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)

Transcriptional regulation of gene expression by hypoxia is an important, but yet only marginally characterized mechanism by which organisms adapt to low oxygen concentrations. The human hepatoma cell line HepG2 is a widely used model for studying hypoxic induction of the hematopoietic growth factor erythropoietin. In an attempt to identify additional genes expressed in HepG2 cells during hypoxia, we differentially screened a cDNA library derived from hypoxic (1% O2) HepG2 cells using probes isolated from either normoxic (21% O2) or hypoxic cells. Two genes were identified, one encoding aldolase, a member of the glycolytic enzymes, and the other encoding alpha 1-antitrypsin which belongs to the family of the acute phase (AP) responsive proteins. Whereas hypoxic induction of glycolytic enzymes is well established, oxygen-dependent regulation of AP genes has not been reported so far. AP proteins are liver-derived plasma proteins whose production during inflammation is either up-regulated (positive AP reactants) or down-regulated (negative AP reactants). In the present study, we demonstrate that on the mRNA level hypoxic stimulation of HepG2 cells led to (i) an induction of the positive AP reactants alpha 1-antitrypsin, alpha 1-antichymotrypsin, complement C3, haptoglobin, and alpha 1-acid glycoprotein; (ii) a down-regulation of the negative AP reactant albumin; (iii) an up-regulation of the negative AP reactant transferrin; and (iv) unchanged levels of the positive AP reactants alpha- and beta-fibrinogen as well as hemopexin. Cycloheximide inhibited hypoxic up-regulation of AP mRNAs demonstrating that de novo protein synthesis is required for hypoxic induction. Nuclear run-on assays indicate that the hypoxic increase in AP mRNAs is mainly due to transcriptional regulation. The hypoxic response was compared to AP stimulation by interleukin 6. The results suggest that the adaptive response to hypoxia overlaps with, but is not identical with, the AP response mediated by interleukin 6.
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PMID:Hypoxia, a novel inducer of acute phase gene expression in a human hepatoma cell line. 749 59

The rat hepatoma cell line, H-35, responds to IL-1- and IL-6-type cytokines by an increased transcription of specific acute phase plasma protein (APP) genes. Transforming growth factor-beta (TGF-beta), although ineffective on its own in regulating APP genes, modulates the action of the IL-type cytokines. In growing cultures, the IL-6 and IL-11 stimulation of thiostatin and hemopexin is enhanced by TGF-beta, whereas the stimulation of other APP is reduced. The effects of leukemia inhibitory factor, ciliary neurotrophic factor, IL-1, and TNF-alpha are generally attenuated by TGF-beta. Enhancement by TGF-beta of the IL-6-induced response can be explained in part by the fact that TGF-beta, in combination with dexamethasone, stimulates severalfold the expression of the 80-kDa ligand-binding subunit of IL-6R. Serum deprivation of H-35 cells for 3 days leads to an enhanced basal and cytokine-stimulated level of APP gene expression concomitant with a loss of the divergent regulatory effect of TGF-beta. In growth-arrested H-35 cells, TGF-beta still enhances the IL-6R expression but it attenuates all IL-6 effects on APP genes. These data suggest that TGF-beta influences the signal transduction of the IL-type cytokines by separate mechanisms and that the manifestation of the TGF-beta action is modulated by the growth state of the cell culture.
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PMID:Divergent transforming growth factor-beta effects on IL-6 regulation of acute phase plasma proteins in rat hepatoma cells. 750 21

The receptor for granulocyte colony stimulating factor (G-CSFR) and chimeric receptors consisting of the extracellular domain of G-CSFR and the transmembrane and cytoplasmic domain of the leukemia inhibitory factor receptor, gp130, or c-mpl function as homodimeric complexes. These receptors mediate a similar stimulation of gene transcription via separate regulatory elements of acute phase plasma protein genes. To identify the receptor regions within the cytoplasmic domains necessary for transcriptional regulation, the receptors were transiently expressed in rat hepatoma cells. Each receptor form reconstituted G-CSF-induced expression of a chloramphenicol acetyltransferase gene construct containing the cytokine response element of the rat alpha 1-acid glycoprotein gene. This regulation required the presence of two conserved sequence motifs (referred to as box 1 and box 2) in the cytoplasmic domains of each receptor. With the exception of G-CSFR-MPL chimera, the receptors also mediated a similarly high stimulation via the IL-6 response element of the rat beta-fibrinogen and hemopexin genes. Regulation of the IL-6 response element required, however, in addition to boxes 1 and 2, a third sequence motif (box 3). This motif is absent in the cytoplasmic domain of c-mpl, possibly explaining its inability to activate the IL-6 response element. When cells which express receptor forms with prominent box 3 function were treated with suramin, a ligand-independent gene stimulation via the IL-6 response element was observed. The suramin effect probably involves a receptor dimerization mediated by the extracellular G-CSFR domain and by the intracellular regions that include box 3.
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PMID:Signaling by the cytoplasmic domain of hematopoietin receptors involves two distinguishable mechanisms in hepatic cells. 751 79

