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)

Mitf encodes a basic helix-loop-helix-leucine-zipper (bHLHzip) protein that is known to function in the development of melanocytes, pigmented epithelial cells (PECs), osteoclasts, and mast cells. In this paper, we report on the isolation, expression, and overexpression of the chicken Mitf and discuss the role of its protein product in the differentiation and transdifferentiation of PECs. Northern blotting showed that chicken Mitf is predominantly expressed in embryonic retinal pigmented epithelium (PE), but is expressed at low levels in other tissues. A 5' RACE analysis revealed differences in the 5' region Mitf nRNA in PE and other tissues. Immunological analysis revealed that Mitf, the protein encoded by Mitf, is first detected in the nuclei of the optic vesicle cells at embryonic stage 13 in a restricted region covered with mesenchymal cells. From stage 14 to 24, the specific staining is observable in the PE and precursor of the PE, the outer layer of the optic cup. In embryos at stages later than stage 29 the signals for Mitf in the future iris, ciliary body, and posterior retinal regions become faint. These results show that expression of Mitf starts at the optic vesicle stage at which no other marker genes for PECs such as mmp115 and tyrosinase are expressed. Dedifferentiation of cultured retinal PECs (rPECs) was induced by phenylthiourea and testicular hyaluronidase, bFGF, or TGF-beta. Mitf expression was inhibited by these factors and reactivated during redifferentiation of the dedifferentiated cells into rPECs, showing the correlation between Mitf expression and rPEC differentiation. Retrovirus-mediated overexpression of Mtif inhibited bFGF-induced dedifferentiation and transdifferentiation of rPECs to both lens and neural cells. These findings showed that downregulation of Mitf expression is essential for the transdifferentiation of rPEC. Mitf overexpression caused hyperpigmentation in cultured rPECs and suppressed the changes in gene expression induced by bFGF. Mitf overexpression promoted expression of mmp115 and tyrosinase in bFGF-treated rPECs suggesting a critical role for Mitf in rPEC differentiation. Mitf overexpression, however, did not promote expression of another rPEC-specific gene, pP344, in bFGF-treated rPECs. This result suggests the presence of other regulatory genes promoting rPEC differentiation. The expression patterns of pax6 and Mitf are complementary both in vivo in vitro. Overexpression of Mitf inhibited expression of pax6 in cultured rPECs. These observations suggest that Mitf regulates pax6 expression negatively.
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PMID:Role of Mitf in differentiation and transdifferentiation of chicken pigmented epithelial cell. 946 87

The mouse microphthalmia (Mitf) gene encodes a basic-helix-loop-helix-zipper transcription factor whose mutations are associated with abnormalities in neuroepithelial and neural crest-derived melanocytes. In wild type embryos, Mitf expression in neuropithelium and neural crest precedes that of the melanoblast marker Dct, is then co-expressed with Dct, and gradually fades away except in cells in hair follicles. In embryos with severe Mitf mutations, neural crest-derived Mitf-expressing cells are rare, lack Dct expression, and soon become undetectable. In contrast, the neuroepithelial-derived Mitf-expressing cells of the retinal pigment layer are retained, express Dct, but not the melanogenic enzyme genes tyrosinase and Tyrp1, and remain unpigmented. The results show that melanocyte development critically depends on functional Mitf and that Mitf mutations affect the neural crest and the neuroepithelium in different ways.
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PMID:Mutations in microphthalmia, the mouse homolog of the human deafness gene MITF, affect neuroepithelial and neural crest-derived melanocytes differently. 951 32

