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At least 127 records · Page 7Linked to original sources
PubMed1990

Generation of cell lines to study the role played by oncogenes and anti-oncogenes in cell proliferation control.

We report the generation of stable transfectant cell lines by DNA-mediated transfection that overexpress viral and/or cellular oncogenes. Expression of heterologous genes (FBJ- and FBR-v-fos, polyoma large and middle T) was confirmed by Northern hybridization, immunofluorescence and immunoprecipitation. We also describe the isolation of two retinoblastoma cell lines from human tumors. Neuronal and glial markers were used to confirm the origin of these cell lines. Oncogene transfectant and retinoblastoma cell lines will be used to assess Rb expression and the possible role of its gene product in cell proliferation control and neoplasia.

Cell Division↗
PubMed1988

Activated fos oncogene in rat embryo fibroblasts transformed by ras and myc oncogenes.

Rat embryo fibroblasts (REF) were transformed by simultaneous gene transfer of the complementary oncogenes ras and myc using the calcium phosphate coprecipitation method. Cell lines derived from transformation foci expressed in addition to ras and myc cellular oncogene fos while normal REF did not express ras, myc and fos according to the hybridization methods used. The transformed cell lines produced colonies in soft agar and tumors in newborn syngeneic rats. From one tumor a cell line was established which was characterized by a high level of fos gene expression.

Animals↗
PubMed1994

[Drug resistance, oncogenes, and anti-oncogenes in epithelial tumors].

Twenty four squamous cell carcinomas of the head and neck (HNSCC) of stage II to IV were evaluated for the expression of potential markers such as oncogenes and tumor suppressor genes in drug-resistance behavior. We have analysed the c-myc, c-jun, c-raf and N-ras and p53 expression in total RNA preparation from tumor biopsies obtained before treatment. The patients underwent chemotherapy including 5-fluorouracil and cisplatinum. No significant differences in c-raf and N-ras expression were found in responding or resistant patients. However, resistance to chemotherapy was associated with low expression of c-myc (P < 0.025) or high expression of c-jun (P < 0.001). In addition, p53 mRNA pre-therapeutic level was increased in unresponsive patients to chemotherapy (P < 0.05). Therefore, analysis of the expression of c-myc, c-jun oncogenes and p53 tumor suppressor gene in tumor cells before initiation of therapy may define a subset of patients with potentially better prognosis.

Biomarkers, Tumor↗
PubMed1994

Genomic effects of the putative oncogene G alpha s. Chronic transcriptional activation of the c-fos proto-oncogene in endocrine cells.

Somatic mutations of the alpha subunit of Gs (G alpha s) have been detected in a variety of endocrine tumors. To test whether G alpha s is an oncogene, we investigated the genomic effects of G alpha s protein in which the GTPase activity had been inactivated. Results from transient transfection studies show that such proteins increase 1) transcription of a reporter gene driven by the minimal cAMP-responsive element (TGACGTCA) and 2) c-fos transcription in several endocrine cell lines (GH3, AtT20, and PC12). By promoter deletion analyses and genetic inactivation of cAMP-dependent protein kinase, we show that this transcriptional stimulation by G alpha s impinges on several regulatory elements within the c-fos promoter and operates within the protein kinase A pathways. Stable PC12 cell lines were established to analyze long-term effects of constitutively active G alpha s. Cell lines expressing mutated G alpha s have elevated cAMP levels and increased AP1 binding activity. Transcription of a variety of genes, including c-fos, c-jun, and junB, is increased in these cells. The strong and permanent effects of G alpha s on early immediate genes, and c-fos in particular, may be responsible for the oncogenic potential of G alpha s in endocrine cells.

Animals↗
PubMed2001

Structural basis of oncogenic activation caused by point mutations in the kinase domain of the MET proto-oncogene: modeling studies.

Missense mutations in the tyrosine kinase domain of the MET proto-oncogene occur in selected cases of papillary renal carcinoma. In biochemical and biological assays, these mutations produced constitutive activation of the MET kinase and led to tumor formation in nude mice. Some mutations caused transformation of NIH 3T3 cells. To elucidate the mechanism of ligand-independent MET kinase activation by point mutations, we constructed several 3D models of the wild-type and mutated MET catalytic core domains. Analysis of these structures showed that some mutations (e.g., V1110I, Y1248H/D/C, M1268T) directly alter contacts between residues from the activation loop in its inhibitory conformation and those from the main body of the catalytic domain; others (e.g., M1149T, L1213V) increase flexibility at the critical points of the tertiary structure and facilitate subdomain movements. Mutation D1246N plays a role in stabilizing the active form of the enzyme. Mutation M1268T affects the S+1 and S+3 substrate-binding pockets. Models implicate that although these changes do not compromise the affinity toward the C-terminal autophosphorylation site of the MET protein, they allow for binding of the substrate for the c-Abl tyrosine kinase. We provide biochemical data supporting this observation. Mutation L1213V affects the conformation of Tyr1212 in the active form of MET. Several somatic mutations are clustered at the surface of the catalytic domain in close vicinity of the probable location of the MET C-terminal docking site for cytoplasmic effectors.

