Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027960 (mole)
 21,279 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PNL2 is a novel monoclonal antibody, which has recently been introduced as an immunohistochemical reagent to stain melanocyte and tumors derived thereof. In the present study, we analyzed the immunoreactivity of this mAb in various normal tissues, melanocytic nevi, primary and metastatic melanoma, nonmelanocytic tumors, including histologic mimickers of melanoma as well as angiomyolipoma, and multiple cell lines derived from different tumors types. We used several tissue microarray panels as well as selected conventional sections from tissue blocks. For metastatic melanoma, immunoreactivity for PNL2 was compared with A103 (Melan-A/MART-1), T311 (tyrosinase), HMB45 (gp100), and D5 (MITF). Positive staining with PNL2 was found in normal melanocytes and neutrophils, but no other normal cell type. Among melanocytic lesions, both benign nevi as well as primary malignant melanomas, especially epithelioid variants thereof, were commonly immunopositive. Only 1 of 13 desmoplastic melanomas reacted with PNL2. PNL2 showed high sensitivity for metastatic melanoma (87%). In comparison, 82% of metastatic melanomas were positive for A103, 76% for HMB45, 92% for T311, and 84% for D5. The combined use of all five reagents minimized the number of immunonegative cases. None of the selected nonmelanocytic tumors (carcinomas or soft tissue neoplasms) was positive for PNL2 in this series except for angiomyolipomas and chronic myeloid leukemias and 1 single case of a malignant peripheral nerve sheath tumor with heterologous differentiation (malignant Triton tumor). Despite its reactivity with neutrophils, PNL2 appears to be a valuable supplementary reagent for the diagnosis of melanocytic tumors.
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PMID:Immunohistochemical analysis of novel monoclonal antibody PNL2 and comparison with other melanocyte differentiation markers. 1572 10

At the end of the last decade, sporadic melanomas were still considered a genetic black box. Fortunately, in the last few years the box has been opened bringing to light melanoma-relevant oncogenes, aberrant signal transduction pathways, critical alterations in the melanoma cell cycle that go beyond p16INK4a, and melanoma- microenvironment interactions that are essential for tumor progression. This review will discuss some of the latest findings in melanoma research including the critical role of the MAPK pathway in the genesis of melanoma and senescence of nevi, the paradoxical tumor suppressor and oncogenic activities of the transcription factor MITF, and the unexpected oncogenic activities of the low molecular weight forms of cyclin E.
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PMID:Recent advances in melanoma research. 1672 Mar 71

We studied gene expression in 18 melanocytic nevi with and four nevi without the V600E mutation in the BRAF gene using HG-U133A 2.0 microarray with 22,277 transcripts. Data analysis revealed 92 genes up-regulated and 105 genes down-regulated in nevi with the mutation compared to nevi without mutation. Pathway analysis showed that differentially regulated genes mapped to 10 genetic networks. The major network included genes involved in cell death, cell cycle, and cellular growth and proliferation. Up-regulated genes in nevi with the mutation included CDKN2A, CDKN1C, and MITF; whereas down-regulated genes included those involved in apoptotic and other pathways. Principal component analysis identified 22 probe sets (20 genes) that caused separate segregation of nevi with and without mutations. In conclusion, our data showed differences in gene expression between nevi with and without the V600E BRAF mutation. Moreover, nevi with mutations showed over-expression of genes involved in melanocytic senescence and cell cycle inhibition.
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PMID:Differential gene expression in melanocytic nevi with the V600E BRAF mutation. 1769 95

Human pigmentation appears to be one of the main modulators of individual risk of developing malignant melanoma (MM). A large number of genes are known to be involved in rare pigmentary disorders and explain most of the variation in pigmentation phenotypes seen in human populations. This Spanish case-control study included 205 patients with melanoma and 245 control subjects. Thirty-one single nucleotide polymorphisms (SNPs) in genes that had been mainly associated with congenital pigmentation syndromes (ADTB3A, ATRN, CHS1, EDNRB, HPS, KIT, MGRN1, MITF, MLANA, MYO5A, MYO7A, OA1, OCA2, PAX3 and SOX10) were selected. We found that the variant allele of OCA2 R419Q (rs1800407) was associated with increased risk of MM (OR 1.55, 95% CI 1.04-2.31, P = 0.03). This effect on melanoma risk appeared to be stronger among individuals with solar lentigines, or at least 50 nevi. We also describe, for the first time, an association with the variant S1666C (rs2276288) in the MYO7A gene (OR 1.35; 95% CI 1.04-1.76; P = 0.03). Again, this association appeared to be stronger in several phenotypic groups such as individuals with fair skin and those with childhood sunburns. We also found that several variants in the pigmentation genes considered were associated with intermediate phenotypic characteristics. Our findings highlight the potential importance of pigmentation genes in sporadic MM susceptibility.
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PMID:Pigmentation-related genes and their implication in malignant melanoma susceptibility. 1932 Jul 33

