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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The uptake of radio-labeled hemoglobin-haptoglobin complex (Hb-Hp) by human hepatoma PLC/PRF/5 and HepG2 cells was investigated in an attempt to characterize the uptake process and intracellular transport. Human hepatoma cells took up Hb-Hp in a receptor-mediated manner. Scatchard analysis of binding revealed that PLC/PRF/5 and HepG2 cells exhibited about 21,000 and 63,000 haptoglobin receptors/cell, with a dissociation constant (Kd) of 8.0 and 17 nM, respectively. Human hepatocytes in primary culture also expressed about 84,000 receptors/cells, with a Kd of 7.4 nM. The hemoglobin-haptoglobin complex was internalized and subsequently the internalized Hb-Hp was slowly degraded in the cells. Preincubation of the cells with Hb-Hp resulted in a decrease in binding of the radioactive Hb-Hp to the cell surface, and was accompanied with an accumulation of intracellular receptors. The uptake of Hb-Hp by the cells was not inhibited by 100 microM chloroquine or by 10 mM methylamine, but was inhibited by 50 microM monodansylcadaverine. Hemoglobin-heme taken up by the cells induced microsomal heme oxygenase. Thus, human hepatoma PLC/PRF/5 and HepG2 cells can take up Hb-Hp by haptoglobin receptor-mediated endocytosis and Hb-Hp probably causes translocation of the haptoglobin receptors from the cell surface to the cell interior where they can be degraded. The internalized heme-moiety of hemoglobin can regulate the expression of heme oxygenase.
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PMID:Expression of haptoglobin receptors in human hepatoma cells. 135 88

The effects of human interleukin-6 (hIL-6), the major acute-phase inducer, on the level of the transcript of microsomal heme oxygenase (HO) were examined in a human hepatoma cell line, Hep3B. Messenger RNAs (mRNAs) encoding HO and haptoglobin (Hpt) increased after hIL-6 treatment in a time- and dose-dependent manner. hIL-6 had no effect on the induction of heat-shock protein 70 (hsp70) mRNA, suggesting that the induction of HO by hIL-6 is regulated by a different mechanism from that which mediates the heat-shock induction of this enzyme. The hIL-6-mediated induction of HO mRNA was completely abrogated by simultaneous treatment of cells with actinomycin D, but not with cycloheximide, suggesting that the induction occurs at the level of transcription. A nuclear factor was shown both in untreated, and in the hIL-6-treated Hep3B cells that binds specifically to the IL-6-responsive element (IL6-RE) of the human HO gene. These findings suggest that HO is a positive acute-phase reactant in this human liver-derived cell line, and that the nuclear factor specific to the IL6-RE may be involved in the activation of the HO gene after hIL-6 treatment.
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PMID:Heme oxygenase is a positive acute-phase reactant in human Hep3B hepatoma cells. 137 18

Hemopexin-mediated heme transport into mouse hepatoma (Hepa) cells and human promyelocytic (HL-60) cells stimulates the expression of heme oxygenase via transcriptional activation (Alam, J., and Smith, A. (1989) J. Biol. Chem. 264, 17637-17640). Incubation of both these cell types in serum-free medium containing heme-hemopexin is shown here also to increase the steady-state level of metallothionein (MT) mRNA in a time- and dose-dependent manner. Heme-hemopexin is a far more effective inducer (12-fold) of the MT isozyme 1 (MT-1) in Hepa cells than nonprotein-bound heme (4-fold). Apohemopexin has no effect on MT-1 expression, and incubation with heme-hemopexin of mouse L fibroblasts that lack hemopexin receptors does not affect MT-1 expression. Thus, an interaction between the heme-hemopexin complex and its receptor is necessary for increased accumulation of MT-1 transcripts. In vitro nuclear "run-on" analysis indicates that the heme-hemopexin-mediated accumulation of MT-1 mRNA is regulated primarily at the level of initiation of transcription. A highly labile protein is required for constitutive MT-1 gene expression and acts to repress transcription. Transcriptional activation by heme or metals may require decreased concentrations or inactivation of the repressor as well as an additional inducer-specific trans-acting factor. Inhibition of protein synthesis augments the heme-hemopexin-mediated accumulation of MT-1 mRNA. Activation of heme oxygenase (HO) gene transcription by heme requires the synthesis of one (or more) heme-inducible proteins that are labile or become labile upon cycloheximide-sensitive processing or activation. Our comparison of MT and HO points to significant differences in the mechanisms of gene regulation by heme. The concomitant regulation of gene expression of MT-1 and HO in response to heme-hemopexin appears to be a concerted adaptive response of the cells, mediated at the level of the plasma membrane hemopexin receptor, and may relate to the proposed role of MT as an intracellular antioxidant or to a need to sequester zinc which otherwise would compete with iron and occupy sites on regulatory proteins such as the iron-responsive elements.
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PMID:Heme-hemopexin-mediated induction of metallothionein gene expression. 164 22

