Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The INK4a-ARF locus, localized on 9p21, encodes two tumor suppressor proteins, p16INK4a and p14ARF, acting respectively through the CDK4-pRb and the p53 pathways. Familial melanoma (comprising between 8 and 12% of all melanoma cases) is a genodermatosis transmitted as an autosomal dominant trait, often associated with clinically atypical moles (AN). Germline mutations of p16INK4a are found in up to 20-30% of melanoma prone families. Mutated families often contain more than three family members affected and/or comprise at least one relative with multiple melanomas. Most of these mutations have been shown to affect p16INK4a protein function (i.e. CDK4 binding or pRB phosphorylation). Germline mutations of p16INK4a are also found in a lesser extend in sporadic multiple melanoma and in familial pancreatic cancer. The INK4a-ARF locus plays also an important role in skin carcinogenesis. P16INK4a UV induced mutations (CC:GG > TT:AA tandem transition or C:G > T:A transition at dipyrimidic site) are found in 12% of sporadic skin carcinomas, mainly in epidermoid tumors, and seem to occur independently of p53 mutations. Xeroderma pigmentosum (XP) is characterized by an inheritable DNA repair defect (involving the nucleotid excision repair (NER) system) predisposing to skin carcinomas. In skin tumors from (XP) patients, p16INK4a UV induced mutations occur more frequently, are often multiple, and significantly associated with the presence of p53 mutations. Such data, which could be related to the XP genetic instability and indicates a possible cooperative effect of inactivation of these pathways in the tumoral process of XP skin tumors.
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PMID:[The INK4a-ARF locus: role in the genetic predisposition to familial melanoma and in skin carcinogenesis]. 1174 99

Dual inactivation of PTEN and INK4a/ARF tumor suppressor genes is a common feature observed in a broad spectrum of human cancer types. To validate functional collaboration between these genes in tumor suppression, we examined the biological consequences of Pten and/or Ink4a/Arf deficiency in cells and mice. Relative to single mutant controls, Ink4a/Arf-/-Pten+/- mouse embryonic fibroblast cultures exhibited faster rates of growth in reduced serum, grew to higher saturation densities, produced more colonies upon low density seeding, and showed increased susceptibility to transformation by oncogenic H-Ras. Ink4a/Arf deficiency reduced tumor-free survival and shortened the latency of neoplasias associated with Pten heterozygosity, specifically pheochromocytoma, prostatic intraepithelial neoplasia, and endometrial hyperplasia. Compound mutant mice also exhibited an expanded spectrum of tumor types including melanoma and squamous cell carcinoma. Functional synergy between Ink4a/Arf and Pten manifested most prominently in the development of pheochromocytoma, prompting an analysis of genes and loci implicated in this rare human neoplasm. The classical pheochromocytoma genes Ret, Vhl, and Nf-1 remained intact, a finding consistent with the intersection of these genes with pathways engaged by Pten and Ink4a/Arf. Notably, conventional and array-comparative genomic hybridization revealed frequent loss of distal mouse chromosome 4 in a region syntenic to human chromosome 1p that is implicated in human pheochromocytoma. This study provides genetic evidence of collaboration between Pten and Ink4a/Arf in constraining the growth and oncogenic transformation of cultured cells and in suppressing a wide spectrum of tumors in vivo.
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PMID:Genetic analysis of Pten and Ink4a/Arf interactions in the suppression of tumorigenesis in mice. 1181 30

The aim of this study was to investigate antitumour activity of cisplatin, dacarbasine, cyclophosphamide and a new compound from the nitrosourea group--acetamido-CNU ((2-chloroethyl)-1-nitroso-3-(methylenecarboxamido)-urea)--applied with or without local hyperthermia (43.5 degrees C/60 min). The tumour model for the investigation of antitumour activity was a mouse melanoma B16 transplanted into the footpad. Dacarbasine, cyclophosphamide and acetamido-CNU applied as a single treatment had statistically significant antitumour activity, while cisplatin applied as a single agent had no effect. Local hyperthermia alone had statistically significant antitumour activity. The best therapeutic effect (synergistic) was obtained when combined treatment (cytotoxins plus local hyperthermia) was used. Synergistic therapeutic results were achieved even when cisplatin and hyperthermia were combined, although cisplatin was ineffective when given as a single agent. Therapeutic results achieved with acetamido-CNU (newly synthesized compound) applied alone were similar to the therapeutic results achieved with dacarbasine or cyclophosphamide. In combined therapy (acetamido-CNU + HT), achieved therapeutic results were significantly better (p < 0.05) than results achieved by combining cisplatin and hyperthermia or dacarbasine and hyperthermia.
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PMID:Cell killing of melanoma B16 in vivo by hyperthermia and cytotoxins. 1182 Apr 69

