Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have examined the mechanism of transformation of a line of immortalized hamster dermal fibroblasts (4DH2 cells) following treatment with the simple alkylating agents, N-methyl-N-nitrosourea (MNU), N-ethyl-N-nitrosourea (ENU) and dimethyl sulphate (DMS). Treatment of 4DH2 cells with the potent point mutagens MNU and ENU gave rise to a spectrum of foci of different sizes, including progressively growing large foci and compact small foci. In contrast, treatment with the weak point mutagen DMS produced mostly large foci. The ability of cell lines derived from morphologically transformed foci to grow in soft agar in general reflects their original size. Thus most cell lines derived from large foci grew in soft agar while most lines derived from small foci did not. Transfection of cellular DNAs into the parent 4DH2 cell line and into NIH3T3 mouse fibroblasts has revealed the presence of dominantly acting transforming genes in the chemically transformed cell lines. Thus DNA from five of six cell lines derived by culturing large foci and from one of three cell lines derived by culturing small foci induced efficient morphological transformation of the recipient cells. Southern analyses of DNA from primary and secondary transfectants showed that several of the transforming genes transferred in these experiments were not closely related to H-ras, K-ras or N-ras.
Carcinogenesis 1988 Sep
PMID:Morphological transformation of immortalized hamster dermal fibroblasts following treatment with simple alkylating carcinogens. 304 38

Ultraviolet (UV) light is an important environmental mutagen and one of the major factors in the etiology of skin cancer in man. In this study we have addressed the question whether UV light can activate in vitro the N-ras proto-oncogene into an active oncogene, and whether pyrimidine cyclobutane dimers or (6-4) photoproducts are the premutagenic lesion. To that end, the cloned human N-ras proto-oncogene (pN-ras) was irradiated with UV light (254 nm) which results in the formation of cyclobutane dimers and (6-4) photoproducts and the irradiated DNA was transfected into Rat-2 cells. Whereas untreated pN-ras never gave foci upon transfection into Rat-2 cells, UV-irradiated pN-ras (100-300 J.m-2) yielded 1-2 foci/micrograms DNA. The DNAs of 49 primary foci were subjected to a second round of transfection. 13 of these were positive. The DNAs that did not give rise to secondary foci invariably contained high copy numbers of pN-ras. The DNAs from the secondary foci had only a low copy number of pN-ras. Using synthetic oligonucleotide probes we have found that all N-ras genes that gave rise to secondary foci contained a mutation at positions in codon 12 or 61. Only one primary transformant, negative in the secondary transformation assay, was shown to harbor a mutated N-ras gene. From these results we conclude that UV light can activate N-ras genes. Mutations were preferentially found at the 61st codon (11), harboring a TT doublet, while only 3 mutations were found at the 12th codon and none at the 13th codon, both harboring CC doublets. Of the 14 point mutations analysed 6 represented transitions and 8 transversions. No specific base-substitution could be regarded as predominant. Furthermore, treatment of the irradiated N-ras plasmids with photoreactivating enzyme prior to transfection, which specifically monomerizes cyclobutane dimers but not other photoproducts, reduced the transformation frequency several fold. None of the 36 DNAs from the primary foci obtained after transfection of photoreactivating enzyme-treated N-ras gave rise to secondary foci. These DNAs all contained high copy numbers of unmutated pN-ras. From this result we conclude that cyclobutane dimers, and not (6-4) photoproducts, are the major premutagenic lesions, responsible for the activation of N-ras. The possible role of ras genes as targets for UV-induced carcinogenesis is discussed.
 ...
PMID:Activation of N-ras induced by ultraviolet irradiation in vitro. 306 Aug

