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)

Seven tumour suppressor genes (Chk1, Chk2, Apaf1, Rb1, p53, p16(INK4a) and p14(ARF)) and two oncogenes (N-ras and BRAF) were screened in nine human malignant melanoma (HMM) cell lines for point mutations or small deletions/insertions by DGGE, TGGE and SCCP analysis. For the first time in human mesothelioma, Chk1 gene mutations were detected in two of the nine investigated HMM cell lines. P53 gene mutations were found in three cell lines and p16(INK4a) mutations in 5. Mutation of the Chk1 gene implies a novel disruption mechanism of the p53 pathway in HMM, without affecting p53 itself. According to our knowledge, this is the first mutation screening of Chk1, Chk2, Apaf1 and Rb1 in human malignant mesothelioma.
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PMID:Mutational analysis of 9 different tumour-associated genes in human malignant mesothelioma cell lines. 1607 86

The genetic basis of melanoma susceptibility among Greek patients is uncharacterized. From 107 consecutive cutaneous melanoma patients, we analyzed the CDKN2A and CDK4 loci among 18 early-onset (< or =40 years) and two multiplex melanoma cases. Overall, we found three CDKN2A mutations (3/20; 15%), including one novel nonsense mutation (Trp110Stop) and two Arg24Pro missense alterations. There were no mutations in ARF or CDK4. CDKN2A mutations are not uncommon among Greek melanoma patients considering that none of the mutation carriers reported a family history of melanoma.
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PMID:Germline CDKN2A mutations among Greek patients with early-onset and multiple primary cutaneous melanoma. 1637 56

Human melanoma susceptibility is often characterized by germ-line inactivating CDKN2A (INK4A/ARF) mutations, or mutations that activate CDK4 by preventing its binding to and inhibition by INK4A. We have previously shown that a single neonatal UV radiation (UVR) dose delivered to mice that carry melanocyte-specific activation of Hras (TPras) increases melanoma penetrance from 0% to 57%. Here, we report that activated Cdk4 cooperates with activated Hras to enhance susceptibility to melanoma in mice. Whereas UVR treatment failed to induce melanomas in Cdk4(R24C/R24C) mice, it greatly increased the penetrance and decreased the age of onset of melanoma development in Cdk4(R24C/R24C)/TPras animals compared with TPras alone. This increased penetrance was dependent on the threshold of Cdk4 activation as Cdk4(R24C/+)/TPras animals did not show an increase in UVR-induced melanoma penetrance compared with TPras alone. In addition, Cdk4(R24C/R24C)/TPras mice invariably developed multiple lesions, which occurred rarely in TPras mice. These results indicate that germ-line defects abrogating the pRb pathway may enhance UVR-induced melanoma. TPras and Cdk4(R24C/R24C)/TPras tumors were comparable histopathologically but the latter were larger and more aggressive and cultured cells derived from such melanomas were also larger and had higher levels of nuclear atypia. Moreover, the melanomas in Cdk4(R24C/R24C)/TPras mice, but not in TPras mice, readily metastasized to regional lymph nodes. Thus, it seems that in the mouse, Hras activation initiates UVR-induced melanoma development whereas the cell cycle defect introduced by mutant Cdk4 contributes to tumor progression, producing more aggressive, metastatic tumors.
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PMID:Spontaneous and UV radiation-induced multiple metastatic melanomas in Cdk4R24C/R24C/TPras mice. 1654 Jun 42

Melanomagenesis is a complex phenomenon in which environmental, genetic and host factors play a role. Sun burns in early childhood are a known risk factor in melanoma development. Alteration of prosurvival genes such as Ras and Akt and loss of function of the p16(INK4a)-CDK4/6-pRb and p14(ARF)-HDM2-p53 pathways are strongly associated with human melanoma. We have demonstrated that normally occurring skin hypoxia represents a previously unappreciated host promoting factor in melanomagenesis. Melanocytes that express oncogenes such as Akt, and are therefore genetically unstable, show a transform phenotype only in a mild hypoxic environment that resembles the hypoxic status of the skin. Hypoxia, therefore, is not just a prerogative of advanced neoplasia; physiologic tissue hypoxia, through the activity of HIF1alpha, can function as a promoting factor in tumorigenesis.
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PMID:Skin hypoxia: a promoting environmental factor in melanomagenesis. 1676 Jun 49

Skin cancer is the most common cancer worldwide. Its incidence is doubling every 15-20 years likely because of an aging population, changes in behaviour towards sun exposure, and increased UV light fluency at the earth surface due to ozone depletion. In this review, we summarize the most important genetic changes contributing to the development of malignant melanoma, basal cell carcinoma and squamous cell carcinoma, the main tumor entities arising in the skin. While our understanding of the oncogenes and tumor suppressor genes involved in the development and progression of skin tumors is still fragmentary, recent advances have shown alterations affecting conserved signalling pathways that control cellular proliferation and viability. These pathways include INK4alpha/Rb, ARF/p53, RAS/MAPKs, and sonic hedgehog/Gli.
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PMID:Molecular biology of malignant melanoma and other cutaneous tumors. 1687 May 33

