Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been shown that the co-occurrence of melanoma and pre-existing naevus is not a random event and that acquired naevi may be precursors of melanoma. A critical area of chromosomal loss at 9p21 has been implicated in the genesis of malignant melanoma, representing a site of frequent somatic chromosomal deletions in melanoma. Allelic deletions within this chromosomal region most often include the tumour suppressor gene p16. The objective of this study was to search for allelic deletions on chromosome 9p21 in naevus cell clusters. A microdissection-based approach was used to analyse 30 archived primary cutaneous melanomas and associated naevi for loss of heterozygosity (LOH) at 9p21 using the polymorphic DNA markers D9S171 and IFNA. LOH was detected in 10 out of 27 informative naevi (37%) at D9S171 and in eight out of 19 (42%) at IFNA in the dissected naevus cell clusters, and in nine out of 27 (33%) at D9S171 and seven out of 19 (36%) at IFNA in the associated melanomas. In eight out of 46 (17%) cases, LOH was detected simultaneously in the naevus and the associated melanoma using both markers. Our results suggest a causal relationship for the development of melanoma within a pre-existent associated naevus. These data support the hypothesis that lesions within 9p21 play an important role in early melanoma development, since these genetic alterations are found in histologically benign melanoma-associated naevi.
Melanoma Res 2003 Apr
PMID:Melanoma ex naevo: a study of the associated naevus. 1269 Mar 9

Putative tumour suppressor genes CDKN2A and CDKN2B (on chromosome 9p21) and CDKN2A-interacting cell growth regulatory genes CDK4 and Id-1 have been demonstrated to be involved in the pathogenesis of malignant melanoma (MM). Mutation analysis of these candidate genes was performed in MM families from southern Italy with three or more affected members or two affected members and one or more relative with histologically diagnosed atypical naevus. Two CDKN2A mutations, Arg24Pro and 1-292 G>A, were observed in two (15%) families; except for CDKN2A and Id-1 polymorphisms, no sequence variations were detected in the remaining genes. Screening among 119 sporadic MM cases revealed two additional CDKN2A mutations at very low prevalences. Identification of a large shared haplotype at 9p21 in some MM families negative for CDKN germline mutations suggests that other CDKN-inactivating mechanisms may be responsible for MM predisposition or, alternatively, additional susceptibility gene(s) may be present on chromosome 9p21. Fluorescence in situ hybridization analysis of a subset of MM tissue sections seemed to indicate that the D9S171 locus may be involved in MM pathogenesis.
Melanoma Res 2003 Dec
PMID:Mutation analysis of candidate genes in melanoma-prone families: evidence of different pathogenetic mechanisms at chromosome 9P21. 1464 20

Melanoma is the most aggressive of skin cancers because of its high resistance to currently available therapy. Although melanoma cells often retain wild-type p53 tumour suppressor protein and express it at high levels, the p53 mediated apoptosis pathway is suppressed. Histone deacetylase (HDAC) inhibitors are a promising group of compounds inducing differentiation, growth arrest and apoptosis in tumour cells in preclinical studies. We have studied the cellular effects of trichostatin A (TSA), a HDAC inhibitor, in a panel of melanoma cell lines and its mechanism of action in relation to p53. TSA stabilized wild-type p53, but p53 protein accumulation was overridden by simultaneous downregulation of p53 mRNA leading to a decrease in p53 protein. While growth arrest was induced in all cell lines studied and apoptosis in most (6/7), these cellular effects were independent of the p53 status of the cells. Inhibiting p53 function by a dominant negative p53 (p53(175His)) confirmed that the HDAC inhibitor induced apoptosis was independent of wild-type p53, even though TSA slightly activated p53 in a reporter assay. The results indicate that while the action of TSA is independent of p53, the activation of the apoptosis pathway by the HDAC inhibitors may provide therapeutic approaches for melanoma treatment.
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PMID:Melanoma cell lines are susceptible to histone deacetylase inhibitor TSA provoked cell cycle arrest and apoptosis. 1589 16

