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Query: UNIPROT:P06889 (Mol)
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Histopathological examination of thymomas often fails to predict their malignant potential because the morphology of invasive or metastatic thymomas does not differ significantly from that of benign, encapsulated thymomas. In order to find a marker of aggressiveness in thymomas, 21 cases (9 non-invasive, 8 invasive and 4 metastatic thymomas) were examined for expression of the ras oncogene product p21 by immunohistochemistry and immunoblot analysis. Immunohistochemical study, using a serially diluted monoclonal antibody, NCC-RAS-001, demonstrated that neoplastic thymoma cells generally contained more p21 than normal thymic epithelial cells. Immunoblot analysis using another monoclonal antibody (NCC-RAS-004) also confirmed the increased concentration of p21 in all but one of the thymomas by comparison with normal thymic tissue. One metastatic thymoma did not have a band of p21 recognized by NCC-RAS-004 and was believed to have a deletion of the epitope recognized by this antibody. In addition, another metastatic thymoma showed abnormal electrophoretic mobility of p21. The increased amount of p21 in thymomas suggests that this protein has a role in the oncogenesis or progression of thymoma. The high incidence of a p21 molecular abnormality in metastatic thymomas indicates that the abnormality of this protein could be used as a possible marker of aggressive behavior.
Virchows Arch B Cell Pathol Incl Mol Pathol 1990
PMID:Expression of ras p21 protein by thymoma. 197 93

Inactivation of the cellular p53 gene is a common feature of Friend virus-induced murine erythroleukemia cell lines and may represent a necessary step in the progression of this disease. As well, frequent loss or mutation of p53 alleles in diverse human tumors is consistent with the view of p53 as a tumor suppressor gene. To examine the significance of p53 gene inactivation in tumorigenesis, we have attempted to express transfected wild-type p53 in three p53-negative tumor cell lines: murine DP16-1 Friend erythroleukemia cells, human K562 cells, and SKOV-3 cells. We found that aberrant p53 proteins, which differ from wild-type p53 by a single amino acid substitution, were expressed stably in these cells, whereas wild-type p53 expression was not tolerated. The inability of p53-negative tumor cell lines to support long-term expression of wild-type p53 protein is consistent with the view that p53 is a tumor suppressor gene.
Mol Cell Biol 1991 Jan
PMID:Expression of wild-type p53 is not compatible with continued growth of p53-negative tumor cells. 198 14

The purpose of this study was to determine whether dietary n-3 polyunsaturates (PUFA) can affect the frequency of N-nitrosomethylurea (NMU)-induced Ha-ras mutations in virgin female F344 rat mammary glands. Two groups of 15 rats each were fed isocaloric diets containing either 23% w/w corn oil or corn oil plus menhaden oil (1:1) at starting 14 d before NMU administration (day 50 of age) and continuing for 13 wk. Mammary gland samples were taken serially at 3, 5, 9, and 13 wk post-NMU treatment. Total cellular DNA was isolated and analyzed by a newly devised enriched amplification procedure that involves predigestion of normal Ha-ras alleles at codon 12, amplification of the mutant alleles, and restriction fragment length polymorphism analysis. Selective amplification enabled the detection of Ha-ras mutations as early as 3 wk post-NMU treatment. Approximately 40-50% of all glands and 75% of all rats tested had the Ha-ras codon 12 mutation. No significant differences were found between the two dietary groups at any time point, indicating that the mammary tumor-inhibiting effect of n-3 PUFA is probably not exerted at the level of the Ha-ras activation step in NMU tumorigenesis.
Mol Carcinog 1991
PMID:Dietary N-3 fatty acids do not affect induction of Ha-ras mutations in mammary glands of NMU-treated rats. 204 52

Octopine and nopaline strains of Agrobacterium tumefaciens were found to differ in virulence on Nicotiana glauca. This difference is due to the absence of a functional virF locus, which is necessary for efficient tumorigenesis on N. glauca, from the nopaline Ti plasmids. Genetic studies and DNA sequence analysis of the virF locus revealed that virF embraces one open reading frame coding for a hydrophilic protein with a molecular mass of 22,437 Da. Transcription of virF is directed from left to right, towards the T region, and is strongly induced by the phenolic compound acetosyringone. We established that virA and virG, two genes known to be essential for induction of the vir regulon, are necessary for acetosyringone-induced virF expression, implying that virF is a member of this vir regulon. Agrobacterium virF mutants can be complemented for tumor induction by co-infection with avirulent Agrobacterium 'helper' strains. We found that such 'helper' strains must express not only the virF gene but also the vir operons virA, virB, virD and virG.
Plant Mol Biol 1990 Feb
PMID:Octopine and nopaline strains of Agrobacterium tumefaciens differ in virulence; molecular characterization of the virF locus. 210 93

