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

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

Oculocutaneous albinism (OCA) type 4 is a newly identified human autosomal recessive hypopigmentary disorder that disrupts pigmentation in the skin, hair and eyes. Three other forms of OCA have been previously characterized, each resulting from the aberrant processing and/or sorting of tyrosinase, the enzyme critical to pigment production in mammals. The disruption of tyrosinase trafficking occurs at the level of the endoplasmic reticulum (ER) in OCA1 and OCA3, but at the post-Golgi level in OCA2. The gene responsible for OCA4 is the human homologue of the mouse underwhite (uw) gene, which encodes the membrane-associated transporter protein (MATP). To characterize OCA4, we investigated the processing and sorting of melanogenic proteins in primary melanocytes derived from uw/uw mice and from wild-type mice. OCA4 melanocytes were found to be constantly secreted into the medium dark vesicles that contain tyrosinase and two other melanogenic enzymes, Tyrp1 (tyrosinase-related protein 1) and Dct (DOPAchrome tautomerase); this secretory process is not seen in wild-type melanocytes. Although tyrosinase was synthesized at comparable rates in wild-type and in uw-mutant melanocytes, tyrosinase activity in uw-mutant melanocytes was only about 20% of that found in wild-type melanocytes, and was enriched only about threefold in melanosomes compared with the ninefold enrichment in wild-type melanocytes. OCA4 melanocytes showed a marked difference from wild-type melanocytes in that tyrosinase was abnormally secreted from the cells, a process similar to that seen in OCA2 melanocytes, which results from a mutation of the pink-eyed dilution (P) gene. The P protein and MATP have 12 transmembrane regions and are predicted to function as transporters. Ultrastructural analysis shows that the vesicles secreted from OCA4 melanocytes are mostly early stage melanosomes. Taken together, our results show that in OCA4 melanocytes, tyrosinase processing and intracellular trafficking to the melanosome is disrupted and the enzyme is abnormally secreted from the cells in immature melanosomes, which disrupts the normal maturation process of those organelles. This mechanism explains the hypopigmentary phenotype of these cells and provides new insights into the involvement of transporters in the normal physiology of melanocytes.
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PMID:Tyrosinase processing and intracellular trafficking is disrupted in mouse primary melanocytes carrying the underwhite (uw) mutation. A model for oculocutaneous albinism (OCA) type 4. 1282 39

For proper melanin production, several specific enzymes such as tyrosinase, tyrosinase-related protein 1 (TRP-1) and dopachrome tautomerase are required. Their expressions are increased after exposure to UVB. However, it is not known how long tyrosinase and TRP-1 activities continue after UV irradiation in vivo. The purpose of this study is to measure the changes in expressions of tyrosinase, TRP1, and MITF after exposure to UV on skin in a Korean population. We established an immunohistochemical staining protocol for specimens which were obtained from UV-irradiated skin in five healthy Korean males on the 2nd, 5th, 7th, 28th, and 56th days after UV irradiation. Tyrosinase, TRP-1, and MITF expressions increased until 7 days after UV irradiation and then dropped to the basal constitutive level 4 and 8 weeks later. Interestingly, tyrosinase increased prior to TRP-1. This study reveals the time-sequence of melanin-synthesized enzymes and provides important information for the clinical evaluation of the effectiveness of whitening agents.
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PMID:The expression of melanogenic proteins in Korean skin after ultraviolet irradiation. 1457 56

Oculocutaneous albinism (OCA) is caused by a deficiency of melanin synthesis and characterized by generalized hypopigmentation of skin, hair, and eyes. Due to the hypopigmentation of the retinal pigment epithelium, OCA is usually associated with congenital visual impairment, in addition to an increased risk of skin cancer. OCA is a genetically heterogeneous disease with distinct types resulting from mutations in different genes involved in the pathway which results in pigmentation. OCA1 is associated with mutations in the TYR gene encoding tyrosinase. OCA2 results from mutations in the P gene encoding the P protein and is the most common form of OCA. OCA3, also known as rufous/red albinism, is caused by mutations in the TYRP1 gene, which encodes the tyrosinase-related protein 1. Recently, OCA4 was described as a new form of OCA in a single patient with a splice site mutation in the MATP gene (or AIM1), the human ortholog of the murine underwhite gene. The similarity of MATP to transporter proteins suggests its involvement in transport functions, although its actual substrate is still unclear. We screened 176 German patients with albinism for mutations within the MATP gene and identified five individuals with OCA4. In this first report on West European patients, we describe 10 so far unpublished mutations, as well as two intronic variations, in addition to two known polymorphisms.
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PMID:Mutations in the MATP gene in five German patients affected by oculocutaneous albinism type 4. 1472 13