Catalytic Domain↗
PubMed1990

Different promoter elements are required for the induced expression of c-fos and c-jun proto-oncogenes by the v-mos oncogene product.

The Mos protein is a serine/threonine protein kinase that is likely to be a part of signal transduction pathways that regulate cell growth. We show here that expression of the v-Mos protein leads to a transient transcriptional activation of the c-fos and the c-jun proto-oncogenes in NIH 3T3 cells. Different cis-acting promoter elements are responsible for this effect. In the c-fos promoter the dyad symmetry element (DSE, also known as serum response element, SRE) is sufficient to confer responsiveness to the v-Mos protein. In the c-jun promoter the 12-0-tetradecanoyl-phorbol-13-acetate (TPA) response element (TRE) mediates this effect. Various Mos mutants with decreased transforming activity have diminished trans-acting activity on the c-fos and c-jun promoters. These results suggest that the highly transforming v-Mos protein exerts at least some of its effects through the induction of expression of the c-fos and c-jun protooncogenes.

Animals↗
PubMed1989

Removal of an mRNA destabilizing element correlates with the increased oncogenicity of proto-oncogene fos.

AU-sequence motifs present in the 3' untranslated region (UTR) of many rapidly inducible messenger RNAs have been proposed to mediate their selective degradation. We have analyzed by quantitative nuclease S1 analysis the mRNA decay-rates of viral (v)/c-fos deletion mutants following transfection in a transient assay system. A 67 nucleotide mRNA destabilizing element, encompassing three conserved AUUUA motifs, was identified in the c-fos 3' UTR. The transforming ability of several v/c-fos recombinants correlates with the removal of the AU-rich sequence. Insertion of a c-fos DNA fragment containing the destabilizing element into the alpha-globin 3' UTR confers high instability to the otherwise stable alpha-globin mRNA. We conclude that a major parameter of oncogenicity by the c-fos gene is predicated by the presence or absence of AT-rich sequences located in the 3' non-coding region.

Animals↗
PubMed1996

The combination of p53 and age predict cancer specific death in advanced stage (FIGO Ic-IV) of endometrial carcinoma of endometrioid type. An immunohistochemical examination of growth fraction: Ki-67, MIB-1 and PC10; suppressor oncogene protein: p53; oncogene protein: p185 and age, hormone treatment, stage, and histologic grade.

OBJECTIVE: Early surgical stage (FIGO Ia + b) is an excellent predictor of survival in endometrial carcinoma of endometrioid type (EC), in contrast to advanced stage which only predict cancer specific death (CSD) in approximately 20-30% of the patients. The value of growth fraction, p53 and p185 as predictor of CSD in EC was studied. STUDY DESIGN: One hundred and eleven patients (45% hormone-users) with EC were entered prospectively and consecutively into an immunohistochemical study of growth fraction (Ki-67, MIB-1 and PC10), suppressor oncogene protein (p53) and oncogene protein (p185). RESULTS: All markers except p185 intercorrelated significantly, although weakly, however, marked differences were found in median values of the markers of growth fraction (GF). It was shown that immunohistochemical demonstration of p53 and p185 proteins and stage correlates independently with CSD in EC. CONCLUSION: The study indicates that the markers of GF do not give exact information about the proliferative compartment of the EC, and it is shown that p53 correlate to CSD, while stage indicate crude death.

Age Factors↗
PubMed1970

Oncogenic purine derivatives: evidence for a possible proximate oncogen.

Two additional urinary metabolites of the chemical oncogen 3-hydroxyxanthine are now identified as 8-chloroxanthine and 8-methylmercaptoxanthine. Such products are thought to be derived from a reactive intermediate which can be tentatively considered to be a proximate oncogen. Since each of these 8-substituted xanthines has also been obtained in vitro by reactions of 3-acetoxyxanthine with chloride ion or methionine, their production in vivo can be explained as resulting through the metabolic formation of an activated ester with a reactivity similar to that of the chemical model.

Animals↗
PubMed1989

[Studies on oncogene of nasopharyngeal carcinoma. II. Identification of the oncogene in human nasopharyngeal carcinoma cell line].

DNA transfection studies using NIH3T3 cells as recipient had previously led to the identification of a transforming gene present in the CNE-2 cell line. Some oncogenes were used as probes to screen DNA of secondary foci, and the results showed that the transforming gene present in the CNE-2 cell line has detectable homology to the C-Ha-ras oncogene.