Haem oxygenase is a heat-shock protein in several rat tissues, as well as in certain human cells such as Hep3B hepatoma cells. In common with other heat-shock-protein genes, both the human and the rat haem oxygenase genes contain a heat-shock element (HSE) in their promoter regions. In the present study we have identified a factor in nuclear extracts of human Hep3B cells which binds specifically to the HSE of the human haem oxygenase gene. The factor in Hep3B cells was significantly induced within 1 h after heat-shock treatment, and the induction was blocked by treatment of cells with actinomycin D or cycloheximide. The factor was not detected in human HepG2 hepatoma cells, which exhibit the heat-mediated induction of heat-shock protein 70 mRNA, but not that of haem oxygenase mRNA. These findings suggest that the heat-inducible nuclear factor is increased at the level of transcription and that it may activate the human haem oxygenase gene via the HSE after heat treatment.
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PMID:A heat-inducible nuclear factor that binds to the heat-shock element of the human haem oxygenase gene. 187 20

Synthesis of the iron-storage protein ferritin is thought to be regulated at the translational level by the cytosolic content of chelatable iron. This response to iron is regulated by the iron-modulated binding to ferritin mRNAs of a repressor protein, the iron regulatory element-binding protein. From measurements made in a cell-free system, regulation of the iron regulatory element-binding protein has been recently suggested to involve direct interaction with hemin. The following observations on the synthesis of ferritin and of heme oxygenase (HO), the heme-degrading enzyme, in rat fibroblasts or hepatoma cells lead us to conclude that chelatable iron is a direct physiological regulator of ferritin synthesis in intact cells: (i) the inhibitor of heme degradation, tin mesoporphyrin IX, reduces the ability of exogenous hemin to induce ferritin synthesis but enhances HO synthesis; (ii) the iron chelator desferal suppresses the ability of hemin to induce synthesis of ferritin but not of HO; (iii) the heme synthesis inhibitor succinylacetone does not block iron induction of ferritin synthesis; (iv) there is no apparent relationship between the ability of various metalloporphyrins to inactivate the iron regulatory element-binding protein in cell-free extracts and their capacity to induce ferritin synthesis in intact cells; (v) administered inorganic iron significantly induces the synthesis of ferritin but not of HO; (vi) addition of delta-aminolevulinic acid to stimulate heme synthesis represses the ability of inorganic iron to induce ferritin synthesis while activating HO synthesis. Taken together, our results demonstrate that (i) release of iron by HO plays an essential role in the induction of ferritin synthesis by heme and (ii) chelatable iron can regulate ferritin synthesis independently of heme formation.
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PMID:Regulation of ferritin and heme oxygenase synthesis in rat fibroblasts by different forms of iron. 199 60

This review starts with a description of certain features of mammalian ferritins and their DNA and RNA structures relevant to translational control of ferritin synthesis. Although the amino acid sequences of the two ferritin subunits (H and L) diverge in about 50% of the coding region, their five alpha-helices and the exon sizes of their genes are compatible with the proposition that they diverged from a single ancestral gene. Of particular note is their long 5'-untranslated regions (5'UTRs) which include a 28-nucleotide sequence almost completely identical in the H- and L-subunits of a range of species. This motif near the cap region of the 5'-UTR, which forms a specific stem-loop structure, provides for regulation of the translation of H- and L-ferritin mRNAs. When intracellular levels of chelatable iron are not in excess, a large reserve of H- and L-mRNAs is present in the cell sap, restrained from translation by a protein with an Mr of about 90-100,000 which binds to the stem-loop structure. When excess iron floods the cytosol, this protein/RNA complex appears to dissociate and the 40S ribosome subunit is now able to initiate ferritin protein synthesis so that the dormant mRNAs become active and are transferred to the polyribosomes. The mechanism whereby the binding protein is regulated in response to iron is currently under investigation. The regulatory protein occurs in the cell sap and is present in several interchangeable forms which appear to differ in the redox state of specific sulphydryls within the protein. Under some circumstances, the abundance of these forms appears to be altered by intracellular iron status. It is unclear how iron influences binding of the regulatory protein to ferritin mRNA. Some investigators consider that iron binds in the form of heme to the regulatory protein, for which they offer in vitro evidence. We have examined the role of heme versus inorganic chelatable iron in the regulation of ferritin and heme oxygenase synthesis in rat fibroblasts and hepatoma cells. By manipulating the flow of iron between the intracellular chelatable iron and heme iron pools we have concluded that chelatable iron can act as a regulator of ferritin synthesis in a manner which is independent of heme formation. This conclusion does not exclude a role for heme in some specialized cell types.
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PMID:Translational regulation of ferritin synthesis by iron. 213 57

