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)

Chemotherapeutic agent-induced DNA cleavage gives rise to apoptosis in a subpopulation of SK-N-SH human neuroblastoma cells; the remaining cells undergo Schwann cell-like differentiation. Like other neural crest and primitive neurectodermal tumor-derived cell lines, SK-N-SH cultures contain cells of neural (N-type) and epithelial (substrate-adherent, or S-type) phenotypes. Using isolated N-type and S-type cells from neuroblastoma, medulloblastoma, melanoma and glioma cell lines, we demonstrate that the determinants of the response to DNA cleavage are intrinsic properties of the cell. Furthermore, using a series of analogues of enediyne deoxyribonucleic acid (DNA) cleaving agents, we show that the molecular target of these agents is likely to be the same in N- and S-type cells, implying that the difference in response characteristics is a function of different distal pathways that are triggered by DNA cleavage. We demonstrate that the concentration of the DNA damaging agent used, and not the specific characteristics of the damage it produces, is the trigger for production of the cellular response. Response type does not correlate with previously published values for expression of the apoptosis modulators Bcl-2, Bcl-XL, wildtype p53, or, in medulloblastoma lines, p75.
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PMID:Determinants of the response of neuroblastoma cells to DNA damage: the roles of pre-treatment cell morphology and chemical nature of the damage. 862 28

DNA-damaging agents such as ionizing radiation (IR) activate the tumor suppressor p53, and, in turn, p53 transactivates a number of downstream effector genes such as GADD45, CIP1/WAF1, and MDM2. The induction of these downstream genes following IR appears to be strictly dependent upon the presence of wild-type functional p53 known to evoke G1 arrest. In this study, we characterized 56 cell lines from 9 different tumor types with predetermined p53 genotype by measuring the induction of GADD45, CIP1/WAF1, and MDM2 relative mRNA levels after IR. A higher fraction of melanoma lines had wild-type (wt) p53 (5/8, or 63%) compared to the nonmelanoma lines (11/48, or 23%). Most wt p53 (nonmelanoma) cell lines (11/12, or 92%) showed clear induction of both GADD45 and CIP1/WAF1. On the other hand, many wt p53 melanoma lines (4/5, or 80%) showed normal induction of CIP1/WAF1, but little or no induction of GADD45. Despite this defect in GADD45 induction, we found that all wt p53 melanoma lines exhibited strong G1 arrest and increased levels of p53 protein after IR. The results demonstrated that radiation-induced G1 arrest could occur by the p53-CIP1/WAF1 pathway without appreciable induction of GADD45 in melanoma lines. Time course experiments demonstrated prolonged induced expression of CIP1/WAF1 mRNA transcripts in melanoma lines in which GADD45 induction was lacking, suggesting some sort of compensatory mechanism involving CIP1/WAF1, in cell lines with defective GADD45 induction. We could reproduce this compensatory effect in RKO colon carcinoma cells in which GADD45 expression was blocked by constitutive antisense vectors. These findings reveal that defective induction of GADD45 following IR is common in human melanoma cell lines.
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PMID:An abnormality in the p53 pathway following gamma-irradiation in many wild-type p53 human melanoma lines. 863 Oct 22

Treatment of a human breast cancer cell line (MDA-MB-435) in nude mice with a recombinant adenovirus containing the human interferon (IFN) consensus gene, IFN-con1 (ad5/IFN), resulted in tumor regression in 100% of the animals. Tumor regression occurred when virus was injected either within 24 hr of tumor cell implantation or with established tumors. However, regression of the tumor was also observed in controls in which either the wild-type virus or a recombinant virus containing the luciferase gene was used, although tumor growth was not completely suppressed. Tumor regression was accompanied by a decrease in p53 expression. Two other tumors, the human myelogenous leukemic cell line K562 and the hamster melanoma tumor RPMI 1846, also responded to treatment but only with ad5/IFN. In the case of K562 tumors, there was complete regression of the tumor, and tumors derived from RPMI 1846 showed partial regression. We propose that the complete regression of the breast cancer with the recombinant virus ad5/IFN was the result of two events: viral oncolysis in which tumor cells are being selectively lysed by the replication-competent virus and the enhanced effect of expression of the IFN-con1 gene. K562 and RPMI 1846 tumors regressed only as a result of IFN gene therapy. This was confirmed by in vitro analysis. Our results indicate that a combination of viral oncolysis with a virus of low pathogenicity, itself resistant to the effects of IFN and IFN gene therapy, might be a fruitful approach to the treatment of a variety of different tumors, in particular breast cancers.
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PMID:Treatment of a human breast cancer xenograft with an adenovirus vector containing an interferon gene results in rapid regression due to viral oncolysis and gene therapy. 863