Sex-linked barring, a common plumage colour found in chickens, is characterized by black and white barred feathers. Previous studies have indicated that the white bands are caused by an absence of melanocytes in the feather follicle during the growth of this region. Here, we show that Sex-linked barring is controlled by the CDKN2A/B locus, which encodes the INK4b and ARF transcripts. We identified two non-coding mutations in CDKN2A that showed near complete association with the phenotype. In addition, two missense mutations were identified at highly conserved sites, V9D and R10C, and every bird tested with a confirmed Sex-linked barring phenotype carried one of these missense mutations. Further work is required to determine if one of these or a combined effect of two or more CDKN2A mutations is causing Sex-linked barring. This novel finding provides the first evidence that the tumour suppressor locus CDKN2A/B can affect pigmentation phenotypes and sheds new light on the functional significance of this gene.
Pigment Cell Melanoma Res 2010 Aug
PMID:Sex-linked barring in chickens is controlled by the CDKN2A /B tumour suppressor locus. 2037 21

DNA methylation plays a major role in cancer by silencing tumour suppressor genes. In melanoma, only a discrete number of methylated genes have been identified so far. After the treatment of melanoma cells with a DNA methyltransferase inhibitor and subsequent transcriptomic profiling, we had identified earlier a cohort of melanoma progression-associated genes regulated by methylation. Here, we identified which of these genes are directly methylated in melanoma cell lines and tissues. First, we examined 16 genes by bisulphite sequencing in the WM793 isogenic cell line model series. Five of these genes (CYBA, FABP5, MT1E, TSPY1 and TAC1) displayed increased methylation in several invasive cell lines compared with the parental WM793 cells, indicating their involvement in progression. Next, we analyzed several matched primary/metastatic tumours using methylation-specific PCR, which revealed that MT1E (one of the five genes assessed) was methylated in the largest proportion of tumours. Examination of a larger cohort of samples showed that 1 of 17 (6%) of the benign naevi, 16 of 43 (37%) primary tumours and 6 of 13 (46%) of the metastases displayed MT1E methylation. In addition, ectopic over-expression of MT1E mediated sensitization to cisplatin-induced apoptosis. Overall, these studies suggest that MT1E is a potential tumour suppressor gene, whose loss may promote resistance to apoptosis-inducing therapies.
Melanoma Res 2010 Oct
PMID:Metallothionein 1E is methylated in malignant melanoma and increases sensitivity to cisplatin-induced apoptosis. 2084 33

The aetiology of melanoma, the most lethal form of skin cancer, is complex, involving both genetic and environmental components. Over the past decade, many genetic alterations affecting melanoma development have been identified and more recently a new epigenetic level of regulation has increasingly been explored. MicroRNA (miRNA)-mediated epigenetic regulation of tumour suppressor genes and oncogenes has been shown to play a central role in melanomagenesis. Over the past few years, many studies combining miRNA expression arrays and quantitative reverse transcriptase-PCR assays have identified different miRNAs deregulated during melanoma progression. Several groups have focused their efforts on understanding the functional role of these different miRNAs in melanoma, identifying their direct targets and elucidating their mechanisms of regulation. This review summarizes the present knowledge of miRNA dysregulation in melanoma. On the basis of the current literature, we present a network of miRNA interactions involved in melanoma progression. Some of these key miRNAs may have utility as diagnostic markers or in targeted treatments.
Melanoma Res 2012 Apr
PMID:MicroRNA regulation of melanoma progression. 2220 51

