected after transfer to membranes, (2) single bands or discrete multiple bands were obtained, (3) co-incubation of multiple monoclonal antibodies had no interference, and (4) banding patterns were non-overlapping. Antigens were selected based upon their association with melanoma and the availability of respective monoclonal antibodies. Antigens were melanoma antigen recognized by T-cells (MART-1), tyrosinase, tyrosinase-related protein 1 (TRP-1), S100, vimentin, glycoprotein 130 (gp130), a carcinoembryonic antigen (CEA)-like marker, KBA-62 and NKI-C3. Actin positive controls could be assessed simultaneously. Test samples were separated by polyacrylamide gel electrophoresis in a 4-15% polyacrylamide gradient, transferred to polyvinylidine fluoride membrane, blotted using a Fast-Blot apparatus (Pierce), and developed using diaminobenzidine/metal. Melanoma cell lines were immunophenotyped using this panel immunoblot, and were compared to a standard control and to non-melanoma cells. Up to four antigens could be detected simultaneously in a single lane of the immunoblot, using a single test sample of greater than 100000 cells.
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PMID:A panel immunoblot using co-incubated monoclonal antibodies for identification of melanoma cells. 1122 74

Zinc alpha-2-glycoprotein is secreted by a variety of normal and malignant epithelial cells and overexpression by tumors has been implicated in cancer cachexia. To investigate biologic properties of zinc alpha-2-glycoprotein further, stable transfectants of recombinant human zinc alpha-2-glycoprotein were created in the B16F10 murine melanoma cell line. Both B16-recombinant human zinc alpha-2-glycoprotein clones with strong expression of zinc alpha-2-glycoprotein and vector-transfected B16 cells treated with exogenous zinc alpha-2-glycoprotein had decreased melanin production in vitro. Furthermore, B16-recombinant human zinc alpha-2-glycoprotein clones formed amelanotic tumors in vivo, despite their melanin production in vitro. Although no qualitative differences in tyrosinase mRNA expression could be detected by reverse transcription-polymerase chain reaction, B16-recombinant human zinc alpha-2-glycoprotein tumors had decreased levels of tyrosinase protein and minimal tyrosinase activity. Purified zinc alpha-2-glycoprotein also decreased tyrosinase activity in vector-transfected B16 tumor sections in vitro. Taken together, these studies demonstrate that zinc alpha-2-glycoprotein inhibits melanin production by B16 melanoma cells via post-transcriptional effects on tyrosinase protein. As zinc alpha-2-glycoprotein decreases melanin synthesis more strongly in vivo than in vitro, however, it is likely that zinc alpha-2-glycoprotein affects melanin synthesis through indirect mechanisms as well. Zinc alpha-2-glycoprotein also inhibits melanin production by melan-A primary melanocytes in vitro. As zinc alpha-2-glycoprotein is normally produced by epidermal keratinocytes, these studies raise the possibility that epidermal-derived zinc alpha-2-glycoprotein may play a part in normal regulation of melanin production in vivo, in addition to its previously described role in cancer cachexia.
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PMID:Zinc alpha-2-glycoprotein regulates melanin production by normal and malignant melanocytes. 1219 Aug 71

Periodate-lysine-paraformaldehyde (PLP) has been proposed as a fixative for glycoprotein antigens which should stabilize periodate oxidized polysaccharide chains through lysine mediated crosslinks, either directly or by the intermediation of formaldehyde. In spite of premises and attempts reported in the literature, this fixative has never become popular for the study of membrane antigens of immune system cells, which leads to doubts on its real efficacy. We have addressed this issue in biopsies of human skin and found that PLP followed by cryoprotection with 30% sucrose and cryosectioning, or PLP fixation of isolated epidermal sheets, consistently provided for good preservation of morphology and intense labeling of major histocompatibility complex class II molecules, CD 1 a, CD4, CD8, E-cadherin, cytokeratins in general, cytokeratin-18 in particular, and bromodeoxyuridine, incorporated by cycling cells in vitro, and for the demonstration of tyrosinase enzyme activity. PLP-fixed, osmicated and epon-embedded epidermal sheets proved as good as sheets fixed with a mixture of formaldehyde and glutaraldehyde for electron microscopic morphological analysis. Also, these sheets were amenable to immunoperoxidase staining of Langerhans cell membrane antigen CD1a and keratinocyte membrane antigen E-cadherin before being osmicated and prepared for electron microscopy. In a parallel paper, we had also shown that oral mucosa biopsies fixed in PLP showed good morphology and immunolabeling of CD54, CD80, CD83 and CD86. Therefore, we conclude that PLP can be proposed as a multi-task fixative for light and electron microscopic analysis of membrane, cytoplasmic and nuclear antigens of immune system cells and keratinocytes.
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PMID:Use of periodate-lysine-paraformaldehyde for the fixation of multiple antigens in human skin biopsies. 1259 22

