Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Murine NIH3T3 cells were used to study the effect of ribozymes on H-ras-mediated transformation. Parental 3T3 cells were transfected with the activated H-ras gene. H-ras-transformed cells had altered morphology and increased colony formation in soft agar in contrast to untransfected 3T3 cells. A hammerhead ribozyme (site-specific ribonuclease) designed to cleave codon 12 (GUC) of the activated H-ras RNA was expressed in transformed cells. 3T3 clones expressing the ras ribozyme displayed decreased expression of activated H-ras RNA. The ras ribozyme reversed the transformed phenotype to resemble that of untransfected 3T3 cells. Furthermore, 3T3 cells containing the ras ribozyme were shown to suppress transformation when they were subsequently transfected with activated H-ras. Insertion of a mutant ribozyme largely devoid of cleaving capacity into H-ras-transformed cells resulted in smaller reductions in H-ras gene expression and colony formation in soft agar when compared with the ras ribozyme. Finally, the ras ribozyme alone did not perturb normal 3T3 cell growth. This study suggests the possible utility of anti-oncogene ribozymes as suppressors of tumor cell growth as well as inhibitors of cellular transformation.
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PMID:Suppression of H-ras-mediated transformation in NIH3T3 cells by a ras ribozyme. 794 47

The possible roles of certain oncogenes in the development of pituitary tumors has not been investigated. We have examined the expression of c-myc, c-fos, and c-myb in a number of human pituitary tumors by ribonuclease protection assays, as these oncogenes have been implicated to have roles in the pathogenesis of other human tumors (12, 13, 15, 16). In several tumors examined (9 of 30) c-myc was expressed at levels 4-9 times greater than the level detected in normal postmortem pituitary. Although a larger percentage of negative immunohistochemical-staining tumors overexpressed c-myc, c-myc over-expression was not limited to this group of tumors. c-Fos was overexpressed in 1 of 30 tumors examined at a level 5.8-fold higher than that detected in normal postmortem pituitary. This tumor stained positive for ACTH by immunohistochemistry and was considered highly aggressive, demonstrating invasion beyond the sella turcica; however, when other ACTH-staining and invasive pituitary tumors were examined, no abnormality in the expression of c-fos was detected. In 30 tumors, c-myb was expressed at approximately the same level as that detected in normal postmortem pituitary. We conclude that c-myc is overexpressed in a subgroup of pituitary tumors and that this overexpression occurs broadly among the different groups of immunohistochemical-staining tumors. c-Fos overexpression appears to be much less common in pituitary tumors and does not necessarily correlate with the ability of the tumor to become invasive. c-Myb does not appear to have a role in the pathogenesis of pituitary tumors.
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PMID:c-myc, c-fos, and c-myb gene expression in human pituitary adenomas. 802 38

We have used in situ hybridization for RNA to localize cells containing mRNA for the 92 kd gelatinase in carcinomas of the lung. We used archival material to analyze sections from 12 cases of squamous cell carcinomas of the lung including six stage I and three stage II and from three cases of adenocarcinoma of the lung. Presence of mRNA in the tissue was verified by in situ hybridization for gamma actin. The 92 kd gelatinase mRNA was found in all 12 squamous cell carcinomas tumors and was highly expressed in the tumor cells themselves. In addition, it was found in host stromal cells surrounding the tumor, but not in normal lung fibroblasts. In contrast it was not found in the adenocarcinomas of the lung or in the stroma surrounding these tumors. The mRNA for the 92 kd gelatinase was present in normal pulmonary tissue, bronchial epithelium, basal cell hyperplasia of bronchial epithelium, alveolar macrophages, and focally in bronchial mucous glands. It was not present in normal alveoli, vascular cells, cartilage, or most lymphocytes. We corroborated the presence of the mRNA for the 92 kd gelatinase by ribonuclease protection assay. The levels of mRNA for the 92 kd gelatinase in two specimens of squamous cell carcinoma were 6- to 10-fold greater than in the nonneoplastic tissue and two adenocarcinoma specimens.
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PMID:Localization of the 92 kd gelatinase mRNA in squamous cell and adenocarcinomas of the lung using in situ hybridization. 812 37

