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

Malignant undifferentiated sarcomas were induced in 11 of 15 (73.3%) newborn Syrian hamsters by s.c. inoculation of a recombinant DNA (pBK/c-rasA) containing BK virus (BKV) early region gene and the activated human c-Harvey-ras(c-Ha-ras) oncogene derived from T24 bladder carcinoma. The two genes inoculated independently as well as a recombinant DNA of BKV early region gene and normal human c-Ha-ras proto-oncogene were not tumorigenic. Tumor-derived cell lines propagated in culture were immortalized and had growth characteristics consistent with a fully transformed phenotype. Tumors and tumor cell lines showed tandem insertions of pBK/c-rasA in high copy number and expressed BKV- and c-Ha-ras-specific transcripts as well as BKV T-antigen and c-Ha-ras protein with a molecular weight of 21,000. We conclude that BKV DNA requires interaction with other oncogenic functions for tumorigenicity. These findings may be relevant to the role of BKV in human neoplasia, where cooperation or synergism between BKV and cellular oncogenes could occur as an aspect of the multifactorial process of carcinogenesis.
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PMID:Induction of malignant subcutaneous sarcomas in hamsters by a recombinant DNA containing BK virus early region and the activated human c-Harvey-ras oncogene. 282 40

Steady-state levels of c-Has-ras and c-Ki-ras RNA in gestating and lactating rat mammary gland were measured. The c-Ha-ras-specific RNA level increased during gestation and declined with the onset of lactation. On the contrary, the level of c-Ki-ras RNA remained unchanged both during gestation and lactation. There was no change in the level of ras-transcripts in either growing or regressing 7,12-dimethylbenz[a]anthracene-induced mammary tumors. Intravenous infusion of prolactin or implantation of pituitary-derived tumor, which secretes mammotropic hormone, in virgin female rats resulted in decreased levels of c-Ha-ras RNA and no change in c-Ki-ras RNA levels. Our results suggest the transcription of c-Ha-ras and c-Ki-ras genes is differentially regulated.
Carcinogenesis 1987 Dec
PMID:Differential regulation of c-Ha-ras and c-Ki-ras gene expression in rat mammary gland. 282 87

For many DNA-damaging agents, the extent of damage at any given base site is influenced by the DNA sequence surrounding that site. Most agents that alkylate the guanine N7 position, including mechlorethamine (nitrogen mustard) and benzo[a]pyrene diol epoxide, alkylate oligo-guanine sequences preferentially. Since these data suggest that guanine-cytosine(GC)-rich regions in genes could be preferred sites of damage by these agents, GenBank was searched for genes containing 30 bp sequences of greater than 90% GC (GC runs). While primate, rodent, other mammalian, vertebrate and animal virus genes constituted 57% of the annotated entries, they included 90% of the entries with the GC runs. In addition, the percentage of oncogenes in the group of the entries with GC runs was higher than that in the overall database. One gene of interest containing GC runs was the human c-Ha-ras oncogene. All seven GC runs in the c-Ha-ras gene are in the 5'-flanking region, rather than in the coding sequences. In fact, some of the GC runs are contained in Sp1-binding enhancer sequences. Gel analysis of the alkylation of cloned c-Ha-ras DNA by several carcinogenic alkylating agents strongly suggest that in this gene GC runs can be preferred sites of damage. These observations suggest mechanisms by which DNA damage at sites other than oncogene coding sequences may play a role in carcinogenesis and/or chemotherapy.
Carcinogenesis 1988 Nov
PMID:GC-rich regions in genomes as targets for DNA alkylation. 284 98

Altered c-Ha-ras genes have been frequently detected in the DNA of spontaneous or chemically induced mouse liver tumors. To determine if ras gene mutation is a frequent event during liver carcinogenesis in rats, we examined the transforming activity of DNA from liver tumors that developed in rats injected with methyl(acetoxymethyl)nitrosamine (DMN-OAc) after a partial hepatectomy. Three weeks after the injection of DMN-OAc, rats were fed a diet containing phenobarbital. This carcinogen acts only on replicating liver cells. Six of eight tumor DNAs induced the transformation of NIH 3T3 cells. The transforming activity was stable upon a second round of transfection, and the transformants were tumorigenic in nude mice. Southern blot analysis of transformant DNAs showed that the transforming activity was not due to the acquisition of a ras (Ha, Ki, or N), neu, myc, A-raf, v-raf, erbA, or erbB gene of rat origin. Several transformants' restriction enzyme sensitivity was analyzed, and their activity indicated that similar transforming sequences were present in at least two tumors and that one tumor contained two different transforming sequences. These results suggest that during hepatocarcinogenesis induced in rats by DMN-OAc, alterations in the ras gene family occur infrequently or not at all and that several different genes (which are not homologous to common oncogenes) become activated and are capable of transforming NIH 3T3 cells.
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PMID:Transforming activity of DNA from rat liver tumors induced by the carcinogen methyl(acetoxymethyl)nitrosamine. 285