Blotting, Southern↗
PubMed1976

[A RNA extract from oncogenic and non oncogenic strains of Agrobacterium tumefaciens is an indispensable element for the induction of tumors in Datura stramomium].

An RNA bound to the reverse transcriptase of Agrobacterium tumefaciens has been isolated and shown to be oncogenic for stem tissues of Datura stramonium grown under axenic conditions. The tumorous nature of the cellular change induced by the infectious rna was demonstrated by serial grafts of tumors on Datura stems and by cultivation of tumorous tissue in vitro on a medium without supplemental auxins and cytokinins. Active cellular proliferation within tissues of Datura stems was a prerequisite for expression of the oncogenic potential of the RNA. Further, infectious RNA was isolated from avirulent and attenuated strains of Agrobacterium tumefaciens including attenuated derivatives of strain AC58 which have been "heat-cured" of the plasmid associated with virulence. It is proposed that the infectious RNA is an essential but not the sole component of the tumor-inducing mechanism of the crown-gall bacterium.

Cell-Free System↗
PubMed1997

Targeted disruption of the epidermal growth factor receptor impairs growth of squamous papillomas expressing the v-ras(Ha) oncogene but does not block in vitro keratinocyte responses to oncogenic ras.

We have assessed the role of epidermal growth factor receptor (EGFR) signaling in biological responses to the v-ras(Ha) oncogene using primary keratinocytes from Egfr -/- mice and wild-type littermates. On the basis of several criteria, Egfr -/- keratinocytes were unresponsive to either acute or chronic exposure to several EGFR ligands but were stimulated to proliferate in response to several other mitogens. Although conditioned medium from primary keratinocytes transduced with v-ras(Ha) retrovirus (v-ras(Ha) keratinocytes) was a potent mitogen for wild-type but not Egfr -/- keratinocytes, v-ras(Ha) transduction of primary keratinocytes of either genotype resulted in a strong mitogenic response, arguing against an obligatory role for EGFR activation in v-ras(Ha)-mediated stimulation of keratinocyte proliferation. Infection with high-titer v-ras(Ha) retrovirus altered the keratin expression pattern in keratinocytes of both genotypes, suppressing differentiation-specific keratins K1 and K10 while activating aberrant expression of K8 and K18. In wild-type but not Egfr -/- cultures, K1 and K10 were also suppressed following infection at lower retroviral titers, presumably as a result of paracrine EGFR activation on uninfected cells present in these cultures. Squamous papillomas produced by grafting Egfr -/- v-ras(Ha) keratinocytes onto nude mice were only 21% of the size of wild-type v-ras(Ha) tumors, and a striking redistribution of S-phase cells was detected by immunostaining for bromodeoxyuridine. In Egfr -/- v-ras(Ha) papillomas, the fraction of total labeled nuclei detected in suprabasal layers was increased from 19 to 39%. In contrast, the basal layer labeling index of Egfr -/- papillomas was reduced to 34%, compared to 43% in wild-type tumors. Our results indicate that, although autocrine EGFR signaling is not required for keratinocyte responses to oncogenic ras in culture or benign tumor formation in nude mouse grafts, disruption of this pathway impairs growth of v-ras(Ha) papillomas by a mechanism that may involve alterations in keratinocyte cell cycle progression and/or migration in vivo.

Animals↗
PubMed1987

Human c-fos proto-oncogene mapped to chromosome 14, band q24.3-q31. Possibilities for oncogene activation by chromosomal rearrangements in human neoplasms.

The human c-fos proto-oncogene was mapped by in situ hybridization to chromosome 14, band q24.3-q31. As a probe we used 3H-labelled mouse c-fos RNA transcribed in vitro by SP6-RNA-polymerase. Of a total of 40 grains on chromosome 14, 19 (47.5%) were located within the 14q24.3-q31 region (p much less than 0.001). Mechanisms for c-fos to gain transforming ability by a break in a critical part of the gene have recently been described. Thus there are several possibilities for chromosomal aberrations within the 14q24.3-q31 region to be responsible for c-fos deregulation and which may result in neoplastic growth. Such specific aberrations are found in a variety of human neoplasms.

Animals↗
PubMed2006

WS5, a direct target of oncogenic transcription factor Myc, is related to human melanoma glycoprotein genes and has oncogenic potential.