Autocrine expression of polypeptide growth factors may be important in the growth regulation of cancer cells. Different growth factor activities have been identified in a variety of tumors. This article describes a case of malignant ascites in a patient recently treated for breast cancer. The use of growth factor mRNA expression as a factor to differentiate between breast and ovarian origins of cancer cells contained in malignant ascites was examined. Expression of insulin-like growth factor-I (IGF-I), IGF-II, and transforming growth factor alpha mRNA was examined by ribonuclease protection assay. The tumor cells expressed IGF-II and transforming growth factor alpha, but not IGF-I mRNA. This pattern of growth factor expression is compatible with a breast cancer primary of the malignant cells contained in the ascites fluid. Therefore, IGF-I mRNA expression may be useful in distinguishing between adenocarcinomas of breast or ovarian origins.
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PMID:Case report: use of insulin-like growth factor-I gene expression to distinguish between breast and ovarian cancer. 814 Nov 35

A nucleolar endoribonuclease from mouse Ehrlich ascites tumor cells, that has been implicated in the endonucleolytic cleavage of mouse precursor ribosomal RNA, specifically and stably binds an in vitro-derived rRNA transcript containing the +650 early processing site. The specificity of binding was demonstrated by mobility shift analysis, glycerol gradient velocity sedimentation analysis, and UV-crosslinking studies. Binding did not require Mg2+ and therefore was not dependent on cleavage; however, binding was dependent on the presence of the early +650 processing site since a pre-rRNA transcript with the +650 processing site deleted failed to compete in binding. A small nucleolar RNA component was not required for the formation of this stable complex or for the specific cleavage of a processing competent pre-rRNA transcript. UV crosslinking studies using 32P-labeled 5-azidouridine-substituted pre-rRNA with bound nucleolar endoribonuclease identified three closely sized polypeptides of approximately 50, approximately 48, and approximately 45 kDa, respectively, that specifically crosslinked to the processing competent rRNA transcript. These three polypeptides species were identified following ribonuclease digestion and electrophoresis on a SDS-polyacrylamide gel. An identical pattern of labeled polypeptides was also identified from gel mobility shift analysis where the specifically shifted material was U.V. crosslinked. The largest of these polypeptides corresponded to the estimated size of the nucleolar endoribonuclease, while the lower molecular weight species may represent partially proteolyzed enzyme. Overall, these results suggest that the unique specificity of the nucleolar endoribonuclease may, in part, be attributed to the formation of a stable complex at the +650 processing site for mouse preribosomal RNA, and that formation of this unique stable complex affords a means to specifically label the limited amount of available partially purified enzyme for sequence analysis.
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PMID:Selection of a preribosomal RNA processing site by a nucleolar endoribonuclease involves formation of a stable complex. 828 28

The Epstein-Barr virus (EBV)-associated B-cell lymphoproliferative disorders that arise in immunosuppressed individuals are considered to resemble EBV-transformed in vitro lymphoblastoid cell lines (LCLs) with a mature activated B-cell phenotype. In this study of human lymphoproliferative disorders in the severe combined immunodeficiency mouse model, however, we demonstrate that EBV-infected tumor cells are not LCL-like but are predominantly plasmacytoid and that this phenotype correlates with reduced expression of EBV latent genes. B-cell tumors developed within 3-6 weeks after injection of LCLs into severe combined immunodeficiency mice. The tumors and the injected LCLs were analyzed by flow cytofluorometry for B-cell differentiation and activation markers and by ribonuclease protection assay for cellular and viral gene expression. No differences in the expression of CD19 and CD21 were observed. However, a decrease in CD23, CD11a (lymphocyte function-associated antigen LFA-1), and CD58 (LFA-3) expression and an increase in CD38 (a plasma-cell-associated antigen), CD54 (intracellular adhesion molecule ICAM-1), and HLA class I in the tumor cells relative to the LCLs was observed. Two-color flow cytofluorometric analysis showed that the predominant population (> 80%) in LCLs was CD23hi/CD38lo and that the major population in LCL-derived tumors was CD23lo/CD38hi. Cell cycle analysis showed that, in contrast to actively cycling LCLs, the majority of tumor cells had exited the cell cycle and were restricted to G0/G1 phase. Finally, and most important, a reduction in mRNA for the EBV latent genes EBV nuclear antigen 2 (EBNA2) and latent membrane protein (LMP1) was observed in the tumors.
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PMID:Plasmacytoid differentiation of Epstein-Barr virus-transformed B cells in vivo is associated with reduced expression of viral latent genes. 838 Apr 97