Reactivities of benzene metabolites (phenol, catechol, hydroquinone, 1,4-benzoquinone, 1,2,4-benzenetriol) and related polyphenols (resorcinol, pyrogallol, phloroglucinol) with DNA were investigated by a DNA sequencing technique using 32P 5'-end-labeled DNA fragments obtained from human c-Ha-ras-1 protooncogene, and the reaction mechanism was studied by UV-visible and electron-spin resonance spectroscopies. 1,2,4-Benzenetriol caused strong DNA damage even without alkali treatment. Alkali-labile sites induced by 1,2,4-benzenetriol were base residues of guanine and adjacent thymine. Catalase, superoxide dismutase and methional inhibited the DNA damage completely, but sodium formate did not inhibit it. 1,2,4-Benzenetriol-induced DNA damage was inhibited by the addition of a Cu(I)-specific chelating agent, bathocuproine, and was accelerated by the addition of Cu(II). The addition of Fe(III) did not create any significant effects on 1,2,4-benzenetriol-induced DNA damage. Electron-spin resonance studies using spin traps demonstrated that addition of Fe(III) increased hydroxyl radical production during the autoxidation of 1,2,4-benzenetriol, whereas the addition of Cu(II) did not. The results suggest that DNA damage was caused by an unidentified active species which was produced by the autoxidation of 1,2,4-benzenetriol in the presence of Cu(II), rather than by hydroxyl radicals. The possibility that 1,2,4-benzenetriol-induced DNA damage is one of the primary reactions in carcinogenesis induced by benzene is discussed.
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PMID:Human DNA damage induced by 1,2,4-benzenetriol, a benzene metabolite. 290 43

The expression of c-Ha-ras-1, Ki-ras, N-ras, abl, src, fos and myc protooncogenes was analyzed in 13 cases of human gastric carcinomas. The transcriptional activity of both fos and myc protooncogenes was found to be disturbed in 47% and 42% of cases, respectively. An overexpression of fos protooncogenes as well as an appearance in some cases of atypical foc-mRNA transcripts were established. Only an elevation of the number of myc mRNA copies was observed. In one patient with gastric carcinoma a c-Ha-ras-1 overexpression was detected due to its amplification both in tumour tissues and in regional metastasis. The expression of other protooncogenes under investigation was similar to those found in normal gastric mucose. In addition, no differences in expression in protooncogenes mentioned above plus sis protooncogene were established in unchanged, premalignant and malignant stomach tissues in the course of N-methyl-N'-nitro-N-nitrosoguanidin-induced carcinogenesis.
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PMID:[Proto-oncogene expression in human carcinomas of the stomach and in the gastric mucosa of rats exposed to N-methyl-N'-nitro-N-nitrosoguanidine-induced gastric carcinogenesis]. 292 5

Using the NIH 3T3 transformation assay system, an activated c-Ha-ras transforming gene has been identified in three distinct early passage colon carcinoma cell lines isolated from an invasive, differentiated, adenocarcinoma. The p21 c-Ha-ras gene product from these cell lines displayed an altered electrophorectic mobility and a point mutation in the DNA coding sequence leading to an amino acid substitution at position 12.
Carcinogenesis 1985 Oct
PMID:c-Ha-ras not c-Ki-ras activation in three colon tumour cell lines. 299 2

Cellular proto-oncogenes can be activated by both point mutations and chromosomal translocations, suggesting that there may be a direct link between exposure to agents which damage DNA and genetic change leading to malignancy. Several groups have therefore analysed mutations found in cellular oncogenes of tumours induced by particular physical or chemical carcinogens. Here, we have analysed the molecular changes at different stages of carcinogenesis in mouse skin tumours induced by initiating and promoting agents. Over 90% of tumours, including premalignant papillomas, initiated with dimethylbenzanthracene (DMBA) have a specific A----T transversion at the second nucleotide of codon 61 of the Harvey-ras (Ha-ras) gene. The frequency of this mutation was dependent on the initiating agent used, but not on the promoter, suggesting that the mutation occurs at the time of initiation. The mutation was heterozygous in most papillomas tested, but was homozygous or amplified in some carcinomas. The development of further chromosomal changes at the c-Ha-ras gene locus is therefore a common feature of tumour progression.
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PMID:Carcinogen-specific mutation and amplification of Ha-ras during mouse skin carcinogenesis. 301 49

Both c-myc and c-Ha-ras 1 oncogenes amplification and enhanced expression were revealed in some human mammary and thyroid carcinomas by the molecular genetic analysis. Amplification proves to be a second possible molecular mechanism of the ras family protooncogene activation besides a point mutation. The coexistence of c-myc and c-Ha-ras 1 in some human primary carcinomas suggests a multistep process of carcinogenesis.
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PMID:[Joint amplification of c-myc and c-Ha-ras oncogenes in human breast and thyroid cancer cells]. 303 47

Rat embryo fibroblast cell line 6 was transfected with plasmid pT24, which contains the activated human bladder c-Ha-ras oncogene, and the cells were grown continuously in the absence or presence of the tumor promoters 12-O-tetradecanoyl phorbol-13-acetate (TPA) or teleocidin. The presence of TPA or teleocidin led to a 6- to 14-fold increase in the number of morphologically transformed foci. No transformed foci were seen when rat 6 cells were transfected with the normal c-Ha-ras oncogene in the absence or presence of TPA, or in cells simply treated with TPA or teleocidin. Enhancement of pT24-induced foci was seen even when the addition of TPA was delayed until day 16. In transfection studies with the drug resistance genes gpt and neo, TPA and teleocidin did not increase the number of Gpt+ or Neo+ colonies. When rat 6 cells were cotransfected with pT24 and neo genes and grown in the absence or presence of TPA, the presence of TPA did not increase the yield of Neo+ colonies but caused a fivefold increase in the number of Neo+ colonies that displayed a transformed morphology. Southern blot analyses of DNAs obtained from these clones indicated that TPA treatment did not influence the extent of integration of either the pT24 or neo gene. DNA samples from all of the morphologically transformed cells displayed a characteristic 2-kilobase SacI fragment homologous to pT24 DNA and expressed relatively high levels of the corresponding mRNA. Our findings indicate that in this system tumor promoters do not simply enhanced the process of DNA transfection per se. Thus, this model system may be useful for analyzing synergistic interactions between tumor promoters and activated oncogenes during multistage carcinogenesis. It may also serve as a simple screening test for detecting new tumor promoters.
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PMID:Oncogene-induced transformation of a rat embryo fibroblast cell line is enhanced by tumor promoters. 309 5


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