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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fusogenic liposome (FL) based on Sendai virus constitutes a unique system that delivers the content efficiently into animal cells in vitro and in vivo. In this study we characterized unilamellar FL as a gene transfer vector in comparison with cationic lipid (CL)-DNA complex. FL transferred genes efficiently into cultured cells even when incubated for as little as 10 min, while CL-DNA complex required at least 30 min to reach the same level of gene expression. FL was also much less cytotoxic than CL-DNA complex under the conditions that resulted in the same level of gene expression. In addition, FL maintained 70% of the transfection activity even in the presence of 40% fetal calf serum (FCS), while CL-DNA complex almost completely lost their activity in the presence of 5% FCS. Furthermore, we found that FL could introduce and express luciferase gene into mouse ascites tumor cells in vivo, but CL-DNA complex could not even at higher concentrations of DNA. We conclude that unilamellar FL is a unique and efficient nonviral vector for gene transfer in vitro and in vivo.
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PMID:Efficient gene transfer into mammalian cells using fusogenic liposome. 857 70

The phorbol-ester tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) is a potent inducer of the metalloproteinase stromelysin in fibroblasts in vivo and in several cultured cell lines. Rat-1 and Rat-2 fibroblasts, however, do not respond to TPA stimulation by induction of stromelysin gene activity, although collagenase promoter-mediated activity is induced threefold by TPA treatment in these cells. We determined that rat fibroblasts expressed protein kinase C(PKC)alpha, PKCdelta, PKCepsilon, and PKCzeta but neither the mRNA nor the protein for PKCbeta. When Rat-2 fibroblasts were stably transfected with an expression vector producing PKCbeta, however, TPA treatment of these variants resulted in a 3.1-fold induction of stromelysin promoter-mediated luciferase activity compared with a 1.3-fold induction in parental Rat-2 cells (P<0.002). Transient transfection of PKCepsilon produced a small but significant increase in TPA-stimulation of both stromelysin- and collagenase-mediated gene expression. These results suggest that there are PKC isotype-specific signaling pathways that can differentially regulate matrix metalloproteinase gene expression.
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PMID:Protein kinase C isotypes required for phorbol-ester induction of stromelysin-1 in rat fibroblasts. 859 79

The importance of ornithine decarboxylase (ODC) to cell proliferation is underscored by the complex array of cell-specific mechanisms invoked to regulate its synthesis and activity. Misregulation of ODC has severe negative consequences on normal cell function, including the acquisition of tumorigenic growth properties by cells overexpressing ODC. We hypothesize that ODC gene expression is a candidate target for the anti-proliferative function of certain tumor suppressors. Here we show that the Wilms' tumor suppressor WT1 binds to multiple sites within the human ODC promoter, as determined by DNase I protection and methylation interference assays. The expression of WT1 in transfected HCT 116, NIH/3T3 and HepG2 cells represses activity of the ODC promoter controlling expression of a luciferase reporter gene. In contrast WT1 expression enhances ODC promoter activity in SV40-transfected HepG2 cells. Both the extent of modulation of ODC gene expression and the mediating WT1 binding elements are cell specific. Constructs expressing WT1 deletion mutants implicate two regions required for repressor function, as well as an intrinsic activation domain. Understanding the regulation of ODC gene expression by WT1 may provide valuable insights into the roles of both WT1 and ODC in development and tumorigenesis.
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PMID:Regulation of ornithine decarboxylase gene expression by the Wilms' tumor suppressor WT1. 860 51

A rapid, quantitative, in vivo assay of cytotoxic responses would facilitate experimental evaluation of the potency of novel vaccine strategies. We have developed an in vivo cytotoxicity assay in which target cells expressing a luciferase reporter gene are implanted as monolayers on polystyrene disks onto the muscle tissue of mice. The luciferase activity retrievable from the adjacent tissue is used as an index of cytotoxicity. Implantation of B16 or NIH/3T3 cells expression the beta-galactosidase gene indicated that the target cells migrated to the muscle tissue from plastic within 4 h and then remained localized in the area of the disk. The amounts of luciferase retrievable from the adjacent tissue a few days post implantation readily detected the immune response induced by allo-immunization of fibroblasts or by production of interleukin-4 by tumor cells co-mixed with implanted reporter cells. Histologic analysis showed a correlation between the amount of luciferase retrieved and the number of viable target cells at the implantation site. Recruitment of immune effector cells which may be responsible for target cell death and luciferase elimination could be readily visualized. This simple cytotoxicity assay can be used as an in vivo assay of the net effect of cytotoxic immune responses.
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PMID:In vivo cytotoxicity assay for assessing immunity. 861 69

