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)

Loss of heterozygosity (LOH) was determined in 45 sporadic primary melanomas at six polymorphic microsatellite markers that flank the INK4a (p16-p14ARF) locus on chromosome 9p21. We also determined allelic loss at two markers on chromosome 9q and two markers at the Rb locus on chromosome 13. Homozygous deletion of the p16 and p14ARF genes was determined by a fluorescent-based quantitative multiplex polymerase chain reaction method. LOH at one or more polymorphic microsatellite markers on locus 9p21 was found in 32 of the melanomas (71%). The highest proportion of LOH was found at markers D9S736 and D9S104, which are telomeric and centromeric to the INK4 locus, respectively. Five melanomas showed LOH at all the analysed markers located on chromosome 9p21. LOH at markers D9S942 and D9S974, which are located close to the p16 and p14ARF genes, was found in 39% and 46% of melanomas, respectively. Analysis of the marker D9S257 on 9q22.1 showed LOH in 13 melanomas (44% of the informative cases). A subset of melanomas with LOH at the INK4 locus also carried inactivating mutations within the p16 coding sequence. Four melanomas carried homozygous deletions at the p16-p14ARF locus. Our results suggest, besides the involvement of the INK4 locus in sporadic melanomas, the possibility of the existence of additional tumour suppressor loci on chromosome 9.
Melanoma Res 1999 Apr
PMID:Loss of heterozygosity at chromosome 9p21 (INK4-p14ARF locus): homozygous deletions and mutations in the p16 and p14ARF genes in sporadic primary melanomas. 1038 Sep 36

During the initiation and progression of malignant melanoma a series of genetic events accumulate, including alterations of chromosome 11q. Recently, an important tumour suppressor gene, the multiple endocrine neoplasia type 1 (MEN1) gene, has been mapped on 11q13 and has been cloned. To assess whether the MEN1 region is involved in tumour initiation and progression, we analysed 23 primary cutaneous melanomas and 17 metastases for loss of heterozygosity (LOH) using two informative polymorphic markers closely linked to the MEN1 gene (PYGM and D11S449). To search for mutations within the gene, single-strand conformation polymorphism (SSCP) analysis was performed using 13 primer sets with designed intronic sequences to amplify the MEN1 coding sequence exons 2 to 10. None of the cases showed LOH at the MEN1 gene locus. By SSCP analysis, no aberrant bands were identified on exons 3 to 10. Analysis of exon 2 revealed the presence of aberrant bands in two of the analysed melanomas. Sequencing analysis revealed a genetic polymorphism at S145S (AGC-->ACT) in both sections. None of the cases analysed showed MEN1 gene mutations. This study represents the first genetic analysis of the MEN1 gene in sporadic melanomas. Our data demonstrate no evidence of deletion or mutation of the MEN1 gene in primary or metastatic melanoma. Therefore, MEN1 gene alterations appear not to be associated with tumorigenesis of malignant melanoma. The MEN1 gene appears to be a highly specific tumour suppressor gene only involving tumours within the spectrum of MEN1 disease.
Melanoma Res 1999 Jun
PMID:Mutation analysis of the MEN1 tumour suppressor gene in malignant melanoma. 1046 80

Malignant melanoma is the deadliest form of skin cancer. Previous studies have shown that the incidence of ras mutation increases with progression of melanoma, but that such mutations may not be present in the earliest radial growth phase melanomas. Recently it has been proposed that introduction of ras mutations into cells deficient in tumour suppressor genes such as p16 (INK4a) is sufficient to induce characteristics of cellular transformation such as anchorage-independent growth and tumour formation in vivo. To test this hypothesis in human melanoma, mutant N-ras, mutant H-ras or wild-type H-ras genes were transfected by electroporation into WM35 cells, a p16-deficient human melanoma cell line of low invasive potential. Increased expression of mutant ras p21 enhanced anchorage-dependent cell growth on tissue culture plastic. In addition, overexpression of mutant N-ras and H-ras, but not of wild-type H-ras, increased the experimental invasive potential, inducing anchorage-independent growth in soft agar, increasing cell motility measured by time-lapse video microscopy, and increasing invasiveness through reconstituted basement membranes. Finally, overexpression of mutant H-ras in melanoma cells was shown to increase tumorigenicity and to induce cachexia when H-ras transfected cell lines were injected subcutaneously in severe combined immunodeficiency (SCID) mice. Thus the addition of activating ras mutations to a melanoma cell line already deficient in p16 leads to enhanced proliferation, survival and migration in vitro and to enhanced subcutaneous tumour formation in vivo. This phenotype is typical of the behaviour of vertical growth phase (VGP) melanoma, and we propose that activation of the ras signalling pathway in the presence of deletions in p16 or related tumour suppressors can induce the VGP melanoma phenotype.
Melanoma Res 1999 Jun
PMID:Overexpression of mutant ras in human melanoma increases invasiveness, proliferation and anchorage-independent growth in vitro and induces tumour formation and cachexia in vivo. 1046 84

