UMLS:C0596263 - FACTA Search

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Query: UMLS:C0596263 (carcinogenesis)
64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

UV radiation is a potent DNA-damaging agent and a known inducer of skin cancer in experimental animals. To elucidate the role of oncogenes in UV carcinogenesis, we analyzed UV-induced murine skin tumors for mutations in codon 12, 13, or 61 of Ha-ras, Ki-ras, and N-ras oncogenes by amplification of genomic tumor DNAs by the polymerase chain reaction followed by dot-blot hybridization to synthetic oligonucleotide probes designed to detect single base-pair mutations. In addition to UV-induced C3H mouse skin tumors, we also analyzed skin tumors induced in the same strain of mice by other carcinogenic agents such as 8-methoxypsoralen + UVA, angelicin + UVA, dimethylbenz-[a]anthracene + UV + croton oil, and 4-nitroquinoline-1-oxide. We found that 4 of 20 UV-induced skin tumors contained either C----A or A----G base substitutions at N-ras codon 61. In addition, 2 of 5 melanomas possessed a G----A transition in N-ras codon 13 and an A----T transversion in N-ras codon 61, respectively. Interestingly, none of the 8-methoxypsoralen + UVA- or angelicin + UVA-induced tumors we analyzed contained mutations in any of the ras genes. However, 1 of 4 4-nitroquinoline-1-oxide-induced tumors exhibited a G----T transversion at Ki-ras codon 12, a potential site for formation of a 4-nitroquinoline-1-oxide adduct with a guanine residue. We also found that 2 nonmelanoma tumors induced by dimethylbenz[a]anthracene + UV + croton oil contained an A----T transversion at Ha-ras codon 61 position 2, which is characteristic of most dimethylbenz[a]anthracene-induced tumors. These results suggest that UV-induced C3H mouse tumors display mutations preferentially in the N-ras oncogene. Since most N-ras mutations in UV-induced tumors occurred opposite dipyrimidine sequences (T-T or C-C), one can infer that these sites are the targets for UV-induced mutation and transformation.
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PMID:N-ras mutation in ultraviolet radiation-induced murine skin cancers. 161 70

A comparative study on HBV status and ets-2, IGF-II, C-myc and N-ras expression in 12 pairs of human primary hepatocellular carcinoma (PHC) and adjacent non-tumorous tissues (NT) showed that integrated forms of HBV DNA were present in 91.5% PHC and 75% NT. No specific integration sites were detected. Three PHC and 4 NT were found to have free forms of HBV DNA, which were defective in 2 PHC and 3 NT, i. e., being able to replicate but not to be secreted into the blood. At least one of four oncogenes studied was overexpressed in the 12 pairs of samples. IGF-II was expressed as 5.0 and 2.0 Kb fetal transcripts in 3 pairs of samples and 1 NT. Six NT had more than one of the four oncogenes that was expressed higher than PHC. This was commonly encountered in tissues with free forms of HBV DNA. The relation between HBV status, expression of ets-2, IGF-II, C-myc and N-ras and carcinogenesis of PHC is discussed.
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PMID:[HBV status and expression of ets-2, IGF-II, C-myc and N-ras in human hepatocellular carcinoma and adjacent nontumorous tissues--a comparative study]. 165 92