We have isolated a gene (WS5) that is specifically expressed at the mRNA and protein level in avian fibroblasts transformed by the v-myc oncogene of avian acute leukemia virus MC29. In a conditional cell transformation system, WS5 gene expression was tightly correlated with v-myc activation. The WS5 gene contains 11 exons, encoding a 733-amino acid protein with a transmembrane region and a polycystic kidney disease (PKD) domain. Near the transcriptional start site, the WS5 promoter contains a cluster of four binding sites for the Myc-Max complex and a binding site for transcription factor C/EBPalpha. Electrophoretic mobility shift assays and chromatin immunoprecipitation showed that Myc, Max and C/EBPalpha bind specifically to these sites. Functional promoter analyses revealed that both the Myc-binding site cluster and the C/EBPalpha-binding site are essential for strong transcriptional activation, and that Myc and C/EBPalpha synergistically activate the WS5 promoter. Ectopic expression of WS5 led to cell transformation documented by anchorage-independent growth. The human melanoma antigen Pmel17, a type I transmembrane glycoprotein, is the mammalian protein with the highest amino acid sequence identity (38%) to WS5. The Pmel17 gene is regulated by the MITF protein, a bHLHZip transcription factor with DNA binding specificities similar to those of Myc/Max. WS5 is also related to human glycoprotein GPNMB expressed in metastatic melanoma cells and implicated in the progression of brain and liver tumors.

Amino Acid Sequence↗
PubMed1996

Oncogenic collaboration of the cyclin D1 (PRAD1, bcl-1) gene with a mutated p53 and an activated ras oncogene in neoplastic transformation.

Cyclin D1 is one of the key regulators in G1 progression in the cell cycle and is also a candidate oncogene (termed PRAD1 or bcl-1) in several types of human tumors. We report a collaboration of the cyclin D1 gene with ras and a mutated form of p53 (p53-mt) in neoplastic transformation. Transfection of cyclin D1 alone or in combination with ras or with p53-mt was not sufficient for focus formation of rat embryonic fibroblasts. However, focus formation induced by co-transfection of ras and p53-mt was enhanced in the presence of the cyclin D1-expression plasmid. Co-transfection of ras- and p53-mt-transformants with the cyclin D1-expression plasmid resulted in reduced serum dependency in vitro. Furthermore, the transformants expressing exogenous cyclin D1 grew faster than those without the cyclin D1 plasmid when injected into nude mice. These observations strengthen the significance of cyclin D1 overexpression through gene rearrangement or gene amplification observed in human tumors as a step in multistep oncogenesis; deregulated expression of cyclin D1 may reduce the requirement for growth factors and may stimulate in vivo growth.

Animals↗
PubMed1995

Proto-oncogenes and oncogenes in epidermal neoplasia.

This review briefly will focus on the role of selected proto-oncogenes and their activated forms during the regulation of cell proliferation, cell death and tumor formation in the epidermis. In addition, the multiple and complex functions of these proteins in normal as well as transformed cells will be discussed.

Animals↗
PubMed1984

Human colon carcinoma Ki-ras2 oncogene and its corresponding proto-oncogene.

We isolated cDNA clones corresponding to the normal human Ki-ras2 gene and to the transforming allele of the Ki-ras2 gene present in the human colon carcinoma cell line SW480. These two cDNAs encode p21 proteins which differ only at the amino acid at position 12. The normal cDNA encodes a glycine at this position, and the transforming allele encodes a valine. Expression of these cDNAs indicates that this amino acid 12 alteration confers oncogenic activity on the mutated gene. Analysis of the relationship of the cDNAs and Kirsten sarcoma virus ras gene to a genomic clone allowed us to identify two alternative 3' coding exons for the Ki-ras2 gene, suggesting that the Ki-ras2 gene encodes two p21 proteins which differ at their carboxy termini. Our data also show that only one of the p21s is necessary to convert cells to a tumorigenic phenotype.

Amino Acid Sequence↗
PubMed1990

[The characteristics of the transformed phenotype and the expression of indicator plasmids in the cells of rat embryonic fibroblasts immortalized by oncogene E1Aad5 and transformed by oncogenes E1Aad5+c-Ha-ras].

Rat embryonal fibroblasts of the second passage have been immortalized or transformed with the E1A region of the human adenovirus type 5 and the cloned c-Ha-ras oncogene. Several cell lines obtained greatly differ according to the criteria of the transformed phenotype: saturation cell density, the ability to be cloned on a substrate and in soft agar, the ability to give tumors in nude mice. We have transiently transfected these immortalized and transformed cell lines with CAT-plasmids containing the CAT gene under the control of promoters of the "cell-cycle dependent" genes (human hsp70 and protooncogene c-fos). The results showed that the expression of hsp-CAT and fos-CAT plasmids differed in great extent depending on whether the cells were immortalized (E1Aad5) or transformed (E1Aad5+Ha-ras). The role of cellular genes and cellular transcription factors influencing the expression of transiently transfected CAT-plasmids has been discussed.

Animals↗