A 23-kDa protein with high affinity for heme (KD = 55 nM), therefore termed heme-binding protein 23 kDa (HBP23), was purified from rat liver cytosol [Iwahara, S., et al. (1995) Biochemistry 34, 13398-13406]. Homology search of the cloned HBP23 cDNA revealed that this protein belongs to a recently recognized class of thiol peroxidases, the antioxidant peroxiredoxin family. Since HBP23 gene expression was highest in the liver, HBP23 mRNA regulation by heme and heavy metals was investigated in cultures of primary rat hepatocytes and mouse hepatoma Hepa 1-6 cells. In both cell cultures HBP23 mRNA levels were upregulated in a time- and dose-dependent manner by heme. Heme-dependent induction of HBP23 mRNA occurred coordinately with that of the heme-metabolizing enzyme heme oxygenase-1, which was recently identified as inducible by oxidative stress. Treatment of primary rat hepatocyte or hepatoma cell cultures with the heavy metals CdCl2 (10 microM) and CoCl2 (300 microM) induced in parallel HBP23 and HO-1 mRNA levels, in the case of CdCl2 to even higher levels than heme. By contrast, mRNA expression of another heme binding protein, hemopexin, was not induced in hepatocyte cell cultures by heme or heavy metals. The data suggest that the expression of HBP23 and HO-1 mRNA is regulated by (a) similar mechanism(s) in liver and that both genes could play a common physiological role as antioxidants and/or in heme metabolism.
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PMID:Expression of the mRNA of heme-binding protein 23 is coordinated with that of heme oxygenase-1 by heme and heavy metals in primary rat hepatocytes and hepatoma cells. 757 27

Heme-hemopexin or cobalt protoporphyrin (CoPP)-hemopexin (a model ligand for hemopexin receptor occupancy) is shown to increase transcription of the metallothionein-1 (MT-1) gene by activation of a signaling pathway. Promoter deletion analysis followed by transient transfection assays show that 110 base pairs (-153 to -43) of 5'-flanking region of the murine MT-1 promoter are sufficient for increasing transcription in response to heme-hemopexin or to CoPP-hemopexin in mouse hepatoma cells. The protein kinase C inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H7), prevented the increase in MT-1 transcription by heme-hemopexin, CoPP-hemopexin, or phorbol 12-myristate 13-acetate, but the protein kinase A inhibitor, HA1004, was without effect. N-Acetylcysteine (NAC) and glutathione, as well as superoxide dismutase and catalase, inhibited both the increase in endogenous MT-1 mRNA and the activation of reporter gene activity by heme-hemopexin, CoPP-hemopexin, and phorbol 12-myristate 13-acetate. In sum, these data suggest that reactive oxygen intermediates are generated by heme-hemopexin via events associated with receptor binding, including protein kinase C activation. Induction of heme oxygenase-1 expression, in contrast to MT-1, is significantly less sensitive to NAC. Deletion and mutation analyses of the MT-1 proximal promoter revealed that the sequence 5'-GTGACTATGC-3' (from -98 to -89 base pairs) is, in part, responsible for the hemopexin-mediated regulation of MT-1 which is inhibited by H7. Regulation via this element is also induced by H2O2 showing that it is an antioxidant response element. Heme itself acts via more distal elements on the MT-1 promoter. In contrast to NAC and glutathione, diethyl dithiocarbamate and pyrrolidine dithiocarbamate, which inactivate reactive oxygen intermediates and chelate Zn(II), synergistically augment the induction of MT-1 mRNA levels and reporter gene activity in response to heme-hemopexin via the antioxidant response element by both metal-responsive element-dependent and -independent mechanisms.
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PMID:Mechanism of metallothionein gene regulation by heme-hemopexin. Roles of protein kinase C, reactive oxygen species, and cis-acting elements. 759 95