MIA (melanoma inhibitory activity) has been previously isolated from the tissue culture supernatant of melanoma cell lines as an autoregulatory activity, inhibiting thymidine incorporation. However, subsequent analyses of melanocytic tumours in vivo have correlated enhanced MIA expression with progression of melanocytic tumours, conflicting with the idea that MIA acts as a tumour suppressor. To investigate the role of MIA in vivo, we have therefore generated a panel of stably transfected B16 cell clones secreting different amounts of MIA. The capacity of these cell clones to form lung metastases in syngeneic C57Bl6 mice was strictly correlated to the level of MIA secretion, but the clones did not differ with respect to their proliferation in vitro. In summary, we suggest that MIA plays a causal role in promoting the metastasis of malignant melanomas, involving inhibition of tumour cell attachment to extracellular matrix molecules within their local milieu.
Melanoma Res 2001 Aug
PMID:Functional role of melanoma inhibitory activity in regulating invasion and metastasis of malignant melanoma cells in vivo. 1147 31

Several genes implicated in the development of various malignancies appear to be of minor relevance in melanoma. We therefore aimed to find a tumour suppressor candidate involved in this malignancy by comparing gene expression in uncultured primary melanoma specimens with those in acquired melanocytic naevi, from which quite often melanomas are known to arise. Applying the subtractive suppression hybridization technique, we generated a subtracted library of candidate genes downregulated in melanoma. Among the cDNA fragments identical to known genes, this library included a cDNA fragment 630 bp in length that is identical to the gene for the human protein phosphatase 2A (PP2A) regulatory subunit B (B56) gamma isoform (PP2A-Bgamma, PPP2R5C). On further evaluation of 15 primary melanoma and 16 acquired melanocytic naevus tissue specimens from independent patients using semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis, expression of this gene was found to be suppressed in melanomas compared with naevi; the difference was statistically significant. As PP2A is known to be a major cellular serine-threonine phosphatase, and has been implicated not only in the regulation of cell growth and division but also in the control of gene transcription and growth factor signal transduction, alterations in the pattern of the regulatory subunits may affect substrate specificity and subcellular localization of the PP2A holoenzyme in melanoma cells.
Melanoma Res 2001 Dec
PMID:The protein phosphatase 2A subunit Bgamma gene is identified to be differentially expressed in malignant melanomas by subtractive suppression hybridization. 1172 4

To date, two genes have been implicated in melanoma pathogenesis. The first, CDKN2A, is a tumour suppressor gene with germline mutations detected in 20% of melanoma-prone families. The second, CDK4, is an oncogene with co-segregating germline mutations detected in only three kindreds worldwide. We examined 16 American melanoma-prone families for mutations in all coding exons of CDK4 and screened additional members of two previously reported families with the Arg24Cys germline CDK4 mutation to evaluate the penetrance of the mutation. No new CDK4 mutations were identified. In the two Arg24Cys families, the penetrance was estimated to be 63%. Overall, 12 out of 12 invasive melanoma patients, none out of one in situ melanoma patient, five out of 13 dysplastic naevi patients, two out of 15 unaffected family members, and none out of 10 spouses carried the Arg24Cys mutation. Dysplastic naevi did not strongly co-segregate with the Arg24Cys mutation. Thus the phenotype observed in melanoma-prone CDK4 families appears to be more complex than just the CDK4 mutation. Both genetic and environmental factors are likely to contribute to the occurrence of melanoma and dysplastic naevi in these families. In summary, although CDK4 is a melanoma susceptibility gene, it plays a minor role in hereditary melanoma.
Melanoma Res 2002 Feb
PMID:Rarity of CDK4 germline mutations in familial melanoma. 1182 58

Mutations in the p53 tumour suppressor gene ( ) have been linked to several types of cancer. We therefore investigated whether such mutations occur in malignant melanomas and, if so, whether they are linked to ultraviolet (sun) light exposure. For the first time, mutations in mucosal membranes and adjacent tissues shielded from sunlight were compared with those in cutaneous melanomas from sun-exposed skin. Archival tissues were obtained from 35 patients with a primary melanoma taken from unexposed mucosal areas and from 34 patients with a primary melanoma located in chronically sun-exposed head and neck skin. was characterized by means of polymerase chain reaction amplification and single-strand conformation polymorphism assay followed by nucleotide sequencing. The results showed that 17.6% of the primary cutaneous and 28.6% of the primary mucosal melanomas had point mutations in. Among the cutaneous melanomas, one showed three mutations in exon 7, and one had two mutations in exon 5; the mutation was in the same allele in both cases. One mucosal melanoma had two mutations in exon 7, both in the same allele, and another had two mutations, one in exon 7 and one in intron 6, both in the same allele. C<--T mutations at dipyrimidine sites, considered fingerprints for ultraviolet light-induced mutations, were about equally distributed among patients with melanomas from chronically sun-exposed areas (six out of nine; 67%) and those with melanomas from unexposed mucosal areas and adjacent skin (eight out of 14; 57%). Our data, demonstrating the presence of such mutations even in melanomas from mucosal membranes, clearly suggest that factors other than, or additional to, ultraviolet radiation are operational in the induction of mutations in melanomas.
Melanoma Res 2002 Oct
PMID:Mutations in the TP53 gene in human malignant melanomas derived from sun-exposed skin and unexposed mucosal membranes. 1239 87