Tyrosinase is a glycoprotein responsible for the synthesis of melanin in melanocytes. A large number of mutations have been identified in tyrosinase, with many leading to its misfolding, endoplasmic reticulum (ER) retention, and degradation. Here we describe the folding and maturation of human tyrosinase (TYR) using an in vitro translation system coupled with ER-derived microsomes or with semipermeabilized cells, as an intact ER source. TYR remained misfolded as determined by its sensitivity to trypsin digestion and its persistent interaction with the ER resident lectin chaperones calnexin and calreticulin when produced in ER-derived microsomes or nonmelanocytic semipermeabilized cells. However, when TYR was translocated into semipermeabilized melanocytes, chaperone interactions were transient, maturation progressed to a trypsin-resistant state, and a TYR homodimer was formed. The use of semipermeabilized mouse melanocytes defective for tyrosinase or other melanocyte-specific proteins as the ER source indicated that proper TYR maturation and oligomerization were greatly aided by the presence of wild type tyrosinase and tyrosinase-related protein 1. These findings suggested that oligomerization is a step in proper TYR maturation within the ER that requires melanocyte-specific factors.
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PMID:Tyrosinase maturation and oligomerization in the endoplasmic reticulum require a melanocyte-specific factor. 1272 9

Cinnamoyl, p-coumaroyl, feruloyl, caffeoyl aloesin, and related compounds were isolated from Aloe species. The antiinflammatory and antioxidative activities of these compounds were examined based on the structure-activity relationship. It was suggested that the bioactivities may link to acyl ester groups in aloesin, together with those of aloesin-related compounds. However, investigations using the contact hypersensitivity response indicated a preventive effect of aloesin on the UV-B-induced immune suppression. Furthermore, aloesin inhibited tyrosine hydroxylase and dihydroxyphenylalanine (DOPA) oxidase activities of tyrosinase from normal human melanocyte cell lysates. These results show that aloesin prevents not only UV-B-induced immune suppression, but also could be a positive pigment-altering agent for cosmetic application. In preclinical study, aloe extract was investigated using phagocytosis and nitroblue tetrazolium chloride (NBT) reduction in adult bronchial asthma, and high molecular-weight materials, such as polysaccharide and glycoprotein fractions, were identified as active ingredients. The neutral polysaccharides, aloemannan and acemannan showed antitumor, antiinflammatory and immunosuppressive activities, and glycoprotein fractions with bradykinindegrading and cell proliferation-stimulating activities were identified from the nondialysate fraction of the gel part of Aloe species. Verectin fractionated from Aloe vera gel was examined biochemically and immunochemically, and verectin antibody was used in the appraisal of commercial Aloe vera gel products. It was reported that aloesin stimulates the proliferation of cultured human hepatoma SK-Hep 1 cells. Thus aloesin, related compounds, and high molecular-weight materials, such as aloemannan and verectin, may act in concert to exert therapeutic properties for wounds, burns and inflammation. The biodisposition of fluoresceinylisothiocyanate (FITC)--labeled aloemannan (FITC-AM) with the homogenate from some organs in mice was demonstrated, and FITC-AM was metabolized to a smaller molecule (MW 3000) by the large intestinal microflora in feces. The modified aloe polysaccharide (MW: 80000) with cellulase under restricted conditions, immunologically stimulated the recovery of UV-B-induced tissue in jury. Thus the modified polysaccharides of aloemannan, together with acemannan (MW: about 600000), are expected to participate in biological activity following oral administration. The effects of tanshinone VI, a diterpenoid isolated from Salvia miltiorrhiza, on the heart are reviewed. First, the effects on the posthypoxic recovery of contractile function of perfused rat hearts were examined. Hypoxia/reoxygenation induced a release of purine nucleosides and bases (ATP metabolites) and resulted in little recovery of contractile force of reoxygenated hearts. Pretreatment of the perfused heart with 42 nM tanshinone VI under hypoxic conditions attenuated the release of ATP metabolites during hypoxia/reoxygenation. Treatment with tanshinone VI enhanced the posthypoxic recovery of myocardial contractility. These results show that tanshinone VI may protect the heart against hypoxia/reoxygenation injury and improve the posthypoxic cardiac function. Second, the effects of tanshinone VI on in vitro myocardial remodeling were examined. Cardiomyocytes and cardiac fibroblasts were isolated from neonatal rat hearts, and simultaneously prepared insulin-like growth factor-1 (IGF-1) induced the hypertrophy of cardiomyocytes. IGF-1 increased the collagen synthesis of cardiac fibroblasts, that is, in vitro fibrosis. The hypertrophy of cardiomyocytes was attenuated in the presence of tanshinone VI in the culture medium. The fibrosis of cardiac fibroblasts was decreased by treatment with tanshinone VI. When tanshinone VI was added to cardiac fibroblast-conditioned medium, the medium-mediated hypertrophy of cardiomyocytes was also attenuated. These results show that tanshinone VI may attenuate in vitro cardiac remodeling. The series of studies has shown that tanshinone VI protects the myocardium against hypoxia/reoxygenation injury and attenuates progression of in vitro myocardial remodeling, suggesting that tanshinone VI is a possible agent for the treatment of cardiac disease with contractile failure.
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PMID:[Anti-inflammatory constituents, aloesin and aloemannan in Aloe species and effects of tanshinon VI in Salvia miltiorrhiza on heart]. 1287 35