The tyrosinase family comprises three members, tyrosinase (Tyr), tyrosinase-related protein 1 (Tyrp1), and dopachrome tautomerase (Dct). Null mutations and deletions at the Tyr and Tyrp1 loci are known and phenotypically affect coat color due to the absence of enzyme or intracellular mislocalization. At the Dct locus, three mutations are known that lead to pigmentation phenotype. However, these mutations are not null mutations, and we therefore set out to generate a null allele at the Dct gene locus by removing exon 1 of the mouse Dct gene. Mice deficient in Dct [Dct(tm1(Cre)Bee)] lack Dct mRNA and dopachrome tautomerase protein. They are viable and do not show any abnormalities in Dct-expressing sites such as skin, retinal pigment epithelium, or brain. However, the mice show a diluted coat color phenotype, which is due to reduced melanin content in hair. Primary melanocytes from Dct knockout mice are viable in culture and show a normal distribution of tyrosinase and tyrosinase-related protein 1. In comparison to the knockout, the slaty mutation (Dct(slt)/Dct(slt)) has less melanin and affects growth of primary melanocytes severely. In summary, we have generated a knockout of the Dct gene in mice with effects restricted to pigment production and coat color.
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PMID:Melanocytes and pigmentation are affected in dopachrome tautomerase knockout mice. 1506 Jan 60

The synthesis of melanin intermediates through tyrosinase (TYR) involves the production of cytotoxic free radicals. By using recombinant adenoviruses that express TYR, tyrosinase-related protein 1 (TYRP1) or DOPAchrome tautomerase (DCT), we analyzed the biological function of these proteins with regard to melanin production and the growth of melanocytes, fibroblasts, melanoma cells and nonmelanoma cancer cells. High-level expression of TYR produced newly synthesized melanin and induced cell death in all of these cells. However, when TYRP1 or DCT was coexpressed with TYR in melanocytes and melanoma cells, TYR-mediated cell death was clearly decreased. This decrease was not observed in nonmelanocytic cells. Western blot analysis and measurement of enzyme activity revealed that the expression of TYRP1 or DCT had little effect on the amount or activity of cointroduced TYR in either the melanocytic or nonmelanocytic cells. In cells expressing both TYR and TYRP1 or TYR and DCT, the total amount of melanin and/or eumelanin increased substantially more than that in cells expressing TYR alone. On the other hand, the level of pheomelanin was similar in these three cell types. These findings suggest that TYRP1 and DCT play an important role in suppressing TYR-mediated cytotoxicity in melanocytic cells without decreasing TYR expression and/or activity. These biological activities of TYRP1 and DCT may work through the interaction with TYR in melanosomal compartment.
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PMID:Tyrosinase-related proteins suppress tyrosinase-mediated cell death of melanocytes and melanoma cells. 1526 82

The secreted protein melanoma inhibitory activity (MIA) is highly expressed in malignant melanoma but not in melanocytes and is associated with tumor progression in vivo. Here, we further investigated the functional role of MIA by inhibiting MIA expression of the human melanoma cell line HMB2 via stable antisense MIA cDNA transfection, and subsequent analysis of the cell clones. MIA-deficient cell clones showed several changes in cell morphology and growth pattern. In monolayer and three-dimensional culture enhanced cell-cell contacts were formed. Furthermore, a re-induction of pigment synthesis in comparison with the amelanotic parental cell line HMB2 was observed. Molecular analyses revealed a re-expression of tyrosinase-related protein 1 (Trp-1) and tyrosinase in the MIA-deficient cell clones necessary for melanin synthesis. In accordance, re-expression of MIA in the MIA-deficient melanoma cell clones resulted in downregulation of Trp-1. To identify the molecular mechanisms of MIA regulating pigmentation, MITF and PAX3, two positive regulators of Trp-1 and tyrosinase transcription, and PIAS3, a negative regulator of MITF activity, were analyzed. Only in MIA-deficient cells, expression of PAX3 mRNA and MITF protein was found. In contrast, strong expression of PIAS3 was detected in HMB2 but not in the MIA-deficient cells. To our knowledge this is the first report demonstrating a correlation between MIA expression and pigmentation and morphology of melanocytic cells.
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PMID:Inhibition of melanoma inhibitory activity (MIA) expression in melanoma cells leads to molecular and phenotypic changes. 1576 Mar 34

