Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have used a mouse mammary tumor virus (MMTV)-infected rat hepatoma cell line as a model system for studying glucocorticoid action. These cells induce tyrosine aminotransferase and MMTV in response to the synthetic glucocorticoid, dexamethasone. The major viral antigen, a glycoprotein of 52,000 daltons (gp52), appears on the surface of infected cells in amounts which reflect the cytoplasmic content of viral RNA. Using an anti-gp52 antiserum and a fluorescence-activated cell sorter (FACS), we have selected variants which display low levels of pg52 in the presence of the hormone. Multiple cycles of enrichment for cells that fluoresce weakly in the presence of hormone have generated a population which fails to produce a detectable increase in cell surface gp52 in response to dexamethasone. This population of nonresponders and a number of independent clones derived from this population were analyzed for their ability to induce gp52 and TAT and for these presence of glucocorticoid receptors. All nonresponder clones exhibited little or no induction of either glucocorticoid-inducible marker. Two of the clones contained reduced levels of glucocrticoid receptor, while the remainder of the clones showed no detectable specific hormone binding. These results provide genetic evidence that a single class of glucocorticoid receptors is involved in the induction of both MMTV and TAT in HTC cells.
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PMID:Isolation of glucocorticoid-unresponsive rat hepatoma cells by fluorescence-activated cell sorting. 610 25

The induction of tyrosine aminotransferase by a variety of steroids was studied in cells from a hepatoma tissue culture (HTC). We have defined a class of steroids that induce TAT synthesis to a higher level than optimal inducers described earlier; these are called supra-inducers. When TAT induction is compared with the binding of the steroids to the cytoplasmic receptor or to their binding in the whole cell, a good correlation between binding in vivo of the hormone and its induction capacity can be established, whereas such a correlation was not systematically observed in vitro. A very short exposure of HTC cells to either dexamethasone or corticosterone is sufficient to induce TAT. When the inducer is removed from the culture medium a few minutes after its administration, the intracellular hormone concentration decreases very rapidly but TAT will be synthesized at its maximal rate. Thus the hormones behave as a starting signal for the optimal synthesis of the enzyme, and their presence in the culture medium is not necessary throughout the entire induction period.
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PMID:Relations between steroid-cell contact, steroid-binding and induction of tyrosine aminotransferase. 611 76

A specific antiserum was used in an enzyme-linked immunoadsorbent assay (ELISA) for tyrosine amino-transferase TAT. Protein A bound on Sepharose was allowed to react with antiserum preincubated with the enzyme. Inhibition curves in the presence of protein A were parallel to those obtained in the absence of protein A. In the case of cell-free synthesized TAT, the complex bound to the solid phase contains the (35S) labelled enzyme; the sensitivity of the test was greatly increased when the bulk of protein was discarded by pretreatment of the reaction mixture at 70 degree and chromatography on DEAE cellulose. The immunoadsorbed polypeptides were analyzed by dodecylsulfate/polyacrylamide gel electrophoresis. The pattern of polypeptides neosynthesized using RNA from different origins (rat liver, hepatoma cells) and after various treatments (glucocorticoid hormones, sodium butyrate) exhibited some different in the TAT region which can be related to the level of the specific mRNA for TAT. This method is very useful for further studies on TAT gene expression and might also shed light on the mechanism of hormonal action and drug processes.
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PMID:[Characterization of tyrosine aminotransferase by an immunoadsorption technic. Application to the measurement of the specific messenger RNA]. 612 32

Of all available liver cells in culture, only primary cultured hepatocytes are known to respond to glucagon in vitro. In the present study we investigated whether glucagon could stimulate amino acid transport and tyrosine aminotransferase (TAT;EC 2.6.1.5) activity (two well-characterized glucagon effects in the liver) in Fao cells, a highly differentiated rat hepatoma cell line. We found that glucagon had no effect on transport of alpha-aminoisobutyric acid (AIB; a non-metabolizable alanine analogue) nor on TAT activity, even though both activities could be fully induced by insulin [2-fold and 3-fold effects for AIB transport and TAT activity, respectively, after 6h; EC50 (median effective concentration) = 0.3 nM], or by dexamethasone (5-8-fold effects after 20 h; EC50 = 2 nM). Analysis of [125I]iodoglucagon binding revealed that Fao cells bind less than 1% as much glucagon as do hepatocytes, whereas insulin binding in Fao cells was 50% higher than in hepatocytes. The addition of dibutyryl cyclic AMP, which fully mimics the glucagon stimulation of both AIB transport and TAT activity in hepatocytes, induced TAT activity in Fao cells (a 2-fold effect at 0.1 mM-dibutyryl cyclic AMP) but had no effect on AIB transport. Cholera toxin stimulated TAT activity to the same extent as did dibutyryl cyclic AMP. These results indicate that the lack of glucagon responsiveness in cultured hepatoma cells results from both a receptor defect and, for amino acid transport, an additional post-receptor defect. Moreover, the results show that amino acid transport and TAT activity, which appeared to be co-induced by insulin or by dexamethasone in these cells, respond differently to cyclic AMP. This suggests that different mechanisms are involved in the induction of these activities by glucagon in liver.
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PMID:Glucagon resistance of hepatoma cells. Evidence for receptor and post-receptor defects. 613 31