Transmembrane domains (TMDs) are known as structural elements required for the insertion into the membrane of integral membrane proteins. We have provided here an example showing that the presence of the TMD is compulsory for the productive folding pathway of a membrane-anchored glycoprotein. Tyrosinase, a type I transmembrane protein whose insertion into the melanosomal membrane initiates melanin synthesis, is misfolded and degraded when expressed as a truncated polypeptide. We used constructs of tyrosinase ectodomain fused with chimeric TMDs or glycosylphosphatidylinositol anchor to gain insights into how the TMD enables the productive folding pathway of the ectodomain. We found that in contrast to the soluble constructs, the membrane-anchored chimeras fold into the native conformation, which allows their endoplasmic reticulum exit. They recruit calnexin to monitor their productive folding pathway characterized by the post-translational formation of buried disulfides. Lacking calnexin assistance, the truncated mutant is arrested in an unstable conformation bearing exposed disulfides. We showed that the transmembrane anchor of a protein may crucially, albeit indirectly, control the folding pathway of the ectodomain.
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PMID:Productive folding of tyrosinase ectodomain is controlled by the transmembrane anchor. 1673 54

Tyrosinase, a copper-containing glycoprotein, is the rate-limiting enzyme critical for melanin biosynthesis in specialized organelles termed melanosomes that are produced only by melanocytic cells. Inhibitors of tyrosinase activity have long been sought as therapeutic means to treat cutaneous hyperpigmentary disorders. Multiple potential approaches exist that could control pigmentation via the regulation of tyrosinase activity, for example: the transcription of its messenger RNA, its maturation via glycosylation, its trafficking to melanosomes, as well as modulation of its catalytic activity and/or stability. However, relatively little attention has been paid to regulating pigmentation via the stability of tyrosinase, which depends on its processing and maturation in the endoplasmic reticulum and Golgi, its delivery to melanosomes and its degradation via the ubiquitin-proteasome pathway and/or the endosomal/lysosomal system. Recently, it has been shown that carbohydrate modification, molecular chaperone engagement, and ubiquitylation all play pivotal roles in regulating the degradation/stability of tyrosinase. While such processes affect virtually all proteins, such effects on tyrosinase have immediate and dramatic consequences on pigmentation. In this review, we classify melanogenic inhibitory factors in terms of their modulation of tyrosinase function and we summarize current understanding of how the quality control of tyrosinase processing impacts its stability and melanogenic activity.
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PMID:Approaches to identify inhibitors of melanin biosynthesis via the quality control of tyrosinase. 1721 41

Proteins and certain carbohydrates contain phenolic moieties, which are potential sites for modification of the function of the biopolymers. In this study, the capability of two different fungal oxidative enzymes, laccase from Trametes hirsuta (ThL) and tyrosinase from Trichoderma reesei (TrT), to catalyze formation of hetero-cross-linking between tyrosine side chains of alpha-casein and phenolic acids of hydrolyzed oat spelt xylan (hOSX) was studied. Formation of reaction products was followed by size exclusion chromatography (SEC), fluorescence spectroscopy, and SDS-PAGE, using specific staining methods for proteins and protein-carbohydrate conjugates. ThL and TrT were observed to differ significantly in their ability to catalyze the formation of protein-carbohydrate conjugates or the linking of the small molecular weight phenolic compounds to alpha-casein. The efficiency of these enzymes to directly cross-link protein also differed notably. TrT was able to cross-link alpha-casein more efficiently than ThL. ThL-catalyzed casein cross-linking was significantly enhanced by ferulic acid, p-coumaric acid, and also hOSX. The main reaction products by ThL appeared to be phenolic acid-bridged alpha-caseins. Indications of hetero-cross-link formation between alpha-casein and hOSX by both oxidative enzymes could be visualized by glycoprotein-specific staining in the SDS-PAGE analysis, although ThL was observed to be more effective in the heteroconjugate formation than TrT.
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PMID:Formation of protein-oligosaccharide conjugates by laccase and tyrosinase. 1842 26