RNA expressions of common integration site (int) genes and several oncogenes were investigated in mammary carcinomas spontaneously developed in different three strains of mice; DD/Tbr, NIH Swiss and BALB/c which harbor DD-MMTV derived from DD/Tbr mouse. Latter two strains of mice were designated NIH/Mtv+ and BALB/Mtv+, respectively. An increased expression of int-1 (wnt-1) and int-2 genes was observed in 56% (9/16) and 50% (8/16) of mammary carcinomas of DD/Tbr mice, respectively. Either int-1 or int-2 RNAs were expressed in 81% (13/16) of the carcinomas of DD/Tbr mice. IN NIH/Mtv+ mice, activation of int-1 and int-2 was observed in 41% (7/17) and 24% (4/17) of mammary carcinomas, respectively. Either int-1 or int-2 RNAs were expressed in 47% (8/17) of the carcinomas examined in this strain. In BALB/Mtv+ mice, on the other hand, either int-1 or int-2 gene were transcribed into RNAs at low frequency (33%: 3/9). These results suggest that the frequency of activation of int genes in mammary carcinomas induced by the same DD-MMTV in three strains of mice is genetically defined characteristics of these strains, and that the involvement of int-1 and int-2 genes in virus-induced mammary carcinogenesis may be influenced by genetic properties of animals. The activation of int-1 and int-2 genes did not clearly correlate with an increase in the expression of oncogenes examined; H-ras, K-ras, N-ras, myc, raf, fgr, fms, erB, mos, and src genes.
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PMID:The different activation of int genes in mammary carcinomas developed in three mouse strains harboring mouse mammary tumor viruses derived from DD/Tbr. 166 Aug 18

We have been studying the effect of oncogenes on differentiation using the human ovarian teratoma-derived cell line PA-1. From this study we have characterized variants representing four stages relevant to multistage carcinogenesis, two non-tumorigenic and two tumorigenic. The two non-tumorigenic cell variants differ in that one is resistant to transformation by ras oncogenes whereas the other can be transformed to tumorigenicity. When these non-tumorigenic PA-1 variants are treated with retinoic acid (RA), a morphogen, they stop dividing, begin to express homeobox genes, and change in morphology. Transfection of an activated N-ras oncogene into ras-resistant non-tumorigenic PA-1 cells does not alter the RA responsiveness of the cells, indicating that expression of the activated oncogene is not sufficient for blocking RA-induced differentiation. Spontaneous activation of an N-ras oncogene leading to tumorigenic transformants and gene transfer-induced N-ras transformants are resistant to these effects of RA. However, another spontaneous transformant of PA-1 cells that does not contain an activated N-ras is responsive to RA. We prepared somatic cell hybrids of the RA-non-responsive, N-ras-transformed and tumorigenic PA-1 cell and the RA-responsive, ras-resistant non-tumorigenic PA-1 cell; the hybrid cell lines continue to express the oncogene but are non-tumorigenic. These non-tumorigenic hybrids are responsive to RA with regard to morphological changes, growth arrest and induction of homeobox gene expression. Tumorigenic revertants of these hybrids arise as a result of the loss of some chromosomes; these hybrid cells express the oncogene but have lost RA responsiveness. These results indicate that tumorigenic transformation in general is not sufficient to induce RA resistance, and resistance to differentiation may be oncogene-specific. In addition, the expression of an activated N-ras oncogene alone is insufficient to induce resistance to RA and ras-induced tumorigenicity is necessary. Therefore, some feature of cellular metabolism that is altered by and discordantly segregates with tumorigenic transformation controls responsiveness to RA. This controlling element is presumably a tumor suppressor.
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PMID:Modulation of differentiation in PA-1 human teratocarcinoma cells after N-ras oncogene-induced tumorigenicity. 168 91

Activation of the Ha-ras proto-oncogene, but not the Ki-ras or N-ras genes, has been found in mammary gland carcinomas induced in female rats by a single dose of methylnitrosourea (MNU). Here we show that a 10-kb restriction fragment containing the Ha-ras gene was extensively methylated by MNU in DNA isolated from mammary glands of female rats 4 h after carcinogen treatment. Fragments of similar size containing either the Ki-ras or N-ras genes were methylated less extensively. The extent of methylation of the three ras genes by MNU correlated with their transcriptional activity. These results suggest that the extent of interaction of a carcinogen with an oncogene, which depends on its transcriptional activity, may be a factor in determining whether the gene is mutated during the initiation of carcinogenesis.
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PMID:Preferential methylation of the Ha-ras proto-oncogene by methylnitrosourea in rat mammary glands. 171 38