We studied the effects of bile acids on inducibility of the transcription factor AP-1 in human colon carcinoma LoVo cells. Firstly, cells were treated with chenodeoxycholic acid and the nuclear extracts from those cells were processed by electrophoretic mobility shift assays to analyze nuclear AP-1 DNA-binding activity. We demonstrated that chenodeoxycholic acid induced AP-1 DNA-binding activity in a dose- and time-dependent fashion. Antibody supershift experiments clearly revealed that the majority of protein components in induced AP-1 DNA-binding activity were the products of oncogenes c-fos and c-jun. On the other hand, DNA-binding activity in the nuclear extracts for either NF kappa B, Sp1, or ATF/CREB was not affected by bile acids, suggesting that the effect of bile acids was rather specific for AP-1. Transient transfection experiments supported this notion: expression of the AP-1-luciferase reporter construct was induced by bile acids in a dose-dependent manner, and expression of either reporter construct for NF kappa B, Sp1, or ATF/CREB was not influenced by treatment of the cells with bile acids. We also demonstrated that those bile acids efficiently activated AP-1-dependent promoter in DLD-1 cells, which (as well as LoVo cells), are derived from colon adenocarcinoma, but not in COLO320DM cells which are from colon carcinoid tumor. Thus, we may indicate that bile acids exclusively induce nuclear AP-1 activity in colon adenocarcinoma cells.
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PMID:Induction of the transcription factor AP-1 in cultured human colon adenocarcinoma cells following exposure to bile acids. 863 Nov 27

Treatment of a human breast cancer cell line (MDA-MB-435) in nude mice with a recombinant adenovirus containing the human interferon (IFN) consensus gene, IFN-con1 (ad5/IFN), resulted in tumor regression in 100% of the animals. Tumor regression occurred when virus was injected either within 24 hr of tumor cell implantation or with established tumors. However, regression of the tumor was also observed in controls in which either the wild-type virus or a recombinant virus containing the luciferase gene was used, although tumor growth was not completely suppressed. Tumor regression was accompanied by a decrease in p53 expression. Two other tumors, the human myelogenous leukemic cell line K562 and the hamster melanoma tumor RPMI 1846, also responded to treatment but only with ad5/IFN. In the case of K562 tumors, there was complete regression of the tumor, and tumors derived from RPMI 1846 showed partial regression. We propose that the complete regression of the breast cancer with the recombinant virus ad5/IFN was the result of two events: viral oncolysis in which tumor cells are being selectively lysed by the replication-competent virus and the enhanced effect of expression of the IFN-con1 gene. K562 and RPMI 1846 tumors regressed only as a result of IFN gene therapy. This was confirmed by in vitro analysis. Our results indicate that a combination of viral oncolysis with a virus of low pathogenicity, itself resistant to the effects of IFN and IFN gene therapy, might be a fruitful approach to the treatment of a variety of different tumors, in particular breast cancers.
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PMID:Treatment of a human breast cancer xenograft with an adenovirus vector containing an interferon gene results in rapid regression due to viral oncolysis and gene therapy. 863

We have examined the molecular mechanisms for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-stimulated prostaglandin synthesis in Mardin Darvey canine kidney cells (MDCK). TCDD stimulates prostaglandin synthesis in these cells, at least in part, by elevating prostaglandin endoperoxide H2 synthase-2 (PGHS-2) levels. TCDD-stimulated transcription of the PGHS-2 gene was maximal (6-fold) within 2 h and resulted in a 100-fold increase in PGHS-2 mRNA and a 25-fold increase in PGHS-2 protein levels by 4 h. Transient transfection experiments using luciferase-reporter plasmids demonstrated that control element(s) responsible for TCDD activation of the murine PGHS-2 promoter in MDCK cells are located in the first 965 nucleotides upstream from the PGHS-2 transcriptional initiation site. A canonical xenobiotic response element, similar to those that control transcription of other well-known TCDD-sensitive genes, is present at position -157, but does not appear to be sufficient for halogenated aromatic hydrocarbon (HAH) activation of the PGHS-2 promoter. TCDD failed to stimulate transcription from the PGHS-2 promoter when reporter plasmids were transfected into Hepa 1c1c7 cells, a line which contains the functional aryl hydrocarbon receptor. It seems likely that inappropriate expression of PGHS-2 may contribute to the toxic effects of TCDD and other HAHs. In particular, PGHS-2 expression may affect those toxic reactions that involve inappropriate cellular growth, such as dermal hyperplasia and tumor formation. It is also likely that elevated synthesis of prostaglandins, which are potent regulators of immune function, could play a role in the immunotoxicity associated with HAH exposure.
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PMID:Regulation of prostaglandin endoperoxide H synthase-2 expression by 2,3,7,8,-tetrachlorodibenzo-p-dioxin. 866 Jun 62