Activated oncogenes restrict cell proliferation and transformation by triggering a DNA damage-dependent senescence checkpoint in response to DNA hyper-replication. Here, we show that loss of the p16(INK) (4a) cyclin-dependent kinase inhibitor and melanoma tumour suppressor facilitates a DNA damage response after a hyper-replicative phase in human melanocytes. Unlike cells expressing activated oncogenes, however, melanocytes depleted for p16(INK) (4a) display enhanced proliferation and an extended replicative lifespan in the presence of replication-associated DNA damage. Analysis of human benign naevi confirmed that DNA damage and loss of p16(INK) (4a) expression co-segregate closely. Thus, we propose that loss of p16(INK) (4a) facilitates tumourigenesis by promoting the proliferation of genetically unstable cells.
Pigment Cell Melanoma Res 2013 Mar
PMID:p16(INK) (4a) deficiency promotes DNA hyper-replication and genetic instability in melanocytes. 2327 22

Melanomas are highly lethal skin tumours that are frequently treated by surgical resection. However, the efficacy of such procedures is often limited by tumour recurrence and metastasis. Caveolin-1 (CAV1) has been attributed roles as a tumour suppressor, although in late-stage tumours, its presence is associated with enhanced metastasis. The expression of this protein in human melanoma development and particularly how the presence of CAV1 affects metastasis after surgery has not been defined. CAV1 expression in human melanocytes and melanomas increases with disease progression and is highest in metastatic melanomas. The effect of increased CAV1 expression can then be evaluated using B16F10 murine melanoma cells injected into syngenic immunocompetent C57BL/6 mice or human A375 melanoma cells injected into immunodeficient B6Rag1-/- mice. Augmented CAV1 expression suppresses tumour formation upon a subcutaneous injection, but enhances lung metastasis of cells injected into the tail vein in both models. A procedure was initially developed using B16F10 melanoma cells in C57BL/6 mice to mimic better the situation in patients undergoing surgery. Subcutaneous tumours of a defined size were removed surgically and local tumour recurrence and lung metastasis were evaluated after another 14 days. In this postsurgery setting, CAV1 presence in B16F10 melanomas favoured metastasis to the lung, although tumour suppression at the initial site was still evident. Similar results were obtained when evaluating A375 cells in B6Rag1-/- mice. These results implicate CAV1 expression in melanomas as a marker of poor prognosis for patients undergoing surgery as CAV1 expression promotes experimental lung metastasis in two different preclinical models.
Melanoma Res 2014 Apr
PMID:Caveolin-1 is a risk factor for postsurgery metastasis in preclinical melanoma models. 2450 May 1

Twenty years ago, the first familial melanoma susceptibility gene, CDKN2A, was identified. Two years later, another high-penetrance gene, CDK4, was found to be responsible for melanoma development in some families. Progress in identifying new familial melanoma genes was subsequently slow; however, with the advent of next-generation sequencing, a small number of new high-penetrance genes have recently been uncovered. This approach has identified the lineage-specific oncogene MITF as a susceptibility gene both in melanoma families and in the general population, as well as the discovery of telomere maintenance as a key pathway underlying melanoma predisposition. Given these rapid recent advances, this approach seems likely to continue to pay dividends. Here, we review the currently known familial melanoma genes, providing evidence that most additionally confer risk to other cancers, indicating that they are likely general tumour suppressor genes or oncogenes, which has significant implications for surveillance and screening.
Pigment Cell Melanoma Res 2015 Mar
PMID:Genetics of familial melanoma: 20 years after CDKN2A. 2543 49

NF1 is a tumour suppressor gene, germline mutations of which lead to neurofibromatosis type 1 syndrome. Patients develop benign tumours from several types of cells including neural crest-derived cells. NF1 somatic mutations also occur in 15% of sporadic melanoma, a cancer originating from melanocytes. Evidence now suggests the involvement of NF1 mutations in melanoma resistance to targeted therapies. Although NF1 is ubiquitously expressed, genetic links between NF1 and genes involved in melanocyte biology have been described, implying the lineage-specific mechanisms. In this review, we summarize and discuss the latest advances related to the roles of NF1 in melanocyte biology and in cutaneous melanoma.
Pigment Cell Melanoma Res 2016 07
PMID:Multiple roles of NF1 in the melanocyte lineage. 2715 59


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