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)

The human metallothionein (MT)-IG gene (hMT-IG) is tandemly linked in a head-to-head fashion with the hMT-IF gene. The hMT-IG gene encodes a MT-I polypeptide and has a tripartite structure. The 5'-flanking region of the hMT-IG gene has a TATAA box, four GC motifs, and at least four metal responsive elements. The 3'-untranslated region has a variation of the polyadenylation signal, AATTAA, and the 3'-flanking region a YGTGTTYY RNA processing signal. This gene is expressed in hepatoma-derived cell lines (Hep G2 and Hep3B2) in response to the heavy metals (cadmium, copper, and zinc) but not to the glucocorticoid analogue dexamethasone. In contrast, the lymphoblastoid cell line (Wi-L2) does not express the hMT-IG gene. These results suggest that the hMT-IG gene is regulated differentially and in a cell type-specific manner. Transient expression studies of the chloramphenicol acetyltransferase (CAT) gene under the transcriptional control of either the hMT-IG or hMT-IF promoter in Hep G2 cells has demonstrated that both promoters contain all the necessary cis-acting elements to elicit a similar pattern of heavy metal inducibility. However, the hMT-IG promoter in all instances is five times more active than the hMT-IF promoter. The differences in promoter activity of these genes could possibly be due to inherent differences in their basal level regulatory sequences. The expression of MT-IGcat in transfected Wi-L2 cells demonstrates that the hMT-IG promoter is not cell type-specific.
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PMID:Structure and expression of the human metallothionein-IG gene. Differential promoter activity of two linked metallothionein-I genes in response to heavy metals. 340 43

We examined in the H4IIE rat hepatoma cell line the relationship between butyrate-induced changes in the nuclease sensitivity of chromatin and changes in transcriptional activity of specific genes. The butyrate-inducible metallothionein I (MT-I) gene underwent a dramatic increase in DNase I sensitivity after 3 h of butyrate treatment. However, genes not transcribed in H4IIE cells underwent the same changes in DNase I sensitivity. Thus, butyrate-induced increases in DNase I sensitivity are not sufficient for the transcriptional activation of a gene. Butyrate treatment has also been reported to alter the sensitivity of sequences to micrococcal nuclease (MNase) in a manner reflecting their tissue-specific expression. Butyrate exposure caused increased digestion of the MT-I gene by MNase. However, butyrate-induced MNase sensitivity also occurred for genes which are neither transcribed in untreated cells nor butyrate inducible. Moreover, cadmium, a potent transcriptional activator of the MT-I gene, does not alter the sensitivity of the MT-I gene to MNase. Thus, the butyrate-induced alterations in MNase sensitivity are neither sufficient for, necessary for, nor indicative of transcriptional activation.
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PMID:Butyrate-induced changes in nuclease sensitivity of chromatin cannot be correlated with transcriptional activation. 343 45

Two isoforms of metallothionein (MT) have been isolated from rainbow trout livers following CdCl2 injections. These MTs have been identified by standard procedures and appear to be similar to mammalian MTs. Total RNA from such induced livers was shown to contain high levels of MT-mRNA activity when translated in cell free systems. This activity was demonstrated to be in the 8 to 10S region of a sucrose gradient. The RNA fractions also showed homology to a mouse MT-I cDNA probe. The exposure of rainbow trout hepatoma (RTH) cells to various concentrations of CdCl2 and ZnCl2 induced the expression of MT and MT-mRNA. Exposure of Chinook salmon embryonic (CHSE) cells to these metals, however, did not result in MT synthesis, suggesting that the MT genes have not become committed to transcription. Instead, an unknown low molecular weight (MW = 14 kDa) protein was induced. This metal-inducible protein (MIP) was capable of binding 109Cd and was stable to heating, while the binding of the metal to this protein was not. These characteristics have been reported for a protein induced in rainbow trout liver following environmental exposure to cadmium. We suggest that both MT and MIP may function in detoxification of heavy metals.
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PMID:Heavy metal-induced gene expression in fish and fish cell lines. 370 34

