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)

Patients with xeroderma pigmentosum (XP) have more than a 1000-fold increased risk of cutaneous melanoma. To determine if the XP DNA repair defect is present in cutaneous pigmentary cells, nevus cells and melanocytes from four large, pigmented nevi were cultured from a 12-year-old girl with XP. Cultured melanocytes showed dendritic morphologic features, contained mature melanosomes, and reacted with monoclonal antibody to tyrosinase. Nevus cells were spindle shaped and expressed nevus cell-associated antigens. Melanocytes, nevus cells, and dermal fibroblasts from the patient with XP all had a similar reduction in DNA repair: unscheduled DNA synthesis was 30% to 50% of that in normal fibroblasts following a 30 J/m2 ultraviolet dose. After a 6 J/m2 ultraviolet dose, the proliferative ability of XP nevus cells and fibroblasts was reduced to 10% of that of normal fibroblasts. This study indicates that cultured melanocytes and nevus cells express the characteristic XP DNA repair defect.
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PMID:Reduced DNA repair in cultured melanocytes and nevus cells from a patient with xeroderma pigmentosum. 291 63

Uveal melanoma usually occurs sporadically in the absence of obvious genetic predisposing factors. However, in rare patients, there is a suggestion that there may be genetic predisposition. Rare occurrences of familial uveal melanoma are believed to be inherited in an autosomal dominant mode. There are a few clinical conditions that can predispose to or be associated with uveal melanoma, including ocular melanocytosis, neurofibromatosis type I, and familial atypical mole and melanoma syndrome. Nonrandom cytogenetic changes in uveal melanoma are characterized by monosomy 3, trisomy 8, and structural or numerical abnormalities of chromosome 6. Alterations of chromosome 9p are less frequently observed. CDKN2 gene, a cutaneous melanoma predisposition gene, is probably not a uveal melanoma predisposition gene as evidenced by the lack of somatic mutations involving this gene in uveal melanoma samples and the absence of germline mutations in familial uveal melanoma patients. Transgenic mouse models developed using a tyrosinase promoter tagged with a mutated ras gene or SV40-Tag oncoprotein develop retinal pigment epithelium tumors that resemble uveal melanoma. We propose that uveal melanoma cases be categorized on genetic basis according to a new classification system. This classification scheme will help to identify and uniformly categorize uveal melanoma patients with genetic predisposition. Such patients offer unique opportunities for studying the genetic aspects of uveal melanoma and, therefore, appropriate tissue samples should be obtained from them for molecular genetic studies. Further studies are needed to fully understand the genetic aspects of uveal melanoma.
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PMID:Genetic aspects of uveal melanoma: a brief review. 897 Jun 1

The decline in cell differentiation commonly associated with malignant progression may be due in part to an increase in alternative splicing of the pre-mRNAs of tissue-specific genes. As a necessary basis for investigating this possibility in a murine model of cutaneous melanoma, the complete qualitative and quantitative inventory of alternative transcripts was sought for the tyrosinase gene in normal mouse skin melanocytes, as this gene plays a key role in melanization. Of 111 alternative mRNAs predicted from known splice sites in the gene, 19 isoforms were detected, and their abundances determined, through a systematized protocol involving splice junction-specific probes, exon-specific restriction enzymes, and quantitative RT-PCR with an RNA internal standard. No unpredicted tyrosinase transcripts were discovered. Two of the transcripts, each involving an intra-exonic deletion and present at relatively low abundance in normal skin, were subsequently found to be consistently upregulated in melanomas.
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PMID:Qualitative and quantitative catalog of tyrosinase alternative transcripts in normal murine skin melanocytes as a basis for detecting melanoma-specific changes. 922 47