An ectopic neural retina is formed at the outer layer of the retina in the silver homozygote (B/B) of the Japanese quail. In situ hybridization and immunohistochemical analysis revealed that cells in the outer layer of retina first expressed a pigment-cell-specific gene, mmp115, and then began to express a neural marker in B/B embryos, indicating that the ectopic neural retina is formed via transdifferentiation of differentiated pigmented epithelial cells (PECs). An in vitro study revealed that cultured retinal PECs (rPECs) from B/B embryos exhibit less pigment granule and a higher growth rate than cells from heterozygotes (B/+). B/+ PECs stopped proliferating when confluency was reached, while B/B PECs continued to proliferate. Some B/B cells overlaid other B/B cells and formed lentoid bodies. Immunological analysis revealed that B/B rPECs transdifferentiated to lens cells and neural cells in vitro with no addition of basic FGF (bFGF), while B/+ rPECs required bFGF to transdifferentiate. Expression of PEC-specific genes, mmp115, tyrosinase, and TRP-1, was downregulated, but that of Mitf and pax6 was upregulated in B/B PECs. Antibody against Mitf stained the nucleus of B/+ PECs but not that of B/B cells, suggesting that the normal Mitf is not present in the silver homozygote due to mutation. Sequence analysis revealed that Mitf from the silver homozygote has an amino acid substitution in the basic region and is truncated in the C-terminal region. Transient transfection analysis revealed that Mitf from the silver homozygote exhibits a lower level of activity than wild-type Mitf with respect to transactivation of the mmp115 promoter. Furthermore, overexpression of chicken Mitf induced normal pigmentation in B/B rPECs. These results strongly suggest that the silver phenotype is caused by the mutation of Mitf and that Mitf plays a critical role in rPEC differentiation and transdifferentiation.
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PMID:Spontaneous transdifferentiation of quail pigmented epithelial cell is accompanied by a mutation in the Mitf gene. 957 28

Mitf (Microphthalmia transcription factor), a basic-helix-loop-helix zipper protein, encoded at the microphthalmia (Mitf) locus, regulates the transcription of the gene encoding tyrosinase, the rate-limiting enzyme in melanin biosynthesis, by binding the DNA sequence CATGTG. This binding site is present also in the genes encoding two tyrosinase related proteins, TRP-1 and TRP-2. To gain insight into the function of Mitf in vivo, we determined whether there was a difference in the levels of these proteins in the RPE/choroid of the vitiligo (Mitfvit) mouse, in which there is a mutation of the Mitf gene. This mouse has alteration of RPE pigmentation and function that presumably leads to slow progressive loss of photoreceptor cells. The RPE/choroid was dissected from eyes of vitiligo and C57BL/6 wild-type mice at postnatal ages 2, 4, 7, 10, 14, 21 and 42 days. Extracts of pooled tissues were subjected to electrophoresis and immunoblotting. The levels of tyrosinase, TRP-1 and TRP-2 were determined densitometrically following immunodetection with rabbit antipeptide antisera. In addition, the tyrosine hydroxylase activity of tyrosinase as assayed radiometrically. Levels of TRP-1 were 3-7 fold greater in control RPE/choroid compared with mutants. This marked difference in protein level was observed at the earliest age examined (P2) and persisted throughout the first two weeks. Tyrosinase levels in mutants were similar to controls at P2 and P4, but were reduced at P10 and beyond. Tyrosinase activity was diminished also in mutants by P10. Levels of TRP-2 were similar between mutants and controls, although the typical decrease seen in controls after P14 was attenuated in the mutant mice. There is a significant reduction in the level of TRP-1 in the RPE/choroid of the Mitfvit mouse. The data suggests that transcription of the gene encoding TRP-1 is extremely dependent upon functional Mitf. It provides in vivo evidence that Mitf regulates the transcription of the gene encoding TRP-1 as well as tyrosinase.
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PMID:Expression of tyrosinase and the tyrosinase related proteins in the Mitfvit (vitiligo) mouse eye: implications for the function of the microphthalmia transcription factor. 959 34