The small leucine-rich proteoglycan biglycan is involved in several physiological and pathophysiological processes through the ability of its core protein to interact with other extracellular matrix molecules and transforming growth factor-beta (TGF-beta). To learn more about the regulation of biglycan core protein expression, we have cloned and sequenced 1218 base pairs from the 5'-flanking region of the human biglycan gene, demonstrated functional promoter activity, and investigated the molecular mechanisms through which various agents modulate its transcriptional activity. Sequencing revealed the presence of several cis-acting elements including multiple AP-2 sites and interleukin-6 response elements, a NF-kappaB site, a TGF-beta negative element, and an E-box. The TATA and CAAT box-lacking promoter possesses many features of a growth-related gene, e.g. a GC-rich immediate 5' region, many Sp1 sites, and the use of multiple transcriptional start sites. Transient transfections of the tumor cell lines MG-63, SK-UT-1, and T47D with various biglycan 5'-flanking region-luciferase reporter gene constructs showed that the proximal 78 base pairs are sufficient for full promoter activity. Several agents among them interleukin-6, and tumor necrosis factor-alpha. were capable of altering biglycan promoter activity. However, in MG-63 cells, TGF-beta1 failed to increase either activity of the biglycan promoter constructs or specific transcription from the endogenous biglycan gene. Since TGF-beta1 also did not alter the stability of cytoplasmic biglycan mRNA as determined from Northern analysis after inhibition of transcription with 5,6-dichloro-1beta-D-ribofuranosylbenzimidazole, an as yet unidentified nuclear post-transcriptional mechanism was considered responsible for the TGF-beta effect in this cell type. These results might help to elucidate the molecular pathways leading to pathological alterations of biglycan expression observed in atherosclerosis, glomerulonephritis, and fibrosis.
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PMID:Transcriptional regulation of the human biglycan gene. 866 74

Infection of quiescent cells with the DNA tumor virus simian virus 40 induces expression of the cellular thymidine kinase (TK) gene a minimum of 10- to 20-fold, and this induction depends upon the viral protein large T antigen (T-Ag). To define both human TK promoter elements and T-Ag functional domains required for transcriptional induction, we have established a system in which stable Rat-1 transfectants harboring TK promoter-luciferase hybrid genes are infected with recombinant adenoviruses expressing either wild-type or mutant forms of T-Ag and luciferase expression is measured as an indicator of promoter activity. The results show that (i) a 135-bp TK promoter fragment is activated 10- to 15-fold by viral infection; (ii) this activation is the result of both T-Ag-dependent and -independent mechanisms; (iii) the T-Ag pRb family-binding domain, but not the p53-binding, helicase, or ATPase domain, is required for activation; and (iv) activation is severely diminished with a TK promoter fragment in which E2F-like-binding sites have been removed. These data demonstrate a requirement for both an E2F-related factor and a pRb family member in activation of the TK promoter by T-Ag. This contrasts with the promiscuous activation of many cellular and viral genes by T-Ag, which is independent of its ability to bind pRb.
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PMID:Activation of the human thymidine kinase (TK) promoter by simian virus 40 large T antigen requires both the T antigen pRb family-binding domain and TK promoter sequences resembling E2F-binding sites. 870 58

The insulin-like growth factor I receptor (IGF-I-R) plays a critical role in transformation events. It is highly overexpressed in most malignant tissues where it functions as an anti-apoptotic agent by enhancing cell survival. Tumor suppressor p53 is a nuclear transcription factor that blocks cell cycle progression and induces apoptosis. p53 is the most frequently mutated gene in human cancer. Cotransfection of Saos-2 (os-teosarcoma-derived cells) and RD (rhabdomyosarcoma-derived cells) cells with IGF-I-R promoter constructs driving luciferase reporter genes and with wild-type p53 expression vectors suppressed promoter activity in a dose-dependent manner. This effect of p53 is mediated at the level of transcription and it involves interaction with TBP, the TATA box-binding component of TFIID. On the other hand, three tumor-derived mutant forms of p53 (mut 143, mut 248, and mut 273) stimulated the activity of the IGF-I-R promoter and increased the levels of IGF-I-R/luciferase fusion mRNA. These results suggest that wild-type p53 has the potential to suppress the IGF-I-R promoter in the postmitotic, fully differentiated cell, thus resulting in low levels of receptor gene expression in adult tissues. Mutant versions of p53 protein, usually associated with malignant states, can derepress the IGF-I-R promoter, with ensuing mitogenic activation by locally produced or circulating IGFs.
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PMID:Wild-type and mutant p53 differentially regulate transcription of the insulin-like growth factor I receptor gene. 871 Aug 68


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