Tumorigenic guinea pig cell lines with mutationally activated N-ras alleles also exhibited up-regulated N-ras mRNA. Mutational activation and mRNA up-regulation were limited to tumorigenic cells; preneoplastic progenitors were unaffected. Therefore, up-regulation occurred at a late stage of carcinogenesis closely associated with acquisition of tumorigenicity. cDNA and S1 protection analysis demonstrated that polyadenylation site of the short N-ras message and the mRNA start sites were different from that reported for human. The promoter region contained no canonical TATA or CCAAT boxes, but exhibited GGGCGG and CCGCCC SPl binding motifs characteristic of growth control genes. Moreover, both mutant and wild-type alleles were up-regulated in a guinea pig line heterozygous for N-ras codon 61. Coordinate N-ras mutational activation and up-regulation in five independent tumorigenic lines with unique chromosome constitutions suggests that both events are required for expression of the neoplastic phenotype.
 ...
PMID:Coordinate N-ras mRNA up-regulation with mutational activation in tumorigenic guinea pig cells. 327 1

It has been well established that specific alterations in members of the ras gene family, H-ras, K-ras and N-ras, can convert them into active oncogenes. These alterations are either point mutations occurring in either codon 12, 13 or 61 or, alternatively, a 5- to 50-fold amplification of the wild-type gene. Activated ras oncogenes have been found in a significant proportion of all tumors but the incidence varies considerably with the tumor type: it is relatively frequent (20-40%) in colorectal cancer and acute myeloid leukemia, but absent or present only rarely in, for example, breast tumors and stomach cancer. No correlation has been found, yet, between the presence of absence of an activated ras gene and the clinical or biological features of the malignancy. The activation of ras oncogenes is only one step in the multistep process of tumor formation. The presence of mutated ras genes in benign polyps of the colon indicates that activation can be an early event, possibly even the initiating event. However, it can also occur later in the course of carcinogenesis to initiate for instance the transition of a benign polyp of the colon into a malignant carcinoma or to convert a primary melanoma into a metastatic tumor. Apparently, the activation of ras genes is not an obligatory event but when it occurs it can contribute to both early and advanced stages of human carcinogenesis.
 ...
PMID:The ras gene family and human carcinogenesis. 328 42

A transforming N-ras gene was isolated from the SHAC human stomach fibrosarcoma cell line. A single-point mutation resulting in the substitution of histidine for glutamine at codon 61 was found in the SHAC transforming allele. The N-ras gene is overexpressed in the tumor cells and transformant cells. The N-ras p21 product was studied by immunoprecipitation and showed no alteration in mobility as compared to the normal p21 protein. The c-myc gene is amplified and overexpressed in these cells. This report gives evidence that an amplified c-myc and a mutated N-ras gene are both present in this tumor cell line and provides support for the idea that co-operation of at least 2 activated cellular oncogenes is required for carcinogenesis.
 ...
PMID:Both N-ras and c-myc are activated in the SHAC human stomach fibrosarcoma cell line. 328 24

DNAs from fourteen fibrosarcomas induced by 3-methylcholanthrene (MCA) in BALB/c mice were analyzed for the presence of transforming oncogenes following transfection on NIH3T3 cells. Six transfection-positive DNAs contained an activated ras gene: four c-K-ras and two c-N-ras. These results demonstrate that c-K-ras is not the only oncogene of the ras family activated in MCA-induced murine fibrosarcomas as was previously indicated.
Carcinogenesis 1988 Aug
PMID:Activated c-K-ras and c-N-ras oncogenes in 3-methylcholanthrene-induced BALB/c fibrosarcomas. 340 50

DNAs from five intestinal adenocarcinomas induced by 2-aminodipyrido[1,2-a:3',2'-d]imidazole, which is present in broiled fish, were subjected to transfection assay using NIH3T3 cells as recipients. The DNA from only one adenocarcinoma induced a morphologically transformed focus. Rat N-ras sequences were detected in the primary transformant and in three tested secondary transformants. In the activated N-ras oncogene, a G----T transversion at the first letter of codon 12 was detected. The original tumor DNA did not hybridize with the oligonucleotide representing the mutated allele, but did hybridize with the one representing the normal allele. From these data we concluded either that the activation of the N-ras oncogene had occurred during the transfection or that the activated N-ras oncogene had been present in a minor population of cells in the original tumor.
Carcinogenesis 1987 Nov
PMID:Activated N-ras oncogene in a transformant derived from a rat small intestinal adenocarcinoma induced by 2-aminodipyrido[1,2-a:3',2'-d]imidazole. 366 49