The TP-ras transgenic mouse line expresses an activated human T24 Ha-ras gene with a mutation in codon 12, regulated by a mouse tyrosinase promoter. The transgene is expressed in melanocytes of the skin, eyes, and brain. The mice develop cutaneous melanoma when treated with 7,12-dimethylbenz[a]anthracene. Cell lines have been generated from the cutaneous tumors and metastatic lesions. By using fluorescence in situ hybridization with mouse whole chromosome paints, the cell lines were characterized for chromosomal abnormalities. Key findings in the tumor cells included translocations of chromosome 4 and alterations in chromosome 6. One tumor cell line contained a double translocation involving chromosomes 3 and 6. To extend the results of the chromosome 4 painting, Southern analysis of the p15INK4B, p16INK4A, and p19INK4D genes was performed. Our data indicated that there were homozygous and partial allelic deletions and polymorphisms in the region of chromosome 4 containing these genes, resulting in the absence or reduced expression of the p16 product. These findings are similar to those reported for human melanoma, and the TP-ras transgenic mouse may therefore be a valuable model for studying novel strategies for melanoma prevention and treatment.
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PMID:Chromosomal and genetic alterations of 7,12-dimethylbenz[a]anthracene-induced melanoma from TP-ras transgenic mice. 932 38

The presence of regional lymph node metastases is one of the most significant prognostic factors for predicting survival in patients with clinical stage I or II cutaneous melanoma. For accurate staging of the primary tumor a sensitive technique is required to detect occult nodal micrometastases. This prospective diagnostic study was designed to evaluate the incidence of nodal micrometastases using nested reverse transcription-polymerase chain reaction (RT-PCR) for tyrosinase in comparison to immunohistochemical examination. Furthermore, the incidence of melanoma micrometastases detected by RT-PCR was analysed in correlation to major prognostic factors. A total of 466 regional lymph nodes from 79 patients with primary cutaneous melanoma (tumor thickness > 0.75 mm) were investigated. In 49 lymph nodes from 31 patients immunohistochemistry demonstrated melanoma metastases. Using tyrosinase RT-PCR, nodal micrometastases were detected in 136 lymph nodes from 52 patients including all lymph nodes positive by immunohistochemical examination. Out of the 417 lymph nodes negative by immunohistochemistry, 87 nodes (21%) were identified to express tyrosinase by the RT-PCR technique. Among the 48 patients negative by immunohistochemical assessment, 21 (44%) had nodal micrometastases (n = 40) using RT-PCR. All 68 lymph nodes from 46 non-melanoma patients serving as negative controls for tyrosinase RT-PCR were negative. The detection of melanocytic nodal micrometastases by tyrosinase RT-PCR is a highly specific method with a sensitivity significantly higher than that achieved by immunohistochemistry (p < 0.0001). Patients with nodal micrometastases identified exclusively by RT-PCR had significantly higher tumor thickness as compared to patients with negative results by RT-PCR (p < 0.01).
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PMID:Lymph node micrometastases of cutaneous melanoma: increased sensitivity of molecular diagnosis in comparison to immunohistochemistry. 969 21

Several laboratories are pursuing the question of whether the expression of pigment genes can be used as a useful marker for tumour progression. However, many melanoma tumours are amelanotic in vivo. The purpose of this study was to examine the relationship between the expression of tyrosinase-related genes [tyrosinase, tyrosinase-related protein-1 (TRP-1) and tyrosinase-related protein-2 (TRP-2)] and pigmentation of melanoma cells. Fourteen cutaneous melanoma cell lines were examined for visible pigment, melanin content, and dopa oxidase activity and findings were related to the previously determined expression of the three tyrosinase-related genes in these cells in culture. Four of the cell lines were also stimulated with alpha-MSH, isobutylmethylxanthine, and forskolin to examine the relationship between induced pigmentation and upregulation of pigmentation genes. There was no simple correlation between pigmentation gene expression and dopa oxidase activity or total melanin content of the 14 melanoma cell lines in culture. In the majority of cells, there was no appreciable pigment, whereas, in contrast, half of the cells showed significant dopa oxidase activity. Upregulation of dopa oxidase activity was achieved by alpha-MSH in two out of four cell lines examined in detail and with IBMX in three out of four of these cell lines. IBMX increased tyrosinase gene expression in all four cell lines; alpha-MSH was without effect; and TRP-1 and TRP-2 expression were largely unaffected by IBMX or alpha-MSH. Modest changes in morphology were noted in response to IBMX. Overall, however, human melanoma cell lines were, with two exceptions, amelanotic in culture despite the fact that 10 out of the 14 lines expressed tyrosinase-related genes. We conclude that measurable pigmentation is not a necessary consequence of the expression of pigmentation genes. An implication of this work is that amelanotic tumours in vivo may nevertheless be positive for tyrosinase-related genes.
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PMID:Human melanoma cell lines show little relationship between expression of pigmentation genes and pigmentary behaviour in vitro. 973 Mar 20