Tyrosinase is a rate-limiting enzyme in mammalian melanogenesis, and is known as a glycoprotein. Post-translational processing of mammalian tyrosinase is required for its folding, sorting, and for enzymatic activity. Here we show for the first time that the mammalian tyrosinase has beta1,6-branched N-glycan structure that can be recognized by binding with specific lectin Leukoagglutinating phytohematoagglutinin (L-PHA). Further, this specific glycoconjugate structure has been shown to have a function relationship in melanin synthesis.
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PMID:Evidence for tyrosinase as a beta1,6 branch containing glycoprotein: substrate of GnT-V. 1865 94

The pathogenic mechanisms of intraocular inflammation had not been well studied until Wacker and his colleagues found retinal soluble antigen (S antigen) and established experimental autoimmune uveitis (EAU), an animal model for autoimmune uveitis. Using this animal model, great progress in understanding the immunopathogenic mechanisms of uveitis was achieved not only in EAU, but also in many inflammatory disorders in humans. Intraocular inflammation is mediated by activated CD4+ T cells. However, the eye has a unique regional immune system which protects intraocular tissues from these pathogenic activated CD4+ T cells and contributes to the homeostasis of the intraocular microenvironment. In the present review article, the role of T cells in immunopathogenic mechanisms of ocular inflammatory disorders as well as in the regional defense system of the eye is highlighted. 1. Immunopathogenic mechanisms of EAU: Experiments using athymic nude rats as well as adoptive transfer of EAU by S-antigen-sensitized T lymphocytes into naive Lewis rats disclosed that T lymphocytes, particularly CD4+ T lymphocytes, play a central role in the immunopathogenic mechanisms of EAU. In addition, immunopharmacological studies showing the intense effects of cyclosporine on EAU with selective immunosuppression to T lymphocytes allowed us to use clinically the agent to treat patients with refractory uveitis of non-infectious origins, such as Behcet's disease. 2. Immunopathogenic mechanisms of uveitis in human: Two clinical uveitis entities commonly seen in Japan, i. e. Vogt-Koyanagi-Harada (VKH) disease and human T-cell leukemia virus type 1 (HTLV-1) uveitis, were studied for their pathogenic mechanisms. (1) VKH disease: We established T cell clones from infiltrating cells in the eyes of VKH patients using limiting dilution methods. CD4+ T cell clones from VKH disease, but not from other uveitis entities, responded to tyrosinase, a melanocyte-associated antigen, and produced inflammatory cytokines, and the response was specific to tyrosinase. Furthermore, DataBank analysis disclosed that tyrosinase had a structural homology with an exogenous antigen, a glycoprotein peptide of cytomegalovirus (CMV). CD4+ T lymphocytes from VKH patients, but not from other diseases, which responded to both tyrosinase and CMV peptide. This indicates that molecular mimicry between CMV peptide and tyrosinase plays an important role in the immunopathogenic mechanisms by which CD4+ T lymphocytes are sensitized to autoantigen of tyrosinase and cause inflammation in VKH disease. (2) HTLV-1 uveitis: Similar to adult T cell leukemia and HTLV-1 associated myelopathy, uveitis in asymptomatic carriers of HTLV-1, prevalent in southern Kyushu, is a distinct clinical entity associated with HTLV-1, a human retrovirus. We analyzed ocular infiltrating cells and found that (a) HTLV-1-infected CD4+ T lymphocytes were significantly accumulated in the eye, and (b) HTLV-1-infected CD4+ T lymphocytes produced a large amount of various inflammatory cytokines. Thus, CD4+ T lymphocytes play a central role in the pathogenic mechanisms of HTLV-1 uveitis. 3. Regional defense system of the eye: As described above, CD4+ T lymphocytes made active by either autoantigens or exogenous pathogens, enter the eye and cause inflammatory responses. However, the eye is known to be an immune privileged site. We focused on ocular pigment epithelial cells because they form a blood-ocular barrier, and they may protect the eye immunologically from infiltrating inflammatory cells. Our major findings by in vitro experiments in mice are (a) ocular pigment epithelial cells have the capacity to suppress activated CD4+ T lymphocytes; (b) the mode of action of iris pigment epithelial cells (IPE) and retinal pigment epithelial cells (RPE) are different: T lymphocyte suppression by IPE requires cell-to-cell contact, whereas suppression by RPE requires soluble factors, but not cell-to-cell contact; (c) both IPE and RPE have the capacity to generate regulatory T cells(Treg), thereby enhancing immune regulation in the eye. In conclusion, CD4+ T lymphocytes activated by either autoantigens or infectious agents play a central role in the pathogenic mechanisms of ocular inflammation, and ocular resident cells such as IPE and RPE suppress the pathogenic activated CD4+ T lymphocytes, thereby contributing to homeostasis of the eye.
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PMID:[Intraocular inflammation and homeostasis of the eye]. 1934 83


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