The multifunctional actions of transforming growth factor beta 1 (TGF-beta 1) indicate that it has a pivotal control function in many physiological and pathological processes. An important property of TGF-beta 1 is its ability to activate its own mRNA expression and thereby increase its own secretion. Two distinct regions of the promoter of the TGF-beta 1 gene are responsive to autoregulation: one 5' to the upstream transcriptional start site and another located between the two major start sites. In both promoter regions, autoinduction is mediated by binding of the AP-1 (Jun-Fos) complex. An important contribution to this positive regulation is the autoactivation of c-jun transcription by AP-1. Cotransfection of antisense c-jun or antisense c-fos expression vectors prevents TGF-beta 1 autoinduction. These results demonstrate that both components of the AP-1 complex are required for TGF-beta 1 autoinduction. Induction of jun expression by TGF-beta 1, as well as jun autoinduction, may amplify the action of TGF-beta 1 during normal development and oncogenesis.
Mol Cell Biol 1990 Apr
PMID:Autoinduction of transforming growth factor beta 1 is mediated by the AP-1 complex. 210 18

To study the relationship between oncogenesis by v-src and normal cellular signalling pathways, we determined the effects of v-src on 3T3-TNR9 cells, a Swiss 3T3 variant which does not respond mitogenically to tumor promoters such as 12-O-tetradecanoyl-phorbol-13-acetate (TPA). We found that src was unable to transform these variant cells, whether the oncogene was introduced by infection with a murine retrovirus vector or by transfection with plasmid DNA. 3T3-TNR9 cells were not inherently resistant to transformation, since infection with similar recombinant retroviruses containing either v-ras or v-abl did induce transformation. Further analysis of Swiss 3T3 and 3T3-TNR9 cell populations infected with the v-src-containing retrovirus revealed that although the amount of v-src DNA in each was approximately the same, the level of the v-src message and protein and the overall level of phosphotyrosine expressed in the infected variants was much less than in infected parental cells. Cotransfection experiments using separate v-src and neo plasmids revealed a decrease in the number of G418-resistant colonies when transfections of TNR9 cells occurred in the presence of the src-containing plasmid, suggesting a growth inhibitory effect of v-src on 3T3-TNR9 cells, as has also been found for TPA itself. Since v-src cannot transform this variant cell line, which does not respond mitogenically to the protein kinase C agonist TPA, we suggest that src makes use of the protein kinase C pathway as part of its signalling activities.
Mol Cell Biol 1990 Aug
PMID:A Swiss 3T3 variant cell line resistant to the effects of tumor promoters cannot be transformed by src. 211 20

The role of v-Ha-ras oncogene in tumorigenesis in an in vitro/in vivo model system was studied by investigating the expression of the Ha-ras gene, gap junctional intercellular communication, and tumorigenicity as endpoints. Infection of a Fischer 344 rat liver epithelial cell line (WB 344) with a retrovirus containing the v-Ha-ras oncogene resulted in altered cell morphology and decreased contact sensitivity. Gap junctional intercellular communication in v-Ha-ras infected WB cells (WBHa-ras), assessed by fluorescence redistribution after photobleaching (FRAP), microinjection/dye transfer, and scrape-loading/dye transfer techniques, was markedly decreased compared with the level in control WB cells. Injection of 10(7) WBHa-ras cells into the portal vein of male F344 rats caused multiple focal hepatic lesions within 1 and 2 wk, merging to large invading tumors after 3 and 4 wk. Examination of the methylation pattern of the Ha-ras gene in WBHa-ras and control WB cells showed that the infected Ha-ras gene was relatively hypomethylated in comparison to the normal cellular Ha-ras gene, indicating a greater potential for expression. There was an increased level of Ha-ras mRNA in hepatomas as compared with both adjacent nontumor liver tissue and liver tissue obtained from normal animals. Three cell lines derived from three different primary hepatic tumors induced by an injection of WBHa-ras cells in a F344 rat displayed similar growth characteristics, levels of gap junctional communication, and methylation patterns as the original WBHa-ras cells. The results of these studies have established a strong positive correlation between expression of the Ha-ras oncogene, reduced gap junctional intercellular communication, decreased contact sensitivity, and tumorigenicity of the v-Ha-ras-infected rat liver epithelial cells.
Mol Carcinog 1990
PMID:Infection of rat liver epithelial cells with v-Ha-ras: correlation between oncogene expression, gap junctional communication, and tumorigenicity. 234 86