Cutaneous malignant melanoma (CMM) is an interesting example of multifactorial disease, where both genetic and environmental factors are involved and interact. Major risk factors include a personal and familial history of melanoma, cutaneous and pigmentary characteristics, sun exposure and reactions to sun exposure. Phenotypic risk factors are likely to be genetically determined. Two high-risk melanoma susceptibility genes-CDKN2A and CDK4-have been identified to date, with a third gene p14(ARF) also being suspected of playing a role. Other high-risk genes are anticipated by the existence of 9p21-unlinked families. A low-risk melanoma-susceptibility gene-MC1R-has also been identified. Current studies aim to identify other susceptibility genes as well as to determine the respective contributions and interactions of the various genetic and environmental factors of CMM and associated phenotypes.
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PMID:Genetic and environmental factors in cutaneous malignant melanoma. 1190 Aug 78

Familial melanoma predisposition is associated with germline mutations at the CDKN2A/ARF locus in up to 40% of families. The exact role of the two proteins encoded by this complex locus in this predisposition is unclear. Most mutations affect either CDKN2A only or products of both genes. Recently a deletion affecting ARF-specific exon 1beta was reported in a family with melanoma and neural tumours. However, the possibility of this deletion also altering the CDKN2A transcript could not be excluded. More convincingly, a 16 base pair insertion in exon 1beta has been reported in an individual with multiple melanomas suggesting a direct role for ARF in melanoma predisposition. We report here a splice mutation in exon 1beta in a family with melanoma that results in ARF haploinsufficiency. The mutation was observed in a mother and daughter with melanoma. A sibling of the mother with breast cancer also had this mutation. Analysis of the melanoma from one individual revealed a 62 bp deletion in exon 3 of the wildtype allele and loss of the mutant allele; these somatic changes would affect both CDKN2A and ARF. These somatic events suggest that concomitant inactivation of both ARF and CDKN2A may be necessary for melanoma development and that mutations in ARF and CDKN2A possibly confer different levels of susceptibility to melanoma, with the former associated with lesser predisposition. In this situation, the events follow a 'three-hit' model as observed in tumours from FAP patients with an attenuated phenotype. Overall, the data suggest a direct role for ARF haploinsufficiency in melanoma predisposition and co-operation between ARF and CDKN2A in tumour formation, consistent with recent observations in Cdkn2a-specific knockout mice.
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PMID:Germline mutation of ARF in a melanoma kindred. 1201 8

The CDKN2A tumour suppressor locus encodes two distinct proteins, p16(INK4a) and p14(ARF), both of which have been implicated in replicative senescence, the state of permanent growth arrest provoked in somatic cells by aberrant proliferative signals or by cumulative population doublings in culture. Here we describe primary fibroblasts from a member of a melanoma-prone family who is homozygous for an intragenic deletion in CDKN2A. Analyses of the resultant gene products imply that the cells are p16(INK4a) deficient but express physiologically relevant levels of a frameshift protein that retains the known functions of p14(ARF). Although they have a finite lifespan, the cells are resistant to arrest by oncogenic RAS. Indeed, ectopic expression of RAS and telomerase (hTERT) results in outgrowth of anchorage-independent colonies that have essentially diploid karyotypes and functional p53. We find that in human fibroblasts, ARF is not induced demonstrably by RAS, pointing to significant differences between the proliferative barriers implemented by the CDKN2A locus in different cell types or species.
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PMID:INK4a-deficient human diploid fibroblasts are resistant to RAS-induced senescence. 1206 7

Cell senescence is the loss of ability to divide after a finite number of divisions, seen in normal mammalian somatic cells and often disrupted in cancer cells. The three genes so far associated with familial melanoma susceptibility--INK4A, CDK4 and ARF, are all implicated in the molecular pathways controlling cell senescence. Here we review those pathways, both as generally studied in fibroblasts and epithelial cells, and as specifically analysed in melanocytes. Key molecular effectors in melanocyte senescence appear to include some in common with other cell types - telomere attrition and the p16/RB pathway, and one that is not commonly mentioned in this connection, the cAMP signalling pathway that also regulates melanocyte differentiation. These findings are discussed in relation to the role of cell senescence in the development and molecular genetics of melanoma and its precursor lesions.
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PMID:Molecular regulation of melanocyte senescence. 1210 Apr 89