Genetic and cell culture analyses have shown that the development of melanocytes from neural crest-derived precursor cells critically depends on the tyrosine kinase receptor KIT and the basic-helix-loop-helix-leucine zipper transcription factor MITF. KIT and MITF show complex interactions in that MITF is needed for the maintenance of Kit expression in melanoblasts and KIT signaling modulates MITF activity and stability in melanocyte cell lines. Using primary neural crest cell cultures from embryos homozygous for a Kit null allele marked by an inserted LacZ gene (Kit(W-LacZ)), we show that the onset of Mitf expression in melanoblasts does not require KIT. In fact, provided that the melanocyte growth factor endothelin-3 is present, a small number of MITF/beta-Gal-positive cells can be maintained for at least 2 weeks in Kit(W-LacZ)/Kit(W-LacZ) cultures. These cells express several pigment cell-specific genes that are thought or have been shown to be activated by MITF, including dautochrome tautomerase, pMel 17/Silver and tyrosinase-related protein-1, but lack expression of the MITF target gene tyrosinase, which encodes the rate-limiting enzyme in melanin synthesis. Consequently, the cells remain unpigmented. Addition of cholera toxin, which elevates cAMP levels and mimics part of the KIT signaling pathway, increases the number of MITF-positive cells in Kit(W-LacZ)/Kit(W-LacZ) cultures, leads to tyrosinase expression, and induces the differentiation of melanoblasts into mature, pigmented melanocytes. Even when added on day 5-6 of culture, cholera toxin still rescues tyrosinase expression and differentiation. The results thus demonstrate that the presence of MITF is not sufficient for tyrosinase expression in melanoblasts and that KIT signaling influences gene expression during melanocyte development in a gene-selective manner.
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PMID:Signaling and transcriptional regulation in the neural crest-derived melanocyte lineage: interactions between KIT and MITF. 1107 59

Transformation of mouse melanocytes with a variety of exogenous oncogenes or chemical carcinogens frequently results in irreversible loss of pigmentation. We have infected mouse melanocytes with a temperature-sensitive mutant of the simian virus 40 (SV40) large tumour antigen to study the molecular mechanisms underlying depigmentation during melanocyte transformation. The results show that, out of six cell lines analyzed at the permissive temperature of the oncoprotein, three epidermal and two dermal melanocyte clones remained pigmented and retained the ability to synthesize melanin and to express the melanocyte-specific genes, including tyrosinase, tyrosinase related protein-1, tyrosinase related protein-2 and Mitf. In contrast, one dermal melanocyte clone (DMEL-3) gradually depigmented. This depigmentation was characterized by enhanced growth and down-regulation of melanocyte-specific gene expression. When the oncogene was inactivated by culture at the non-permissive temperature, the pigmented phenotype in DMEL-3 cells could be rescued, and there was a corresponding time-dependent increase in melanocyte-specific gene expression. After extended passage, this rescue could not be achieved. Our results provide direct evidence for the role of the SV40 large T antigen in melanocyte de-differentiation. Expression of Pax-3, a transcription factor implicated in melanocyte differentiation, was unaltered during the SV40-initiated de-differentiation, and de-differentiated melanocytes expressed normal levels of Pax-3 message. We speculate on the mechanism by which the oncoprotein might be regulating Mitf gene expression and of the role of Pax-3 in this process.
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PMID:SV-40 large T antigen reversibly inhibits expression of tyrosinase, TRP-1, TRP-2 and Mitf, but not Pax-3, in conditionally immortalized mouse melanocytes. 1123 12

Angiomyolipomas (AMLs) show a characteristic immunoreactivity with melanocyte differentiation markers such as monoclonal antibody (mAb) HMB45, which detects melanocyte differentiation antigen gp100 and mAb A103 reacting with Melan-A/MART-1. Monoclonal antibody T311 to tyrosinase (a key enzyme of melanogenesis) and mAb D5 to the microphthalmia (Mitf) antigen are two newly available markers of melanocytic differentiation. The authors tested 15 AMLs with T311 and D5 by immunohistochemistry and a subset of 3 cases by reverse transcription-polymerase chain reaction for their expression of tyrosinase and Mitf mRNA. T311 showed poor sensitivity in AMLs because only focal staining was seen in 1 out of 15 cases, although tyrosinase mRNA was found in all tested cases. Mitf mRNA was present in 3 of 3 tested cases, and D5 was positive in 15 of 15 AMLs. However, D5 immunostaining often was focal and not as homogeneous as A103, which was analyzed in a previous study. D5 staining also could be seen in other cell types such as normal renal tubular cells, macrophages, and renal cell carcinoma. The current results show that in contrast with HMB45 and A103, T311 has little or no value in the diagnosis of AMLs. D5 may be useful in a panel of antibodies in the diagnosis of AMLs.
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PMID:Immunohistochemical and reverse transcription-polymerase chain reaction expression analysis of tyrosinase and microphthalmia-associated transcription factor in angiomyolipomas. 1127 11