A transforming activity associated with Chinese nasopharyngeal carcinoma (NPC) cell line CNE2 DNA has been identified by transfer into nontransformed promotion-sensitive mouse JB6(P+) C141 cells. To clone this transformation-associated sequence, we carried out three cycles of transfection, followed by cloning of anchorage-independent transformants in soft agar. A tertiary CNE/JB6 clonal transfectant cell line 625 whose DNA showed transforming activity, as indicated in both soft-agar assay and nude-mice implantation, was used to make a genomic library in the vector lambda dash. Using the human repeated sequence Blur 8 to screen the library, we obtained 10 human Alu-positive clones. A cloned Alu-positive insert of 16 kbp, CNE 323, was characterized in detail. CNE 323 transferred moderate transforming activity when introduced into JB6 P+ cells and showed no homology to Ha-, Ki-, or N-ras genes; human promotion sensitivity genes; src, myb, jun, myc, fos, raf, or int-2 oncogenes; or epidermal growth factor receptor. The isolated CNE 323 DNA sequence appeared to preserve the genomic structure of the original sequence found in CNE2 cells and in nude mouse tumors induced by CNE2 cells or by CNE/JB6 transfectant cells, indicating that the cloned NPC sequence was activated during NPC carcinogenesis and not during transfection or construction of the library, and that the cloned sequence or a larger sequence of which it was part played a role in tumor formation. Finally, we identified a 1.3-kb mRNA that hybridizes to a subclone of the 16-kb NPC sequence in CNE2 cell poly (A)+ RNA.
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PMID:Isolation and partial characterization of a transformation-associated sequence from human nasopharyngeal carcinoma. 171 41

The DNA sequences around codons 12, 13, and 61 of the ras gene were analyzed by polymerase chain reaction and direct sequencing in 18 intrahepatic cholangiocarcinomas. The ras gene mutations were found in 9 of 18 (50%): 6 in K-ras codon 12, 1 in K-ras codon 13, 1 in K-ras codon 61, and 1 in N-ras codon 12. The incidence of mutations was higher in the hilar type of intrahepatic cholangiocarcinomas, especially when these tumors were large. The incidence and spectrum of the mutations were almost the same as those reported in colon cancers, possibly indicating similar etiologic agent(s) in the carcinogenesis of both cancers.
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PMID:High incidence of ras gene mutation in intrahepatic cholangiocarcinoma. 173 10

Expression of protooncogenes c-myc, N-myc, c-fos, Ha-ras 1, Ki-ras 2, yes, abl, src, N-ras, met and mos was studied in human gastric tumors and in rat gastric mucosal membrane during gastric carcinogenesis induced in rats by means of N-methyl-N'-nitro-N-nitroso guanidine (MNNG). Elevated expression of protooncogenes c-myc, c-fos, Ha-ras 1, Ki-ras 2, N-myc and Raf 1 was observed in carcinomas of human stomach. Amplification of Ha-ras 1 protooncogene was found in the human gastric tumor and metastasis. Point mutation was not detected in 12 the codon of Ha-ras I protooncogene. Expression of these protooncogenes was not altered during gastric carcinogenesis induced by MNNG in rats. However, within early steps of cancerogenesis (9 days, 3 months) amplification of ribosomal genes occurred in rat gastric mucosal membrane and in adenocarcinoma developed, while the tumor growth was accompanied by activation of mitochondrial genes.
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PMID:[Biochemical and molecular biological aspects of stomach cancer development in human and animal]. 181 23