DNAs from rat nasal and mouse skin carcinomas and fibrosarcomas induced by the alkylating agents methylmethane sulfonate (MMS), beta-propiolactone (BPL), and dimethylcarbamyl chloride (DMCC) were tested for their ability to transform NIH3T3 cells by DNA transfection. Each of eight MMS-induced rat nasal carcinomas and two of five BPL-induced mouse skin tumors were positive in the transfection assay while all of four fibrosarcomas and six carcinomas induced by DMCC were negative. Anchorage independent growth, tumorigenicity in nude mice, and secondary transfection confirmed the transformed phenotype of the positive transfectants. The transfectants from MMS-induced tumor DNAs did not contain restriction fragments homologous to rat H-, K- or N-ras oncogenes although exogenous (rat) tumor-derived DNA sequences were detected in transfectant genomes by Southern analysis. In contrast a BPL-induced mouse skin tumor showed evidence of containing activated H-ras. These results suggest specificity among causal chemical carcinogens for activation of transforming genes in experimental tumors.
Carcinogenesis 1985 Dec
PMID:Carcinogen specificity in the activation of transforming genes by direct-acting alkylating agents. 406 47

We studied demethylation within the transgene promoter in transgenic mice carrying the N-ras proto-oncogene driven by the mouse mammary tumor long terminal repeat (MMTV/N-rasN) and the relationship of demethylation to transgene overexpression and tumorigenesis. Demethylation at Fspl or Clal sites correlated with age of the animal and transgene expression in nontumorous mammary gland. Demethylation preceded expression in this tissue. In lymphomas and mammary tumors, the promoter Fspl and Clal sites were significantly more demethylated than in nontumorous control tissues. The Aval, Cfol, and Hpall sites were also found to be undermethylated in older animals and showed differences between tumor and control tissues. Two additional sites (Eagl and Narl) remained fully methylated in all tissues. In contrast with normal tissue, demethylation at the Fspl and Clal sites and expression were not correlated in tumor tissue. An increase in expression in normal tissue initially occurred and was correlated with the level of promoter demethylation; this increase was followed by a further increment in transgene expression when tumors developed. Thus, promoter demethylation leading to transgene overexpression was associated with long-latency tumorigenesis in MMTV/N-rasN transgenic mice. Demethylation of proto-oncogene promoters may therefore be a mechanism of carcinogenesis that requires further investigation in human tumors.
 ...
PMID:Promoter demethylation in MMTV/N-rasN transgenic mice required for transgene expression and tumorigenesis. 757 4

We used high fidelity PCR and constant denaturant capillary electrophoresis (CDCE) [Khrapko et al. (1994) Nucleic Acids Res., 22, 364-369] to separate wild type and different mutant N-ras exon 1 and 2 sequences. The set of plasmids containing N-ras cDNA, wild type or mutant sequences representing all transforming amino acid-substituting single base pair changes in codons 12, 13 (exon 1) and 61 (exon 2), were amplified using Pfu polymerase in a limited cycle polymerase chain reaction. One of the primers used for the amplification of each exon included a 40 nucleotide GC rich sequence that created high and low melting domains. The amplified fragments 151 bp (exon 1) and 150 bp (exon 2) were run on the CDCE with the 'denaturant zone' temperature of the capillary corresponding to the melting temperature of 111 bp (exon 1) and 110 bp (exon 2) low melting domains. The separation was achieved between wild type and mutant sequences as homoduplexes in 15 out of 19 cases, as a single base substitution alters the electrophoretic mobility of a partially melted double stranded fragment. The denaturation and reannealing of wild type and mutant fragments together created wild type/mutant heteroduplexes. All the heteroduplexes were well resolved from wild type homoduplex. In the current form mutant sequences were detected at a frequency of 10(-3) in the presence of wild type. This study has resulted in obtaining electrophoretic spectrum of different N-ras mutants on CDCE as homoduplexes as well as heteroduplexes.
Carcinogenesis 1995 Nov
PMID:Separation of transforming amino acid-substituting mutations in codons 12, 13 and 61 the N-ras gene by constant denaturant capillary electrophoresis (CDCE). 758 84


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>