Experiments were carried out on Buffalo rats with implantable Morris hepatoma 5123 growing in the skeletal muscles of the limbs. Mutein VI (a protein which differs from the native TNF-alpha molecule in its N-terminal amino acid composition) was administered at a dose of 10 micrograms per rat once a day in a cycle of 8 days. Control animals were given saline (PBS). Ultrastructural changes within the pulmonary tissue were evaluated with an electron transmission microscope (TEM), with special attention paid to endothelial cells and alveolar epithelial cells. Quantitative analysis of neoplastic metastases to the lungs was carried out. The animals given mutein VI compared to those injected with PBS demonstrated a decrease in the number of metastases. TEM pictures showed accumulations of eosinophilic granulocytes and monocytes in the lumen of the blood vessels. Enhanced activity of endothelial cells was observed. In pulmonary alveoli conglomerates of fibrin, and fragments of damaged cells were found, with erythrocytes, granulocytes and macrophages in their vicinity. The epithelium of pulmonary alveoli showed signs of considerable damage, including necrosis. The mutein VI-hrec TNF-alpha was found to block the neoplastic process, illustrated by a reduction in the volume of lung parenchyma occupied by neoplastic metastases. Also, the ultrastructural changes observed in the pulmonary tissue indicate the possibility of peripheral action of mutein VI after its administration to rats carrying the Morris hepatoma.
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PMID:Studies on pulmonary tissue after administration of mutein VI-HREC TNF-alpha into implantable experimental Morris hepatoma. 906 67

Recent studies have indicated that two elements in addition to the glucocorticoid response element (GRE) are involved in the induction of the endogenous TAT gene in FuS-5 rat hepatoma cells. The first is the 21 bp glucocorticoid modulatory element (GME) at -3648 bp, which causes reporter constructs to display both a left shift in the dose-response curve for glucocorticoids and increased percentages of agonist activity for antiglucocorticoids. The second is a negative element at -3340 to -3050 that blocks the action of the GME. This last observation raised the question of how GME activity can be expressed in Fu5-5 cells in the intact TAT gene that contains both the GME and the negative element. The present study identifies a third element, a "neutralizing" sequence, that restores the activity of the GME even when otherwise inactivated by the negative element. This neutralizing sequence was located within the region surrounding the GREs of the TAT gene but is separate from the GREs. The activity of the individual GME and negative elements was found to depend upon spacing. However, in combination with the natural GRE, the native TAT gene spacing of the GME and negative elements was able to reproduce the activity of the intact gene. Thus, a total of three additional elements (an activator, a negative element, and a neutralizer) appear to cooperate with the GREs in glucocorticoid induction of the TAT gene in Fu5-5 cells. While such a grouping of elements may be novel among steroid regulated genes, it is a not uncommon occurrence for the transcriptional control of other genes.
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PMID:Modulation of TAT gene induction by glucocorticoids involves a neutralizing sequence. 971 42

The insulin response element (IRE) in the IGFBP-1 promoter, and in other gene promoters, contains a T(A/G)TTT motif essential for insulin inhibition of transcription. Studies presented here test whether FKHR may be the transcription factor that confers insulin inhibition through this IRE motif. Immunoblots using antiserum to the synthetic peptide FKHR413-430, RNase protection, and Northerns blots show that FKHR is expressed in HEP G2 human hepatoma cells. Southwestern blots, electromobility shift assays, and DNase I protection assays show that Escherichia coli-expressed GST-FKHR binds specifically to IREs from the IGFBP-1, PEPCK and TAT genes; however, unlike HNF3beta, another protein proposed to be the insulin regulated factor, GST-FKHR does not bind the insulin unresponsive G/C-A/C mutation of the IGFBP-1 IRE. When HEP G2 cells were cotransfected with FKHR expression vectors and with IGFBP-1 promoter plasmids containing either native or mutant IREs, FKHR expression induced a 5-fold increase in activity of the native IGFBP-1 promoter but no increase in activity of promoter constructs containing insulin unresponsive IRE mutants. These data suggest that FKHR, and/or a related family member, is the important T(G/A)TTT binding protein that confers the inhibitory effect of insulin on gene transcription.
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PMID:FKHR binds the insulin response element in the insulin-like growth factor binding protein-1 promoter. 1038 7