In the treatment of cutaneous melanoma, provisional therapeutic strategies have been designed to combat tumour load using T cells that are sensitized with peptides derived from melanoma autoantigens, such as glycoprotein 100 (gp100), melanoma antigen recognized by T cells 1 (MART-1 or MelanA), tyrosinase and tyrosinase-related protein 1 (TRP-1). We recently found that gp100, MART-1 and tyrosinase are heterogeneously expressed in human cutaneous melanoma (De Vries et al (1997) Cancer Res 57: 3223-3229). Here, we extended our investigations on expression of these immunotherapy candidate proteins to uveal melanoma lesions. Cryostat sections from 11 spindle-type, 21 mixed and epithelioid tumours and four metastasis lesions were stained with antibodies specifically recognizing gp100, MART-1, tyrosinase and TRP-1. In addition, we used the DOPA reaction to detect tyrosinase enzyme activity as a confirmation of the tyrosinase immunohistochemical results. High expression of gp100, MART-1 and tyrosinase was found in the uveal melanoma lesions: 80% of the lesions displayed 75-100% positive tumour cells. TRP-1 positivity was slightly less: approximately 65% of the lesions stained in the 75-100% positive tumour cell category. All uveal melanoma lesions were positive for the four markers studied, this being in contrast to cutaneous melanoma where 17% of the advanced primary lesions and metastases were negative. The presence of these antigens was a little lower in metastases. We conclude that uveal melanomas and their metastases express melanocyte-lineage immunotherapy candidate proteins very abundantly. Uveal melanomas differ in this respect from cutaneous melanoma, in which the expression of these immunotherapy antigens was much more heterogeneous. This makes uveal melanoma a suitable candidate tumour for immunotherapeutic approaches.
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PMID:High expression of immunotherapy candidate proteins gp100, MART-1, tyrosinase and TRP-1 in uveal melanoma. 982 Jan 72

The sentinel node has been reported to be representative for the presence or absence of metastatic melanoma in the draining lymph node basin. In this study, for the first time sentinel nodes and adjoining nonsentinel nodes were analyzed for micrometastatic disease using tyrosinase reverse transcription-polymerase chain reaction (RT-PCR) in comparison with standard immunohistochemistry. Successful identification of the sentinel nodes using a gamma probe-guided surgery was achieved in 73 (92%) of 79 patients with cutaneous stage I and II melanoma (tumor thickness > or =0.75 mm). A total of 794 regional lymph nodes, 148 sentinel nodes, and 646 adjoining nonsentinel nodes were evaluated. Tyrosinase RT-PCR was shown to increase the sensitivity for melanoma cell detection in sentinel nodes significantly (49% positivity) as compared with immunohistochemistry using antibodies against HMB-45 antigen and S-100 protein (18% positivity). Examination of sentinel nodes was highly predictive in determining the presence of regional lymph node micrometastasis by immunohistochemistry (99%) and RT-PCR (89%). Interestingly, detection of nodal micrometastasis by RT-PCR showed a strong positive correlation with tumor thickness of primary cutaneous melanoma. These results suggest the clinical significance and emphasize the importance of tyrosinase RT-PCR for detection of melanoma micrometastasis in sentinel nodes.
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PMID:Detection of melanoma micrometastasis in sentinel nodes by reverse transcription-polymerase chain reaction correlates with tumor thickness and is predictive of micrometastatic disease in the lymph node basin. 1040 6