The presence of melanin pigment within the iris is responsible for the visual impression of human eye colouration with complex patterns also evident in this tissue, including Fuchs' crypts, nevi, Wolfflin nodules and contraction furrows. The genetic basis underlying the determination and inheritance of these traits has been the subject of debate and research from the very beginning of quantitative trait studies in humans. Although segregation of blue-brown eye colour has been described using a simple Mendelian dominant-recessive gene model this is too simplistic, and a new molecular genetic perspective is needed to fully understand the biological complexities of this process as a polygenic trait. Nevertheless, it has been estimated that 74% of the variance in human eye colour can be explained by one interval on chromosome 15 that contains the OCA2 gene. Fine mapping of this region has identified a single base change rs12913832 T/C within intron 86 of the upstream HERC2 locus that explains almost all of this association with blue-brown eye colour. A model is presented whereby this SNP, serving as a target site for the SWI/SNF family member HLTF, acts as part of a highly evolutionary conserved regulatory element required for OCA2 gene activation through chromatin remodelling. Major candidate genes possibly effecting iris patterns are also discussed, including MITF and PAX6.
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PMID:Genetics of human iris colour and patterns. 1961 60

Distinction between benign and malignant melanocytic lesions may be difficult by today's methods, even for highly skilled dermatopathologists, emphasizing the need for improved diagnostic tools. We have studied the discriminative abilities of immunohistochemical (IHC) double stains using the IHC markers Ki67 combined with MART1, and HMB45 combined with MITF. Paraffin-embedded tissue sections from 50 melanomas and 78 benign nevi were stained using a simple simultaneous IHC double staining technique. Both simple semiquantitative estimates of the immunopositivity in the deepest third of the lesions and full-scale quantitative measurements of the Ki67 and HMB45 indices were performed, and scores for melanomas and nevi were compared. The differences between melanomas and nevi were significant (P < 0.0001) using either analysis or stain. The misclassification rates for melanomas and nevi were generally lower for Ki67/MART1 stains than for HMB45/MITF stains. In the simple semiquantitative Ki67/MART1 analysis, the misclassification rates were 6% (2%-17%) for melanomas and 12% (6%-21%) for nevi. In full-scale quantitative analysis the corresponding rates were 4% (1%-14%) and 8% (4%-16%), and by combining Ki67 and HMB45 indices, the misclassification rates were 0% (0%-7%) for melanomas and 13% (7%-22%) for nevi. We conclude that both semiscale and fullscale quantitative analyses of Ki67/MART1 stains are valuable diagnostic tools to distinguish melanomas and nevi with a large degree of certainty. The HMB45/MITF stains may serve as adjuncts to predict malignancy and the diagnostic potential of combining the HMB45 and Ki67 indices are promising. The IHC double stains may potentially reduce misinterpretations of melanomas in histopathology.
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PMID:Immunohistochemical double stains against Ki67/MART1 and HMB45/MITF: promising diagnostic tools in melanocytic lesions. 2161 Apr 57

Slug (Snai2), a member of the Snail family of zinc finger transcription factors, plays a role in the epithelial-to-mesenchymal transformation (EMT) that occurs during melanocyte emigration from the neural crest. A role for Slug in the EMT-like loss of cell adhesion and increased cell motility exhibited during melanoma progression has also been proposed. Our immunohistochemical studies of melanoma arrays, however, revealed that Slug expression was actually higher in nevi than in primary or metastatic melanomas. Moreover, Slug expression in melanomas was not associated with decreased expression of E-cadherin, the canonical Slug target in EMT. Comparisons of endogenous Slug and E-cadherin expression in cultured normal human melanocytes and melanoma cell lines supported our immunohistochemical findings. Expression of exogenous Slug in melanocytes and melanoma cells in vitro, however, suppressed E-cadherin expression, enhanced N-cadherin expression, and stimulated cell migration and invasion. Interestingly, both in tumors and cultured cell lines, there was a clear relationship between expression of Slug and MITF, a transcription factor known to regulate Slug expression during development. Taken together, our findings suggest that Slug expression during melanomagenesis is highest early in the process and that persistent Slug expression is not required for melanoma progression. The precise role of Slug in melanomagenesis remains to be elucidated and may be related to its interactions with other drivers of EMT, such as Snail.
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PMID:Slug expression during melanoma progression. 2250 51