Mutations in the CDKN2A gene underlie melanoma susceptibility in as many as 50% of melanoma kindreds in selected populations, and several CDKN2A founder mutations have been described. Inherited mutations in CDKN2A have been found to be associated with other, non-melanoma cancers including pancreatic cancer (PC) and neural system tumors (NST). Here we report a novel germline mutation in exon 1 of the CDKN2A gene, E27X, which we first detected in melanoma patients living in or originally from a small geographic area bordering Liguria in north-western Italy. A subset of melanoma kindreds positive for this mutation displayed PC and neuroblastoma. E27X generates a premature stop codon, leading to dramatically reduced protein levels of p16 and leaving p14ARF unaltered. As PC and NSTs have been postulated to be preferentially associated with CDKN2A mutations located in exon 2 and/or affecting p14ARF alone, the position of E27X in exon 1alpha provides interesting insights towards clarifying the mechanisms by which the CDKN2A/ARF locus is involved in cancer predisposition.
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PMID:Impact of E27X, a novel CDKN2A germ line mutation, on p16 and p14ARF expression in Italian melanoma families displaying pancreatic cancer and neuroblastoma. 1689 9

A basic toxin from Russell's viper venom of 7.2 kDa (RVV-7) has been purified to homogeneity after partial unfolding by 4 M urea followed by filtration through Centricon-30 membrane. Its N-terminal sequence showed strong homology with snake venom cytotoxins. Cytotoxic activity of RVV-7 has been demonstrated with B16F10 melanoma cells. PLA2 activity was observed in cytotoxin (CX3) from Naja kauthia bearing sequence homology with RVV-7. Phospholipase A2 and trypsin inhibitory activities were also observed with RVV-7. Chemical modification and inhibition studies suggested independent functional sites for these activities. A qualitative assessment of tumor growth inhibition by RVV-7 has been made.
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PMID:Purification and characterization of a low molecular weight multifunctional cytotoxic phospholipase A2 from Russell's viper venom. 1699 39

Linkage to the CDKN2A locus has been demonstrated in approximately 50% of families with hereditary malignant melanoma but only a subgroup of these harbor identified mutations. We here report a Norwegian melanoma-prone family with a novel large germline deletion removing 13707 bps of the CDKN2A gene, including exon 1alpha and approximately half of exon 2. Our finding is the first reported large CDKN2A germline deletion with a breakpoint located within an exon. This type of deletion is not detectable through the direct exon sequencing and may also escape identification by use of multiplex ligation-dependent probe amplification (MLPA) analysis. Here, the defect was identified through detection of a truncated p14(ARF) mRNA and loss of p16(INK4a) mRNA expression from the affected allele. Our finding suggests that atypical, large deletions in the CDKN2A gene may explain linkage to the 9p21 chromosome band without identified gene mutations among melanoma-prone families. Thus, it illustrates the need to include p14(ARF)- and p16(INK4a) transcript analysis when searching for unknown mutations within the CDKN2A locus in melanoma-prone families. Similar deletions with atypical breakpoints may affect other genes involved in cancer disposition, and the need to examine gene transcripts in high-risk families with no mutation identified through conventional testing should be considered.
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PMID:A novel type of deletion in the CDKN2A gene identified in a melanoma-prone family. 1700 21

Since phenoxazine is an essential structure of actinomycin D, which exerts a strong anticancer effect, we examined the anticancer effect of 2-aminophenoxazine-3-one (Phx-3) on mouse malignant melanoma B16 cells in vitro and in vivo. Phx-3 inhibited proliferation of the B16 cells in a dose-dependent manner in vitro. We furthermore studied the in vivo effects of Phx-3 on mouse malignant melanoma B16 cells transplanted in female C57BL/6Cr Slc mice. Treatment with Phx-3 (0.5 mg/kg) completely suppressed the growth of mouse malignant melanoma B16 cells transplanted in mice as compared with the control group. Phx-3 was found to exert few adverse effects, in terms of bodyweight loss, changes in serum levels of blood biochemical parameters such as aspartate transaminase (AST), alanine transaminase (ALT), blood urea nitrogen (BUN) and creatinine, dysfunction of the liver and the kidney examined by pathological methods, piloerection and wasting, when mice were treated with a dose of 0.5 mg/kg. These results suggest that Phx-3 may be used to treat patients affected by malignant melanoma in future.
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PMID:2-aminophenoxazine-3-one suppresses the growth of mouse malignant melanoma B16 cells transplanted into C57BL/6Cr Slc mice. 1707 14

Arginine deiminase (ADI) catalyzes the irreversible hydrolysis of arginine to citrulline and ammonia. It belongs to a newly classified superfamily of guanidino-group-modifying enzymes. Located in the catalytic center of Mycoplasma hominis ADI, some crucial sites (Asp160, Glu212, His268, and Asp270) are highly conserved among these enzymes. Here, we constructed five ADI single mutants D160E, E212D, H268F, H268Y, and D270E, and three double mutants D160E/D270E, D160E/E212D, and E212D/D270E, aiming to evaluate the contributions of these crucial residues to the structure, stability, and enzymatic activity of ADI, and to elucidate their roles in the catalytic process of this family of enzymes. Tryptophan emission fluorescence and circular dichroism were used to analyze the different effects of mutagenesis on these conserved residues on the secondary and tertiary structures of ADI. Urea-induced unfolding and trypsin digestion were applied to measure their stabilities against denaturants and proteases, respectively. Additionally, the enzymatic activities of ADI and its mutants were measured. Here, we report that all the mutations have little effect on the native structure of ADI. However, the substitutions on these crucial sites still interfere with the stability of ADI to different degrees. As these mutations impair both the substrate binding and the substrate induced conformational changes of ADI to different extents, most of the mutants except D160E (preserves about 30% of the enzymatic activity of wild type) have totally lost the enzymatic activity in the hydrolysis of arginine and the inhibitory ability on the proliferation of mouse melanoma cells.
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PMID:Insight into the catalytic mechanism of arginine deiminase: functional studies on the crucial sites. 1708 Apr 55


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