Six families of activated protooncogenes, ras, raf, fur, neu, jun and myc have so far been associated with human lung cancer. Human bronchial epithelial cells in vitro are being used to investigate the functional role of these specific oncogenes and growth regulatory genes in carcinogenesis and tumour progression. When transferred into normal human bronchial epithelial cells by the highly efficient protoplast fusion method, the v-Ha-ras oncogene initiates a cascade of events leading to decreased responsiveness of these cells to inducers of squamous differentiation, aneuploidy and, less frequently, 'immortality' and tumorigenicity with metastasis in athymic nude mice. Transfection of the SV40 T antigen gene results in nontumorigenic cell lines that have a nearly normal pathway of terminal squamous differentiation and can be transformed into malignant cells by transfected Ha-ras, N-ras or Ki-ras. The combination of transfected c-myc and c-raf-1 also transforms human bronchial epithelial cells into neoplastic cells that exhibit some phenotypic traits found in small-cell carcinomas. These and other results indicate that proto-oncogenes dysregulate the pathways of growth and differentiation of human bronchial epithelial cells and play an important role in human carcinogenesis. Analyses of allelic deletion and somatic cell hybrids are being used to identify the chromosomal localization of tumour suppressor genes. We have examined 54 non-small-cell bronchogenic carcinomas with 13 polymorphic markers. Loss of heterozygosity was more frequent than among 23 squamous-cell carcinomas than among 23 adenocarcinomas or eight large-cell carcinomas. Loss of heterozygosity for chromosome 17p was found in 89% of cases of squamous-cell carcinoma and 18% of adenocarcinomas. Analysis of chromosome 11 for allelic deletions revealed two commonly deleted regions (11p13 and 11p15.5). Somatic cell hybrids between normal human bronchial epithelial cells and Hut292DM, a lung carcinoma cell line, had a finite lifespan in vitro and were nontumorigenic in athymic nude mice. Tumour suppressive effects of individual or combinations of specific human chromosomes on Hut292DM are being examined by formation of microcell-cell hybrids. Chromosome 11 has tumour suppressor activity in these hybrids. Both of these studies suggest that tumour suppressor genes play a dominant role in lung carcinogenesis and provide in-vitro model systems for isolating these genes by subtraction library and insertional mutagenesis techniques.
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PMID:Role of oncogenes and tumour suppressor genes in human lung carcinogenesis. 185 68

The C57BL/6 x C3H F1 (hereafter called B6C3F1) mouse is an important animal model for long-term carcinogenesis studies. Maintained under normal laboratory conditions, these mice develop various types of spontaneous tumors during their lifetime. Activated Ha-ras genes have been detected in 66% of spontaneous hepatocellular tumors in the B6C3F1 mouse [Reynolds et al., Science (Washington DC), 237:1309, 1988]. In this study 49 spontaneous non-liver tumors were investigated for oncogene activation by DNA transfection techniques. Of the 49 tumor DNAs analyzed, only 5 yielded multiple foci in the NIH 3T3 focus assay: 2 of 10 pulmonary adenocarcinomas; 0 of 25 lymphomas; 2 of 2 Harderian gland adenomas; 0 of 1 adenocarcinoma of the small intestine; 1 of 6 malignant skin tumors; 0 of 4 hemangiosarcomas; and 0 of 1 lung metastasis of a hepatocellular carcinoma. DNA from six lymphomas which were negative in the NIH 3T3 focus assay were further analyzed for transforming genes by the nude mouse tumorigenicity assay. One of the five lymphomas tested positive with this assay. Southern blot analysis identified five activated ras genes: H-ras in two Harderian gland adenomas; K-ras in one pulmonary adenocarcinoma and in one s.c. adenocarcinoma; and N-ras in one lymphoma. The mutations involved were CG to AT and AT to TA in codon 61 of the Ha-ras genes, GC to AT or TA in codon 12 of the K-ras genes, and a GC to AT mutation in codon 12 of the N-ras gene. Transformant DNA from a pulmonary adenocarcinoma which yielded multiple foci in the transfection assay did not hybridize to DNA probes specific for the K-, H-, and N-ras, raf, neu, and met genes. Thirteen additional tumor DNAs yielded a single focus in the NIH 3T3 transfection assay. The transformant DNAs retransmitted in a second cycle transfection assay. Rearranged and/or amplified raf genes were detected in six of the transformant DNAs. At present we do not know whether these activated raf genes were present in the original tumor DNA. The other seven transformant DNAs did not hybridize with any of the above mentioned specific DNA probes utilized in Southern blot analysis. Unlike liver tumors, the activation of ras protooncogenes is not a frequent event in the development of spontaneous non-liver tumors of the B6C3F1 mouse. The results from this study should aid in understanding the neoplastic development associated with exposure to chemical carcinogens in the B6C3F1 mouse.
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PMID:Activation of protooncogenes in spontaneously occurring non-liver tumors from C57BL/6 x C3H F1 mice. 199 58

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