Epidemiologic studies have linked infection by the human T-lymphotropic virus type I (HTLV-I) with the development of adult T-cell leukemia. The low penetrance of the virus and the long latency for disease manifestation are factors that obscure the role of HTLV-I infection in oncogenesis. We have used an in vitro transformation assay system to determine directly whether the HTLV-I tax gene has transformation potential. Transfection of the tax gene alone into early-passage rat embryo fibroblasts did not induce morphological alterations. However, cotransfection of tax with the selectable marker plasmid pRSVneo gave rise to G418-resistant colonies that could be established as immortalized cell lines. Cotransfection of tax with the ras oncogene into rat embryo fibroblasts gave rise to foci of transformed cells that were highly tumorigenic in nude mice. These data represent a direct demonstration of the oncogenic potential of the tax gene in nonlymphoid cells and establish HTLV-I as a transforming virus.
Mol Cell Biol 1990 Jan
PMID:The human T-lymphotropic virus type I tax gene can cooperate with the ras oncogene to induce neoplastic transformation of cells. 240 46

We have investigated the role of the p53 gene in oncogenesis in vivo by generating transgenic mice carrying murine p53 genomic fragments isolated from a mouse Friend erythroleukemia cell line or BALB/c mouse liver DNA. Elevated levels of p53 mRNA were detected in several tissues of two transgenic lines tested. Increased levels of p53 protein were also detected in most of the tissues analyzed by Western blotting (immunoblotting). Because both transgenes encoded p53 proteins that were antigenically distinct from wild-type p53, it was possible to demonstrate that overexpression of the p53 protein was mostly, if not entirely, due to the expression of the transgenes. Neoplasms developed in 20% of the transgenic mice, with a high incidence of lung adenocarcinomas, osteosarcomas, and lymphomas. Tissues such as ovaries that expressed the transgene at high levels were not at higher risk of malignant transformation than tissues expressing p53 protein at much lower levels. The long latent period and low penetrance suggest that overexpression of p53 alone is not sufficient to induce malignancies and that additional events are required. These observations provide direct evidence that mutant alleles of the p53 oncogene have oncogenic potential in vivo and that different cell types show intrinsic differences in susceptibility to malignant transformation by p53. Since recent data suggest that p53 may be a recessive oncogene, it is possible that the elevated tumor incidence results from functional inactivation of endogenous p53 by overexpression of the mutant transgene. The high incidence of lung and bone tumors suggests that p53 transgenic mice may provide a useful model to investigate the molecular events that underlie these malignancies in humans.
Mol Cell Biol 1989 Sep
PMID:High incidence of lung, bone, and lymphoid tumors in transgenic mice overexpressing mutant alleles of the p53 oncogene. 247 68

Recent years of cancer research have defined the role of key regulatory genes in oncogenesis. Oncogenes and suppressor genes are affected in the process of carcinogenesis either by mutations within the coding region, promoter mutations, or gene amplification. This review describes our studies on gene amplification in mammalian cells, with emphasis on the initiating events induced by carcinogenic chemicals and various types of radiation. The influence of genomic instability, cell dedifferentiation, and the malignant potential of a cell on their capacity to amplify genes is demonstrated by molecular biologic and cytogenetic studies on human and rodent cells. Cells that contain amplified DNA are at risk for chromosomal aberrations, sister chromatid exchanges, and rearrangements. Surviving cells show such cancer-prone genetic consequences.
Mol Toxicol
PMID:Review: gene amplification--a cellular response to genotoxic stress. 249 Sep 79


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