We investigated the need for continuous immunosuppression to maintain experimental tumours derived from human uveal melanoma cells implanted in the choroid of pigmented rabbits. Two groups of pigmented rabbits immunosuppressed with cyclosporin A (CsA) were implanted with human uveal melanoma cells in the suprachoroidal space. After 5 weeks, CsA was discontinued in group 2. Animals were treated with prophylactic antibiotics and examined weekly for tumour growth, weight and secondary effects; blood urea nitrogen levels were measured every two weeks. Autopsies and histopathological studies were performed after death or euthanasia at the end of week 12. The difference between the groups in the development of ophthalmoscopic tumours was not statistically significant 5 weeks after implantation. Tumours in group 1 grew progressively throughout the experiment, whereas group 2 tumours showed marked regression 3-4 weeks after discontinuing CsA. Tumours in group 1 were significantly larger and had greater mitotic activity and showed more ciliary body, optic nerve and extrascleral invasion than tumours in group 2, which showed massive fibrosis, minimal mitotic activity and marked inflammatory cell infiltration. Continuous immunosuppression with CsA seems to be necessary to maintain tumour growth in this experimental model of uveal melanoma.
Melanoma Res 2002 Oct
PMID:The need for continuous immunosuppression with cyclosporin A to maintain an experimental model of uveal melanoma. 1239 85

Cutaneous malignant melanoma (CMM), already known for its highly aggressive behavior and resistance to conventional therapy, has evolved into a health crisis by virtue of a dramatic elevation in incidence. The underlying genetic basis for CMM, as well as the fundamental role for UV radiation in its etiology, is now widely accepted. However, the only bona fide genetic locus to emerge from extensive analysis of CMM suppressor candidates is INK4a/ARF at 9p21, which is lost frequently in familial and occasionally in somatic CMM. The functional relationship between INK4a/ARF and UV radiation in the pathogenesis of CMM is largely unknown. Recently, we reported that hepatocyte growth factor/scatter factor (HGF/SF)-transgenic mice develop melanomas after a single erythemal dose of neonatal UV radiation, supporting epidemiological data implicating childhood sunburn in CMM. Here we show that neonatal UV irradiation induces a full spectrum of melanocyte pathology from early premalignant lesions through distant metastases. Cutaneous melanomas arise with histopathological and molecular pathogenetic features remarkably similar to CMM, including loss of ink4a/arf. A role for ink4a/arf in UV-induced melanomagenesis was directly assessed by placing the HGF/SF transgene on a genetic background devoid of ink4a/arf. Median time to melanoma development induced by UV radiation was only 50 days in HGF/SF ink4a/arf(-/-) mice, compared with 152 and 238 days in HGF/SF ink4a/arf(+/-) and HGF/SF ink4a/arf(+/+) mice, respectively. These studies provide experimental evidence that ink4a/arf plays a critical role in UV-induced melanomagenesis and strongly suggest that sunburn is a highly significant risk factor, particularly in families harboring germ-line mutations in INK4a/ARF.
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PMID:Ink4a/arf deficiency promotes ultraviolet radiation-induced melanomagenesis. 1243 73

Epidemiological studies support a link between melanoma risk and UV exposure early in life, yet the molecular targets of UV's mutagenic actions are not known. By using well characterized murine models of melanoma, we provide genetic and molecular evidence that identifies components of the Rb pathway as the principal targets of UV mutagenesis in murine melanoma development. In a melanoma model driven by H-RAS activation and loss of p19(ARF) function, UV exposure resulted in a marked acceleration in melanoma genesis, with nearly half of these tumors harboring amplification of cyclin-dependent kinase (cdk) 6, whereas none of the melanomas arising in the absence of UV treatment possessed cdk6 amplification. Moreover, UV-induced melanomas showed a strict reciprocal relationship between cdk6 amplification and p16(INK4a) loss, which is consistent with the actions of UV along the Rb pathway. Most significantly, UV exposure had no impact on the kinetics of melanoma driven by H-RAS activation and p16(INK4a) deficiency. Together, these molecular and genetic data identify components of the Rb pathway as critical biological targets of UV-induced mutagenesis in the development of murine melanoma in vivo.
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PMID:Components of the Rb pathway are critical targets of UV mutagenesis in a murine melanoma model. 1253 79


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