Using a p53 encoding cDNA fragment of rainbow trout (Oncorhynchus mykiss) as probe, a lambda clone from a platyfish (Xiphophorus maculatus) genomic library was isolated. DNA sequencing of the insert from this clone revealed that it contained the highly conserved domains IV and V of the p53 polypeptide. To map the Xiphophorus p53 gene, joint segregation analysis of the inheritance of a PstI-generated DNA restriction fragment length polymorphism (RFLP) and the inheritance of 36 polymorphic protein and DNA markers was performed in backcross hybrids of X. clemenciae x (X. clemenciae x X. milleri) and X. helleri x X. (helleri x X. maculatus Jp 163 B) using Oncorhynchus cDNA and Xiphophorus genomic p53 probes, respectively. The p53-hybridizing sequence (TP53) was linked to the ACO1 (cytosolic aconitase) locus in both crosses, and defines a new Xiphophorus linkage group, designated LG XIV. This is the first mapping assignment of a known human tumor suppressor gene in fish. Since ACO1 is not linked with melanoma severity in X. helleri x X. maculatus Jp 163 A backcross hybrids, these data indicate that homozygosity for the X. helleri TP53 genotype in backcross hybrids of the cross type is not associated with genetically regulated malignant melanoma formation in the Gordon-Kosswig hybrid melanoma model.
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PMID:Assignment of the TP53 orthologue to a new linkage group (LG XIV) in fish of the genus Xiphophorus (Teleostei: Poeciliidae). 864 Jul 24

Allelic loss in human cutaneous melanoma has been detected on chromosomes 1p, 6q, 9p, 10q, and 11q. Chromosome 17 contains important tumor suppressor genes such as p53, NM23, and neurofibromatosis type 1 (NF1), which have been implicated in melanoma tumorigenesis. The role of p53 has already been studied by a number of laboratories, showing contrasting results. In the present study, two restriction fragment length polymorphism (RFLP) probes for the NM23 and NF1 genes, together with five other RFLP and four variable number of tandem repeat chromosome 17 probes, were investigated at the loss of heterozygosity (LOH) level in a Southern blot-based assay. The NF1 gene was also tested for LOH by a polymerase chain reaction (PCR)-based approach in two different experiments, using a dinucleotide repeat polymorphic probe at locus D17S250 (17q11.2-q12), and an Alu probe intragenic to the NF1 gene (17q11.2). A PCR single-strand conformation polymorphism assay was included in the study for mutation detection at the NF1-GTPase-activating protein-related domain (GRD). A total of 68 melanocytic tumors were analyzed. LOH was detected in 9 of 87 informative cases (10%). LEW301 (17p11.2-pcen) presented the highest LOH frequency (22%). NM23 showed LOH in 17% of the informative cases, while NF1 did not show either LOH in the Southern blot- and PCR-based experiments or mutations at the NF1-GRD. These results are in concordance with those of previous smaller studies, but when compared with higher LOH frequencies obtained from other chromosomes, these findings indicate that the LOH values found in our study can most likely be attributed to background effect. Thus, chromosome 17 LOH is likely to play and unimportant role as a genetic event in melanoma tumorigenesis. Nevertheless, NF1 merits further study, since homozygous deletions have been detected at this locus in melanoma cell lines.
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PMID:Chromosome 17 allelic loss and NF1-GRD mutations do not play a significant role as molecular mechanisms leading to melanoma tumorigenesis. 864 72

G3361/CP cells, a cisplatin (CDDP)-resistant subclone of the human melanoma cell line G3361, overexpress wild-type p53 protein and demonstrate an increase in the percentage of cells in G0--G1 arrest compared to parental cells. Exposing G3361/CP cells to human recombinant IFN-alpha2a reduces the high basal levels of p53, releases G3361/CP cells from G0-G1 into S phase, and abrogates CDDP resistance. These findings suggest that recombinant IFN-alpha2a disrupts p53-mediated cell cycle regulation to restore CDDP sensitivity in G3361/CP cells.
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PMID:Modulation of p53 expression by human recombinant interferon-alpha2a correlates with abrogation of cisplatin resistance in a human melanoma cell line. 865 90