Patterning of the vertebrate eye appears to be controlled by the mutual regulation and the progressive restriction of the expression domains of a number of genes initially co-expressed within the eye anlage. Previous data suggest that both Otx1 and Otx2 might contribute to the establishment of the different eye territories. Here, we have analysed the ocular phenotype of mice carrying different functional copies of Otx1 and Otx2 and we show that these genes are required in a dose-dependent manner for the normal development of the eye. Thus, all Otx1(-/-); Otx2(+/-) and 30% of Otx1(+/-); Otx2(+/-) genotypes presented consistent and profound ocular malformation, including lens, pigment epithelium, neural retina and optic stalk defects. During embryonic development, optic vesicle infolding was severely altered and the expression of pigment epithelium-specific genes, such as Mitf or tyrosinase, was lost. Lack of pigment epithelium specification was associated with an expansion of the prospective neural retina and optic stalk territories, as determined by the expression of Pax6, Six3 and Pax2. Later in development the presumptive pigment epithelium region acquired features of mature neural retina, including the generation of Islet1-positive neurones. Furthermore, in Otx1(-/-); Otx2(+/-) mice neural retina cell proliferation, cell differentiation and apoptotic cell death were also severely affected. Based on these findings we propose a model in which Otx gene products are required for the determination and differentiation of the pigment epithelium, co-operating with other eye patterning genes in the determination of the specialised tissues that will constitute the mature vertebrate eye.
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PMID:Otx genes are required for tissue specification in the developing eye. 1149 24

Changes in pigmentation are frequently encountered in primary and metastatic melanocytic lesions. Pigmentation is determined by the activity of tyrosinase (TYR), the rate-limiting enzyme in melanin synthesis. Tyrosinase activity can be modulated at the genetic and/or epigenetic level. In this commentary I suggest that pigmentation can serve as an indicator for genetic and metabolic changes as follows. In TYR-negative, amelanotic melanomas cells, downregulation of TYR and other melanocyte-specific gene expression is likely to be mediated by dominantly acting oncogenes with impact on the transcriptional activity of the melanocyte-specific transcription factor Mitf. Ras and c-myc, shown to be active and upregulated in subclasses of melanoma tumors, have the potential to induce these changes. TYR-positive highly pigmented melanoma tumors are likely to reside in aerobic, well-vascularized microenvironment. In contrast, hypo- or amelanotic TYR-positive lesions suffer from reduced TYR activity due to an acidified microenvironment. These lesions might have encountered anaerobic conditions, and have adapted to the reduced oxygen by enhanced glycolysis, leading to extracellular acidification and activation of V-ATPase.
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PMID:Pigmentation in melanomas: changes manifesting underlying oncogenic and metabolic activities. 1220 72

We determined the sensitivity and specificity of 3 novel antibodies (microphthalmia transcription factor [Mitf], Melan-A, and tyrosinase) as markers for melanoma in cytologic preparations and compared the results with those of commonly used markers (S-100 protein [S-100] and HMB-45). We stained 72 cell blocks from 40 patients with melanoma and 32 with nonmelanocytic malignant neoplasms with antibodies against S-100, HMB-45, Mitf, Melan-A, and tyrosinase. Histologic correlation was available in more than 95% of cases. Nuclear stainingfor Mitf and cytoplasmic stainingfor S-100, HMB-45, Melan-A, and tyrosinase in more than 10% of tumor cells was considered positive. All 3 novel markers demonstrated sensitivity superior to S-100 and HMB-45. HMB-45, Melan-A, and Mitf demonstrated specificities of 97%. S-100 protein and tyrosinase were less specific. Sensitivity and specificity for the combination Mitf+/Melan-A+ were 95% and 100%, respectively, whereas they were 80% and 100%, respectively, for S-100+/HMB-45+. Mitf Melan-A, and tyrosinase are sensitive markersfor epithelioid melanoma. Mitf and Melan-A seem more specific than S-100 and tyrosinase. An antibody panel consisting of Mitf and Melan-A is superior to a panel of S-100 and HMB-45 in the diagnosis of melanoma in cytologic specimens.
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PMID:Comparison of five antibodies as markers in the diagnosis of melanoma in cytologic preparations. 1247 87


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