Previously we described the simultaneous quantification of DNA and nuclear protein in unfixed tissue from solid tumors. The resultant 2 parameter flow cytometric analysis has several advantages over that of DNA alone. In this report, we describe a modification of the technique for the analysis of formalin-fixed paraffin-embedded tissue. Paraffin-embedded material was prepared by hydrating sections, incubating in 0.5% pepsin solution, washing, and resuspending in buffer containing nonionic detergent. The nuclei were then stained with fluorescein isothiocyanate and propidium iodide in the presence of ribonuclease. Several solid tumor tissue types have been analyzed, including breast, colon, kidney, and thymus. The best results were obtained when the initial pepsin treatment was for 1.5 h, instead of 0.5 h. Pepsin treatment for 1.5 h improved the CVs of both the DNA and nuclear protein parameters, and did not appear to reduce nuclear protein levels or to cause significant disintegration of nuclei. The DNA/nuclear protein histograms of unfixed and fixed, paraffin-embedded tissue were similar. Since tumor nuclei typically have higher protein levels than DNA-diploid nuclei, the technique reduces population overlapping and permits less subjective identification of DNA aneuploidy.
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PMID:Flow cytometric analysis of DNA and nuclear protein in paraffin-embedded tissue. 844 Jan 53

In independently derived drug-resistant sublines of the mouse lymphoid tumor P388, multidrug resistance is associated with the exclusive overexpression of the mdr3 gene. In P388/VCR cells, mdr3 overexpression occurs in the absence of gene amplification, while in P388/ADM-2 cells overexpression is associated with mdr3 gene amplification. The mechanism underlying mdr3 overexpression in these cells was investigated. Measurement of the rate of transcription by nuclear "run-on" assays showed that increased mdr3 expression in P388/VCR cells was caused by transcriptional activation of the gene. Analysis of the 5' end of mdr3 mRNA transcripts by primer extension indicated that in P388/VCR cells, these mRNAs extended approximately 200 nucleotides upstream exon 2, about 60 nucleotides longer than their counterparts expressed in normal tissues from the known transcription start site of the gene (TS1). Northern blotting experiments using discrete exon and intron probes derived from the 5' end of the gene near TS1, together with ribonuclease protection using a complementary RNA probe from the same region, demonstrated that transcriptional activation in P388/VCR cells occurred from a novel transcription start site named TS3, located either upstream of TS1 or within intron 1 at a site immediately upstream a novel exon. In P388/ADM-2 cells, Northern blotting and ribonuclease protection identified overexpressed mdr3 mRNAs initiating near TS1 and a large partially spliced mdr3 mRNA species initiating upstream of TS1 at a novel initiation site designated TS2. Therefore, mdr3 overexpression in independently derived multidrug-resistant isolates of P388 cells is associated with the appearance of novel transcription start sites in the gene and novel sequences at the 5' end of the overexpressed mRNAs.
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PMID:Transcriptional activation of the mouse mdr3 gene coincides with the appearance of novel transcription initiation sites in multidrug-resistant P388 tumor cells. 845 38