Studies in melanoma patients have shown that unaltered self proteins can function as targets for tumor-reactive CTL. Here, we have investigated in a murine model whether autoreactive CTL can be found against the widely expressed proteins cyclin D1, mdm2, and p53, which are frequently overexpressed in transformed cells. Sixteen MHC class I binding peptides were identified in these proteins, and seven of them consistently stimulated primary CTL in vitro. Avidity measurements revealed that the avidity of peptide-induced CTL differed by >1000-fold. The highest avidity CTL were induced by a peptide derived from mdm2. These CTL recognized target cells expressing mdm2 endogenously, while CTL generated against the remaining peptides were of lower avidity and did not recognize cells expressing relevant proteins endogenously. Generation of high avidity anti-mdm2 CTL required several cycles of peptide stimulation, suggesting that the CTL precursor frequency was low. The data show the normal T cell repertoire contains small numbers of potentially autoreactive CTL. Expansion of these CTL may lead to beneficial autoimmunity against tumors, but, equally, it may be the basis of detrimental autoimmune diseases.
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PMID:A synthetic peptide derived from the tumor-associated protein mdm2 can stimulate autoreactive, high avidity cytotoxic T lymphocytes that recognize naturally processed protein. 868 21

Actinic keratoses (AKs) are small scaly red areas of skin characterised histologically by dysplasia, a minority of which are thought to be precursors of squamous cell carcinoma (SCC), and which show a high frequency of regression. Surprisingly, in view of their benign clinical course, they show a high frequency of loss of heterozygosity (LOH) with a median loss of four loci with almost 20% of lesions showing loss of eight or more alleles, as well as frequent p53 mutation. Loss was common on 3p (31%), 9p (39%), 9q (22%), 13q (52%), 17p (64%) and 17q (46%), and allele loss correlated with dysplasia. Topological disturbance of p21WAF1/CIP1 expression correlated with allele loss but was also seen together with increased wild-type p53 expression and an increase in the fraction of cycling cells in the absence of allele loss or p53 mutation, and is likely to represent an early change. P21WAF1/CIP1 expression appeared independent of p53 status. The frequency of LOH in AKs exceeded that of (invasive) SCCs suggesting that the relation between the accumulation of genetic change and behaviour for non-melanoma skin cancer is not straightforward.
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PMID:Genetic change in actinic keratoses. 870 May 6

Alterations of the p53 tumor suppressor gene are the most frequent genetic abnormalities in human malignancies, but the role of p53 in the etiology of malignant melanomas is unclear. Fifty unselected malignant melanomas were analyzed for p53 overexpression by immunohistochemistry using 3 monoclonal antibodies (MAbs). Fifteen tumors (29.4%) showed positive staining with at least 2 different antibodies. In the first 20 consecutive tumors exons 5-9 and adjacent splice sites of the p53 gene were analyzed by genomic sequencing. There were 4 mutations in 20 metastatic melanomas. Three of 4 mutations were C:G-->T:A transitions. A search of our database of p53 mutations revealed that out of 8 p53 mutations reported by others, 4 are C:G-->T:A transitions at dipyrimidine sites, and one is a tandem CC-->TT mutation. This mutational pattern is comparable with the pattern of p53 mutations in squamous cell and basal cell carcinomas of the skin and is related to exposure to ultraviolet B (UV-B) wavelength radiation. Taken together with a predominance of UV-induced mutations in the CDKN2/ p16 gene demonstrated in melanoma cell lines, our data support a role of sunlight exposure in the etiology of malignant melanoma. The low frequency of p53 mutants in melanomas compared with other types of skin cancers suggests that although mutations in this gene are likely to be involved in the development of some malignant melanomas, they do not play as large a role as in squamous and basal cell carcinomas of the skin.
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PMID:Overexpression and mutations of p53 in metastatic malignant melanomas. 870 1

Mutations of the p53 tumor-suppressor gene are the most common genetic alterations in human cancer, found in approximately 50% of all tumors. The importance of p53 in human cancer attracts attention in molecular studies dealing with the pathogenesis, diagnosis and prognosis in tumor pathology. This review summarizes the current understanding of p53 both on the genetic and protein level. Frequency and spectrum of somatic p53 mutations in the carcinogenesis of breast cancer, colorectal cancer, gastric cancer, hepatocellular carcinoma, squamous-cell carcinoma of the skin and malignant melanoma are discussed including our own investigations and studies published in the literature.
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PMID:[Tumor suppressor gene p53. Theoretical principles and their significance for pathology]. 871 Jul 88


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