A series of four cell lines resistant to the toxic effect of copper were developed from Morris rat hepatoma cells by gradually increasing the concentration of copper in the growth medium. The EC50, that concentration of copper that kills and/or inhibits the growth of 50% of the cells after 72 h, increased 4-fold over that for wild type cells in the most resistant cell line. These cells were also resistant to zinc, cadmium, and mercury toxicity, but not to nickel or cobalt. The amount of copper in the soluble protein pool of the resistant cells increased proportionally with the concentration of copper in the medium in which they were maintained. Associated with copper accumulation was the production of an 18-kDa cysteine-rich protein which complexes a significant amount of the metal. It is suggested that resistance to copper toxicity is due to sequestration of the metal by this protein. When resistant cells were removed from the copper-enriched environment, cellular copper levels rapidly fell to that observed for wild type cells, but no reduction in either the EC50 or the level of the cysteine-rich protein was noted. This suggests that a permanent change responsible for copper resistance had occurred which is maintained in the absence of the metal.
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PMID:Resistance to copper toxicity of cultured hepatoma cells. Characterization of resistant cell lines. 374 69

We examined the chromatin structure of the rat metallothionein I gene, both in uninduced cells and in cells induced by heavy metals or dexamethasone, using hypersensitivity to DNase I as an assay. The metallothionein I gene of the H4IIE rat hepatoma cell line, expressed at basal level, has a single DNase I-hypersensitive site. This site maps between putative hormone and basal level control sequences. Induction of the gene by cadmium or zinc resulted in the appearance of a new hypersensitive site near the start site of transcription, in a region near the metal-regulatory elements. In contrast, induction of the metallothionein I gene by dexamethasone did not alter the basal pattern of hypersensitivity. Thus, different mechanisms of induction of metallothionein transcription lead to distinct alterations in the chromatin containing the 5' sequences regulating the expression of this gene.
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PMID:Alternative inducers of the rat metallothionein I gene cause distinct changes in chromatin structure in the 5' region of the gene. 378 3

Crosslinking of proteins to DNA was studied in live intact Novikoff ascites hepatoma cells exposed in vitro to salts of chromium VI, III, and II, nickel II, cadmium II, and to CoCl2, As2O3, and AlK(SO4)2. DNA-protein complexes were separated by high-speed centrifugation of cells solubilized in buffered 4% sodium dodecyl sulfate and assayed by polyacrylamide gel electrophoresis. Hexavalent chromium compounds formed DNA-protein complexes very efficiently. The trivalent, poorly soluble, cupric chromite was nearly as efficient crosslinker as hexavalent Cr, perhaps because phagocytosis facilitated its entry into the cells. The more basic divalent form produced hardly any crosslinks. Most of the crosslinked proteins were common to all of the chromium salts employed. Nickel salts formed DNA-protein crosslinks less efficiently. Most proteins crosslinked by this metal had a high molecular weight ranging from 94,000 to 200,000. There was little qualitative difference between the crosslinked protein patterns for several various nickel (II) salts. Similar results were obtained for cells incubated with cadmium salts. Most of the proteins crosslinked by cadmium had high molecular weights and were similar to those crosslinked by nickel (II). Relatively weak, but significant, crosslinking was also observed when the Novikoff hepatoma cells were exposed to CoCl2, As2O3, or AlK(SO4)2.
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PMID:DNA-protein crosslinking by heavy metals in Novikoff hepatoma. 380 Mar 74

Ferritin was extracted from human hepatocellular carcinoma tissue and purified using column chromatography, gradient gel electrophoresis and cadmium sulphate crystallization. DEAE cellulose chromatography showed a difference between hepatoma and normal liver ferritin, indicative of a more acidic isoferritin profile in the tumour. Column-purified and crystalline ferritin and that remaining in the mother-liquor after crystallization was subjected to isoelectric focusing. Hepatoma ferritin showed higher concentrations of acidic isoferritins than liver ferritin. This was most obvious with mother-liquor ferritin, as crystallization tended to select out more basic isoferritins. Subunit analysis of hepatoma and liver ferritin showed a higher proportion of heavy subunits in the tumour ferritin, in keeping with the presence of acidic isoferritins. An antibody against hepatoma mother-liquor ferritin was raised in rabbits. However, hepatoma ferritin proved to be antigenically identical with normal liver ferritin, and we were thus unable to develop a specific radioimmunoassay for hepatoma ferritin.
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PMID:Isolation of ferritin from human hepatocellular carcinoma. 609 60