Protein arginine methyltransferase-5 (PRMT5) is a Type II arginine methyltransferase that regulates various cellular functions. We hypothesized that PRMT5 plays a role in regulating the growth of human melanoma cells. Immunohistochemical analysis indicated significant upregulation of PRMT5 in human melanocytic nevi, malignant melanomas and metastatic melanomas as compared to normal epidermis. Furthermore, nuclear PRMT5 was significantly decreased in metastatic melanomas as compared to primary cutaneous melanomas. In human metastatic melanoma cell lines, PRMT5 was predominantly cytoplasmic, and associated with its enzymatic cofactor Mep50, but not STAT3 or cyclin D1. However, histologic examination of tumor xenografts from athymic mice revealed heterogeneous nuclear and cytoplasmic PRMT5 expression. Depletion of PRMT5 via siRNA inhibited proliferation in a subset of melanoma cell lines, while it accelerated growth of others. Loss of PRMT5 also led to reduced expression of MITF (microphthalmia-associated transcription factor), a melanocyte-lineage specific oncogene, and increased expression of the cell cycle regulator p27(Kip1). These results are the first to report elevated PRMT5 expression in human melanoma specimens and indicate this protein may regulate MITF and p27(Kip1) expression in human melanoma cells.
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PMID:PRMT5 is upregulated in malignant and metastatic melanoma and regulates expression of MITF and p27(Kip1.). 2409 63

Malignant peripheral nerve sheath tumors are rare soft tissue sarcomas with histological and immunohistochemical similarities to spindle cell melanoma. Although spindle cell melanoma is significantly more common, both tumors may express S100 and lack staining for HMB-45, Melan-A or MITF. Here we present a case of superficial malignant peripheral nerve sheath tumor with diffuse S100 positivity arising in a subtle neurofibroma in close proximity to an intradermal melanocytic nevus. This configuration had led to prior misdiagnosis as a desmoplastic melanoma arising in the nevus and to sentinel lymph node biopsy. Identification of the background neurofibroma, as well as CD34 positivity raised consideration of a low grade malignant peripheral nerve sheath tumor, which was confirmed via observation of Schwannian differentiation on electron microscopy. The importance of distinguishing these two tumors is stressed owing to the difference in management.
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PMID:Superficial malignant peripheral nerve sheath tumor with overlying intradermal melanocytic nevus mimicking spindle cell melanoma. 2768 11

The MAPK pathway is activated in the majority of melanomas and is the target of therapeutic approaches. Under normal conditions, it initiates the so-called immediate early response, which encompasses the transient transcription of several genes belonging to the AP-1 transcription factor family. Under pathological conditions, such as continuous MAPK pathway overactivation due to oncogenic alterations occurring in melanoma, these genes are constitutively expressed. The consequences of a permanent expression of these genes are largely unknown. Here, we show that FOSL1 is the main immediate early AP-1 member induced by melanoma oncogenes. We first examined its role in established melanoma cells. We found that FOSL1 is involved in melanoma cell migration as well as cell proliferation and anoikis-independent growth, which is mediated by the gene product of its target gene HMGA1, encoding a multipotent chromatin modifier. As FOSL1 expression is increased in patient melanoma samples compared to nevi, we investigated the effect of enhanced FOSL1 expression on melanocytes. Intriguingly, we found that FOSL1 acts oncogenic and transforms melanocytes, enabling subcutaneous tumor growth in vivo. During the process of transformation, FOSL1 reprogrammed the melanocytes and downregulated MITF in a HMGA1-dependent manner. At the same time, AXL was upregulated, leading to a shift in the MITF/AXL balance. Furthermore, FOSL1 re-enforced pro-tumorigenic transcription factors MYC, E2F3 and AP-1. Together, this led to the enhancement of several growth-promoting processes, such as ribosome biogenesis, cellular detachment and pyrimidine metabolism. Overall, we demonstrate that FOSL1 is a novel reprogramming factor for melanocytes with potent tumor transformation potential.
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PMID:The AP-1 transcription factor FOSL1 causes melanocyte reprogramming and transformation. 2848 78


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