Histopathologic parameters of the primary tumor, such as Breslow's tumor thickness and Clark's level of invasion are the current basis for prognostic classifications of primary cutaneous melanoma. Once patients develop regional node metastasis, histopathologic features of the primary melanoma no longer contribute significantly to survival prediction. In this tumor stage, the extent of lymph node involvement is the main prognostic factor. This study addresses the question whether application of a highly sensitive molecular biology assay for detection of submicroscopic melanoma cells in sentinel lymph nodes may be suitable to improve melanoma staging. One hundred and sixteen patients with primary cutaneous melanoma with a total of 214 sentinel lymph nodes were enrolled. Sentinel lymph nodes were analyzed by histopathology including immunohistochemistry and by reverse transcription-polymerase chain reaction for tyrosinase. Patients were examined for tumor recurrences during a follow-up period of 19 mo (median). Disease-free survival probabilities were calculated and independent prognostic factors were determined by multivariate analysis. Using histopathology, micrometastatic nodal involvement was detected in 15 patients (13%). Of the 101 patients with histopathologically negative sentinel lymph nodes, 36 were reclassified by positive tyrosinase reverse transcription-polymerase chain reaction and 65 patients were still negative by reverse transcription-polymerase chain reaction. Recurrences were observed in 23 (20%) of 116 patients. These tumor recurrences were demonstrated in 10 patients (67%) with histopathologically positive sentinel lymph nodes, in nine patients (25%) with submicroscopic tumor cells detected by reverse transcription-polymerase chain reaction, and in four patients (6%) negative by both methods. The differences in recurrence rates were statistically significant (p = 0.01). In a multivariate analysis, histopathologic and reverse transcription-polymerase chain reaction status of the sentinel lymph node were demonstrated to be the only significant prognostic factors for predicting disease-free survival. Tyrosinase reverse transcription-polymerase chain reaction for the detection of minimal residual melanoma in sentinel lymph nodes is a powerful tool to determine patients who are at increased risk for subsequent metastasis. Moreover, a group of patients with high tumor thickness was identified by negative reverse transcription-polymerase chain reaction to be at low risk for recurrent disease. These data may have an impact on future tumor classifications of primary cutaneous melanoma.
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PMID:Examination of regional lymph nodes by sentinel node biopsy and molecular analysis provides new staging facilities in primary cutaneous melanoma. 1073 66

The intraocular pressure-lowering drug latanoprost, a phenyl-substituted analogue of prostaglandin F2 alpha (PGF2 alpha), increases iris pigmentation in a small number of patients. In theory, this could be due to increased melanogenesis or melanocyte proliferation. To distinguish these two possibilities, the present study examined the effects of latanoprost on tyrosinase activity (the rate-limiting step for melanin synthesis) and mitotic index of cultured melanoma lines. Murine cutaneous melanoma lines (S91 and B16), and human uveal (OCM1, OCM3, and OM431) and cutaneous (SK-MEL5 and M21) melanoma lines were cultured with PGE1, PGE2, PGF2 alpha, latanoprost, or the adenylate cyclase stimulating agent forskolin. After treatment, tyrosinase was assayed with respect to its dopa oxidase activity using a colorimetric assay. PGE1, PGE2, PGF2 alpha, and latanoprost greatly increased tyrosinase activity in murine melanoma lines and caused small increases in tyrosinase activity in human uveal and cutaneous melanoma lines. Similar results were obtained with the cAMP-elevating compound forskolin. Cyclic AMP content, as determined by an enzyme-linked immunoassay, was similarly increased by all treatments, with forskolin being the most potent stimulator. Since the species difference in tyrosinase activity was observed without an apparent difference in induction of cAMP, latanoprost would appear to induce tyrosinase activity through a non-cAMP-dependent pathway. Finally, latanoprost and PGF2 alpha did not enhance the mitotic index of human uveal or cutaneous melanoma lines, measured by [6-3H] thymidine uptake, although they increased the mitotic index of one murine cutaneous line. Given that latanoprost induced tyrosinase activity, but did not increase the mitotic index in any of the human melanoma lines studied, this suggests that the in vivo iris pigmentation side effect of latanoprost may not result from increased cell division, but from elevated tyrosinase activity.
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PMID:Effects of latanoprost on tyrosinase activity and mitotic index of cultured melanoma lines. 1087 May 14


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