When Chinese hamster lung (CHL) cells were cultured in medium containing 25 microM cadmium chloride, resistant cells appeared at a frequency of 0.04%. When one of three tumor promoters, 12-O-tetradecanoylphorbol-13-acetate (TPA), aplysiatoxin and dihydroteleocidin B, was added during selection with cadmium chloride, the frequency of appearance of resistant cells increased more than 50-fold. Two of the resistant clones obtained were characterized. Both clones produced much higher levels of metallothionein I mRNA than the parental CHL cells. Southern blot analysis showed that in these resistant cells, metallothionein I genes were amplified approximately 5-fold. Therefore, it seems that tumor promoters can enhance the frequency of gene amplification. One possible mechanism of the action of tumor promoters in oncogenesis is amplification of activated c-onc genes. Consistent with this idea, it has been reported that c-onc genes are amplified in various cancer cells. We also found that the c-Ha-ras and c-myc genes were amplified in a bladder cancer removed surgically and in a transplanted rat hepatocellular carcinoma, Morris hepatoma 7794A, respectively.
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PMID:Increase in frequency of appearance of cadmium-resistant cells induced by various tumor promoters; evidence for the induction of gene amplification. 668 Jul 25

Responses of Reuber H35 hepatoma cells exposed to increasing doses of heat, arsenite ions, or cadmium ions were investigated. Doses which are capable of activating the heat shock transcription factor (HSF) were determined. The activity of this factor in the poststress period was correlated to the recovery of total protein synthesis in this same period. Subsequently, increases of mRNA levels and rates of synthesis of heat shock protein (HSP)60, HSP68, and HSP84 after exposure to the stressors were determined. We generally found that the rate of HSP synthesis correlated well with HSP mRNA levels, supporting the idea that the stress response is regulated mainly at the transcriptional level. A stressor-specific pattern of HSP mRNA induction can be observed. The most striking example is cadmium chloride which does not induce HSP60 nor its mRNA. Interestingly, under these conditions maximal activation of HSF is observed. Therefore, we conclude that more processes than just HSF activations are involved in the induction of heat shock genes.
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PMID:Stressor-specific activation of heat shock genes in H35 rat hepatoma cells. 748 29

Stress proteins (heat shock proteins, HSPs) have been proposed as markers for toxicity. This study has focussed on the pattern of HSP synthesis in relation to cytotoxicity and their dependence on doses of cadmium chloride. We investigated the relationship between cadmium-induced expression of heatshock genes, inhibition of protein synthesis and cell death in a well-differentiated hepatoma cell line, Reuber H35, under exposure conditions ranging to full (> 98%) lethality. We find a non-linearity in the responses of these cells when the duration of cadmium exposure is varied. The results indicate that sublethal concentrations of cadmium can inhibit protein synthesis and also increase the synthesis of certain HSPs. The pattern of heat shock protein induction changes when exposure conditions become more severe. The most strongly inducible heat shock protein, HSP68, is, surprisingly, only synthesized under conditions which lead to severe inhibition of protein synthesis. The comparison of HSP68 mRNA levels and HSP68 synthesis showed that HSP68 mRNA is already induced under conditions where the synthesis of HSP68 protein cannot yet be traced. From these data we conclude that a differential HSP expression takes place. The translational control of HSP synthesis might be explained by the preferential translation of this mRNA under conditions of severe shut-off of general protein synthesis.
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PMID:Relationship between cadmium-induced expression of heatshock genes, inhibition of protein synthesis and cell death. 776 99


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