In this paper, the effects of HMBA on the differentiation of human hepatocarcinoma cell line SMMC-7721 were investigated. After treated with 5 mmol/L HMBA, the proliferation of SMMC-7721 cells was inhibited remarkably, the cell growth inhibitory rate amounted to 64.14%, the cell mitotic index was declined by 53.88%. Light microscopy and transmission electron microscopy showed that the morphology and ultrastructure of the cells treated with HMBA undergone restorational alteration. Cytochemistry and immunocytochemistry assay revealed that the activities of gamma-GT declined and the levels of AFP and PCNA downregulated while the activity of TAT increased significantly after HMBA treatment. In the meantime, flow cytometry analysis showed that HMBA could arrest the cells in G0/G1 phase. The results showed that HMBA could effectively inhibit the proliferation, reverse the malignant morphology and ultrastructure, alter the levels of enzymes and antigens, arrest the cells in G0/G1, and induce the differentiation of human hepatocarcinoma SMMC-7721 cells in vitro.
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PMID:[Differentiation of human hepatocarcinoma SMMC-7721 cells induced by HMBA]. 1254 4

Growth inhibition by transforming growth factor (TGF)-beta 1 has been attributed to the induction of cyclin-dependent kinase inhibitors, among which p21/Waf1 plays a major role in many biological contexts. In the present study, two new intracellular mediators for the induction of p21/Waf1 by TGF-beta 1 were identified in a human hepatocellular carcinoma cell line (JHH-5) expressing mutant-type p53. After addition of TGF-beta 1 to JHH-5 cells, a marked increase of the p21/Waf1 expression preceded the inhibition of DNA synthesis. Expression of IFN regulatory factor (IRF)-1, a known transacting factor for p21/Waf1 promoter, was elevated just before or in parallel with the increase of p21/Waf1. Transduction of antisense IRF-1 inhibited the increase in p21/Waf1 in JHH-5 cells treated with TGF-beta 1 and partially released the cells from the growth arrest by TGF-beta 1. Expression of S100C/A11, a member of the Ca(2+)-binding S100 protein family, also markedly increased after addition of TGF-beta 1. S100C/A11 protein was translocated to and accumulated in nuclei of TGF-beta 1-treated JHH-5 cells, where p21/Waf1 was concomitantly accumulated. When a recombinant S100C/A11 protein was introduced into nuclei of JHH-5 cells, DNA synthesis was markedly inhibited in a dose-dependent manner in the absence of TGF-beta 1. Prior transfection of p21/Waf1-targeted small interfering RNA efficiently blocked decrease of DNA synthesis in JHH-5 cells caused by TAT-S100C/A11 or TGF-beta 1 and markedly inhibited expression of p21/Waf1 protein in the cells. These results indicate that IRF-1 and S100C/A11 mediate growth inhibition by TGF-beta 1 via induction of p21/Waf1.
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PMID:Involvement of interferon regulatory factor 1 and S100C/A11 in growth inhibition by transforming growth factor beta 1 in human hepatocellular carcinoma cells. 1520 26

Tumor hypoxia in a solid tumor mass has long been recognized as a cause of resistance to current cancer therapies, and has also been suggested to be a potent driving force towards malignancy. Recent progress in the understanding of the molecular mechanism of the tumor response to hypoxia has increased attention on targeting hypoxia for cancer therapy. We have generated a hypoxia-targeting fusion protein, TOP3, which is composed of a protein transduction domain (PTD) of HIV TAT, an oxygen-dependent degradation domain (ODD) of HIF-1 alpha, and procaspase-3. Here, we examine the effects of TOP3 in a rat ascites model. First, we clarified that the fluid in ascites from MM1 cells, which are derivatives of AH130 rat ascites hepatoma cells, was highly hypoxic. In vitro, MM1 cells retained protein degradation machinery through the ODD domain, and TOP3 effectively impaired MM1 cell growth in culture under hypoxic conditions by inducing apoptosis. Intraperitoneal administration of TOP3 prolonged the life span of rats bearing a significant amount of malignant ascites, and 60% of the treated animals were cured without recurrence of ascites. Thus, TOP3 had a dramatic effect on malignant ascites and, hence, we propose that rodent malignant ascites is an appropriate platform for testing hypoxia-targeted drugs.
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PMID:Targeting hypoxic cancer cells with a protein prodrug is effective in experimental malignant ascites. 1528 74


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