We previously established a mouse neural crest cell line named NCCmelb4, which is positive for Kit and negative for tyrosinase. NCCmelb4 cells were useful to study the effects of extrinsic factors such as retinoic acids and vitamin D(3) on melanocyte differentiation, but in order to study the development of melanocytes from multipotent neural crest cells, cell lines of melanocyte progenitors in earlier developmental stages are needed. In the present study, we established an immortal cell line named NCCmelb4M5 that was derived from NCCmelb4 cells. NCCmelb4M5 cells do not express Kit and are immortal and stable in the absence of Kit ligand. They are positive for melanocyte markers such as tyrosinase-related protein 1 and DOPAchrome tautomerase and they contain stage I melanosomes. Interestingly, glial fibrillary acidic protein, which is a marker for glial cells, is also positive in NCCmelb4M5 cells, while NCCmelb4 cells are negative for this protein. Immunostaining and a cell ELISA assay revealed that 12-O-tetradecanoylphorbol 13-acetate (TPA) and cholera toxin (CT) induce Kit expression in NCCmelb4M5 cells. Real-time polymerase chain reaction analysis also demonstrated the induction of Kit mRNA by TPA and CT. Microphthalmia-associated transcription factor mRNA is simultaneously enhanced by the same treatment. Kit induced by TPA/CT in NCCmelb4M5 cells disappeared after the cells were subcultured and incubated without TPA/CT. These findings show that NCCmelb4M5 cells have the potential to differentiate into Kit-positive melanocyte precursors and may be useful to study mechanisms of development and differentiation of melanocytes in mouse neural crest cells.
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PMID:Establishment of a kit-negative cell line of melanocyte precursors from mouse neural crest cells. 1589 15

Ultraviolet radiation stimulates pigmentation in human skin, but the mechanism(s) whereby this increase in melanin production (commonly known as tanning) occurs is not well understood. Few studies have examined the molecular consequences of UV on human skin of various racial backgrounds in situ. We investigated the effects of UV on human skin of various races before and at different times after a single 1 minimal erythemal dose UV exposure. We measured the distribution of DNA damage that results, as well as the melanin content/distribution and the expression of various melanocyte-specific genes. The density of melanocytes at the epidermal:dermal junction in different types of human skin are remarkably similar and do not change significantly within 1 wk after UV exposure. The expression of melanocyte-specific proteins (including TYR (tyrosinase), TYRP1 (tyrosinase-related protein 1), DCT (tyrosinase-related protein 2), MART1 (melanoma antigens recognized by T-cells) gp100 (Pmel17/silver), and MITF (micropthalmia transcription factor)) increased from 0 to 7 d after UV exposure, but the melanin content of the skin increased only slightly. The most significant change, however, was a change in the distribution of melanin from the lower layer upwards to the middle layer of the skin, which was more dramatic in the darker skin. These results provide a basis for understanding the origin of different skin colors and responses to UV within different races.
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PMID:Mechanisms of skin tanning in different racial/ethnic groups in response to ultraviolet radiation. 1595 11

The cAMP-dependent pathway up-regulates MITF (microphthalmia-associated transcription factor), important for key melanogenic proteins such as tyrosinase, TRP-1 (tyrosinase-related protein 1) and TRP-2. We asked whether MITF is also a key transcription factor for PKC-beta (protein kinase C-beta), required to phosphorylate otherwise inactive tyrosinase. When paired cultures of human melanocytes were treated with isobutylmethylxanthine, known to increase intracellular cAMP, both protein and mRNA levels of PKC-beta were induced by 24 h. To determine whether MITF modulates PKC-beta expression, paired cultures of human melanocytes were transfected with dn-MITF (dominant-negative MITF) or empty control vector. By immunoblotting, PKC-beta protein was reduced by 63+/-3.7% within 48 h. Co-transfection of an expression vector for MITF-M, the MITF isoform specific for pigment cells, or empty control vector with a full-length PKC-beta promoter-CAT (chloramphenicol acetyltransferase) reporter construct (PKC-beta/CAT) into Cos-7 cells showed >60-fold increase in CAT activity. Melanocytes abundantly also expressed MITF-A, as well as the MITF-B and MITF-H isoforms. However, in contrast with MITF-M, MITF-A failed to transactivate co-expressed PKC-beta/CAT or CAT constructs under the control of a full-length tyrosinase promoter. Together, these results demonstrate that MITF, specifically MITF-M, is a key transcription factor for PKC-beta, linking the PKC- and cAMP-dependent pathways in regulation of melanogenesis.
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PMID:MITF mediates cAMP-induced protein kinase C-beta expression in human melanocytes. 1641 96


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