Germ-line mutations of the CDKN2A tumour suppressor gene have been reported in association with familial melanoma, sporadic melanoma with multiple primary lesions and also pancreatic cancer. We studied the hypothesis that patients with melanoma and additional unrelated cancers may harbour mutations in the CDKN2A gene. Twenty seven patients with histologically confirmed melanoma who also had additional cancers such as breast, colorectal, lymphoma and other neoplasms were studied. We also examined 17 additional patients, 13 of whom had a first-degree relative with melanoma and four who had two or more primary melanomas. Some patients belonged to more than one of these categories. No mutations of the CDKN2A tumour suppressor gene were detected among patients with melanoma and additional cancers. The previously described Met53Ile CDKN2A mutation located in exon 2 was detected in a female patient with melanoma metastatic to the regional lymph nodes, multiple primary cutaneous lesions, atypical naevi and a first-degree relative with melanoma. The studied cohort is too small for firm conclusions. However, it would appear that melanoma and additional, apparently unrelated, cancers developing in the same individual are likely to be related to a combination of low-risk susceptibility genes and environmental factors.
Melanoma Res 2002 Dec
PMID:The CDKN2A tumour suppressor gene: no mutations detected in patients with melanoma and additional unrelated cancers. 1245 45

Deletions detected in cytogenetic and loss of heterozygosity (LOH) studies indicate that at least one tumour suppressor gene maps to the long arm of chromosome 10. Previous deletion mapping studies have observed LOH on 10q in about 30% of melanomas analysed. The PTEN gene, mapping to chromosome band 10q23.3, encodes a protein with both lipid and protein phosphatase activity. Somatic mutations and deletions in have been detected in a variety of cell lines and tumours, including melanoma samples. We performed mutation analyses and extensive allelic loss studies to investigate the role this gene plays in melanoma pathogenesis. We found that a total of 34 out of 57 (60%) melanoma cell lines carried hemizygous deletions of chromosome 10q encompassing the PTEN locus. A further three cell lines carried smaller deletions excluding PTEN. Inactivation of both PTEN alleles by exon-specific homozygous deletion or mutation was observed in 13 out of 57 (23%) melanoma cell lines. The mutation spectrum observed does not indicate an important role for ultraviolet radiation in the genesis of these mutations, and evidence from three cell lines supports the acquisition of PTEN aberrations in culture. Ten out of 49 (20%) matched melanoma tumour/normal samples harboured hemizygous deletions of either the whole chromosome or most of the long arm. Mutations within were detected in only one of the 10 tumours demonstrating LOH at 10q23 that were analysed. These results suggest that PTEN inactivation may be important for the propagation of melanoma cells in culture, and that another chromosome 10 tumour suppressor gene may be important for melanoma pathogenesis.
Melanoma Res 2002 Dec
PMID:PTEN inactivation is rare in melanoma tumours but occurs frequently in melanoma cell lines. 1245 46

Deletions in 1p36 in malignant melanoma have been found in high percentages in nodular melanomas and melanoma metastases. Despite many efforts, no candidate tumour suppressor gene associated with malignant melanoma has so far been found in this region. To further determine a possible tumour suppressor gene locus, we carried out a deletion mapping of chromosome 1p36 at nine microsatellite loci in 74 malignant melanomas. Loss of heterozygosity (LOH) in this region was found in 77% of nodular melanomas (NMs), 86% of metastatic melanomas, but only 20% of superficial spreading melanomas (SSMs). Regarding the allelic losses, the nodular and metastatic melanoma samples could be divided into three groups: one showing LOH at the more telomeric loci D1S243 and D1S468 (1p36.33), one displaying allelic loss at the more centromeric loci D1S214 and D1S253 (1p36.32-31) and one with LOH over all informative loci between D1S243 and D1S160. We did not find any significant correlation between a deletion in any of the investigated loci and the survival data of the patients. However, our results confine the deleted region in malignant melanoma to a very small area around 1p36.32, thus facilitating the search for the tumour suppressor gene with importance in malignant melanoma.
Melanoma Res 2003 Feb
PMID:Microsatellite analysis at 1p36.3 in malignant melanoma of the skin: fine mapping in search of a possible tumour suppressor gene region. 1256 82


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