The gene for human angiogenin (Ang), a member of the ribonuclease superfamily, was fused to a gene encoding a single-chain antibody (sFv) against the human transferrin receptor. Three Ang single-chain immunofusion proteins (AngsFvs) were constructed with variations in the type of linker connecting the VL and VH chain [EGKSSGSGSESKEF, L1 or (GGGGS)3, L2] as well as with or without a spacer (FB) connecting the Ang and sFv (AngFBsFvL1 or L2; AngsFv(L2)]. Although the nature of the linker did not affect the enzymatic activity of the FB-containing fusion proteins, the fusion protein containing the L2 linker was 2.3-fold more effective than the L1 linker in competing with the labeled monoclonal IgG1 antibody for binding to the transferrin receptor. The fusion protein containing the L2 linker without the FB spacer exhibited a 13-fold decrease in binding to the transferrin receptor as well as a decrease in its capacity to degrade tRNA and to inhibit translation in the rabbit reticulocyte lysate compared to its counterpart containing the FB spacer. Binding of placental ribonuclease inhibitor (PRI) to Ang also was affected by the nature of the linker and by the presence or absence of a spacer. PRI bound to Ang and AngFBsFv(L2) and inhibited their ribonuclease activity. A 3-fold greater concentration of PRI, however, did not affect the activity of AngFBsFv(L1) or AngsFv(L2), suggesting that the conformation of these fusion proteins was altered. Binding of monoclonal and polyclonal anti-Ang antibodies to AngsFvs was also used to investigate conformational alterations of the fusion proteins. AngFBsFv(L2) was the least altered while AngFBsFv(L1) exhibited the greatest change in structure. Yet maximal concentrations of all AngsFvs elicited angiogenesis in the chick chorioallantoic membrane assay, demonstrating that Ang in all three fusion proteins remained functionally active. Consistent with all the activities, the fusion protein containing the FB spacer and L2 linker was the most cytotoxic to three different human tumor cell lines. The fusion protein lacking the FB spacer exhibited the least cytotoxicity. These data demonstrate that the linker connecting the VH-VL chains can affect the binding and cellular cytotoxicity of Ang immunofusions and that placement of a spacer between the antibody binding domains and Ang is necessary for optimal activity. Thus, a new class of targeted therapeutic agents containing Ang as the toxic moiety can be designed that potentially will be less immunogenic and less toxic than immunotoxins available currently.
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PMID:Angiogenin single-chain immunofusions: influence of peptide linkers and spacers between fusion protein domains. 855 26

Tumour angiogenesis is a complex multistep process regulated by a number of angiogenic factors. One such factor, platelet-derived endothelial cell growth factor has recently been shown to be thymidine phosphorylase (TP). TP catalyses the reversible phosphorylation of thymidine to deoxyribose-1-phosphate and thymine. Although known to be generally elevated in tumours, the expression of this enzyme in breast carcinomas is unknown. Therefore, we used ribonuclease protection assays and immunohistochemistry to examine the expression of TP in 240 primary breast carcinomas. Nuclear and/or cytoplasmic TP expression was observed in the neoplastic tumour epithelium in 53% of tumours. Immunoreactivity was also often present in the stromal, inflammatory and endothelial cell elements. Although endothelial cell staining was usually focal, immunoreactivity was observed in 61% of tumours and was prominent at the tumour periphery, an area where tumour angiogenesis is most active. Tumour cell TP expression was significantly inversely correlated with grade (P = 0.05) and size (P = 0.003) but no association was observed with other tumour variables. These findings suggest that TP is important for remodelling the existing vasculature early in tumour development, consistent with its chemotactic non-mitogenic properties, and that additional angiogenic factors are more important for other angiogenic processes like endothelial cell proliferation. Relapse-free survival was higher in node-positive patients with elevated TP (P = 0.05) but not in other patient groups. This might be due to the potentiation of chemotherapeutic agents like methotrexate by TP. Therefore, this enzyme might be a prediction marker for response to chemotherapy.
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PMID:The angiogenic factor platelet-derived endothelial cell growth factor/thymidine phosphorylase is up-regulated in breast cancer epithelium and endothelium. 856 30


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