Effects of various stresses were examined on the accumulation of mRNA for microsomal heme oxygenase and a heat shock protein, hsp70, in three human hepatoma cell lines. By heat shock, hsp70 mRNA was induced in all three hepatoma lines, Hep G2, Hep 3B and Hep G2f, while heme oxygenase mRNA was increased only in Hep 3B. Time-courses of the heat shock induction of both mRNAs in Hep 3B were similar. Arsenite caused induction of both mRNAs in all three cell lines, while cadmium increased them in Hep G2 and Hep 3B, but not in Hep G2f cells. These findings suggest that, although both hsp70 and heme oxygenase are heat shock proteins, the mode of induction of mRNAs for these proteins is different.
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PMID:Activation of heme oxygenase and heat shock protein 70 genes by stress in human hepatoma cells. 215 80

Hemopexin (HPX) transports heme to liver parenchymal cells, undergoes receptor-mediated endocytosis, and recycles intact. Incubation of mouse hepatoma (Hepa) cells with heme-HPX causes a rapid dose- and time-dependent increase in the steady-state level of heme oxygenase (HO) mRNA. A maximum induction of 20-25-fold is achieved within 3 h after incubation with 10 microM heme-HPX. This accumulation of HO mRNA results primarily from increased transcription of the HO gene as judged by in vitro nuclear run-on assays. In addition, receptor-mediated transport of heme into Hepa cells significantly decreases the steady-state level of transferrin receptor (TfR) mRNA. While a 25-30-fold decrease in the amount of TfR mRNA is observed within 3 h of incubation of Hepa cells with 10 microM heme-HPX, no significant change in the rate of TfR gene transcription was detected. These regulatory effects of heme-HPX are not restricted to hepatic cells but are also observed in human promyelocytic HL-60 cells. This is the first direct demonstration of receptor-mediated transport of heme by hemopexin regulating gene expression in mammalian cells.
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PMID:Receptor-mediated transport of heme by hemopexin regulates gene expression in mammalian cells. 255 89

Heat shock treatment of human Hep 3B hepatoma cells led to the induction of mRNA for microsomal heme oxygenase. The maximum induction of heme oxygenase mRNA (5----7-fold) was observed with treatment of cells at 43.5 degrees C, for 60 min. The heat-mediated induction of heme oxygenase mRNA was blocked by simultaneous treatment of cells with actinomycin D or cycloheximide. In contrast to Hep 3B cells, cells of another human hepatoma line, Hep G2, showed little induction of heme oxygenase mRNA by heat treatment. These findings suggest that heat shock treatment induces heme oxygenase mRNA in certain human hepatoma cells, but not in others.
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PMID:Heat shock induction of heme oxygenase mRNA in human Hep 3B hepatoma cells. 255 44

Treatment of mouse hepatoma (Hepa) cells with heme or cadmium chloride in serum-free medium causes a rapid increase in the steady-state level of heme oxygenase (HO) messenger RNA. This increase is both dose- and time-dependent. Maximum accumulation of HO mRNA is observed 3 h after addition of either agent. Treatment of Hepa cells with heme or CdCl2 also stimulates the transcription of the HO gene, as judged by in vitro nuclear transcription run-on assays. The maximum rate of HO gene transcription occurs 2 h after treatment with either agent. Comparison of the relative increase in the rate of HO gene transcription with the relative increase in the level of HO mRNA demonstrates that transcriptional activation is the primary mechanism by which heme and cadmium produce the accumulation of HO mRNA in Hepa cells. Cadmium may also influence other processes involved in the expression of HO, since the time course of mRNA accumulation diverges from that of gene transcription. However, neither heme nor cadmium alters the rate of HO mRNA degradation. Cobalt chloride and heat shock, which are potent inducers of HO mRNA in rat liver and rat C6 glioma cells, respectively, have only a small effect on the level of HO mRNA in mouse hepatoma cells.
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PMID:Transcriptional activation of the heme oxygenase gene by heme and cadmium in mouse hepatoma cells. 270 93


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