Hepatitis B virus infection is closely linked to hepatocellular carcinoma (HCC), the pathological mechanism of hepatocarcinogenesis by this virus is not well understood. In order to gain further insight into the molecular mechanism of HCC, we constructed and screened a subtracted c-DNA library which was specific to HCC cells of a woodchuck infected with woodchuck hepatitis B virus. Among eight clones that were isolated based on their differential expressions, we determined nucleotide sequences of two genes whose expressions were most significantly stimulated in HCC. Our results indicate that these two genes appear to be woodchuck counterpart genes of hemopexin (HPX) and alpha-1 acid glycoprotein (AGP), suggesting that the expression of HPX and AGP genes are strongly augmented in tumor cells partly due to transcriptional regulation.
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PMID:Differential gene expression in experimental hepatocellular carcinoma induced by woodchuck hepatitis B virus. 765 24

The promoter regions of three IL-6 inducible genes, hemopexin (Hpx), haptoglobin (Hp) and C-reactive protein (CRP) contain cis-acting IL-6 responsive elements (IL-6REs) which are necessary and sufficient to induce IL-6 transcription activation. Transcription factors of the C/EBP family interact with IL-6REs. Among these, IL-6DBP/NF-IL6 plays a key role in IL-6 signal transduction because its trans-activation potential is induced by IL-6 in the human hepatoma cell line Hep3B. We show here that a different C/EBP-related factor, C/EBP delta/NF-IL6 beta, is the major IL-6 induced protein interacting with IL-6REs in the nuclei of Hep3B cells. In contrast to IL-6DBP/NF-IL6, whose activity in Hep3B cells is modulated by IL-6 via a post-translational mechanism, C/EBP delta/NF-IL6 beta is transcriptionally induced by IL-6. Another contrasting feature is that the C/EBP delta cDNA transfected in Hep3B cells activates transcription from an IL-6RE synthetic promoter in a constitutive manner which is not further enhanced by IL-6. Therefore, in Hep3B cells, two distinct members of the C/EBP family are recruited in the IL-6 signal transduction pathway via different mechanisms.
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PMID:The two C/EBP isoforms, IL-6DBP/NF-IL6 and C/EBP delta/NF-IL6 beta, are induced by IL-6 to promote acute phase gene transcription via different mechanisms. 768 Jan 15

In rat hepatoma H-35 cells, TNF-alpha, like IL-1 beta, stimulates the synthesis and secretion of type 1 acute phase plasma proteins, including alpha 1-acid glycoprotein (AGP), complement component 3 (C3), hemopexin, and haptoglobin. TNF and IL-1 in combination act additively to synergistically on the expression of AGP and C3 but not on hemopexin and haptoglobin. The cytokine stimulation of AGP and C3 genes is further enhanced by hepatocyte growth factor. The effect of TNF is mediated by the type I TNF receptor as judged from the TNF-like effect elicited by the agonist antibodies to type I but not type II TNF receptor. The data suggest that, although TNF and IL-1 share considerable overlap in their signal transduction mechanism, cytokine-specific signal pathways exist that affect a subset of acute phase plasma protein genes. A potential regulatory role is attributed to the transcription factors C/EBP beta and NF-kB based on studies on transiently transfected H-35 cells.
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PMID:TNF-alpha, IL-1 beta, and hepatocyte growth factor cooperate in stimulating specific acute phase plasma protein genes in rat hepatoma cells. 769 42

This study characterizes plasma protein synthesis and its hormonal regulation in a chicken hepatoma cell line, with particular emphasis on fibrinogen. Whereas virtually all aspects of hemopexin, transferrin and albumin production in these cells corresponded to those of cultured primary hepatocytes, fibrinogen was not secreted. Analysis of fibrinogen subunit synthesis revealed a specific defect in synthesis of one subunit, gamma, correlating with a lack of its mRNA. Pulse-chase and electron microscopic studies demonstrate that, despite the inability of these cells to secrete the A alpha and B beta subunits produced, there is no long-term accumulation of unsecreted fibrinogen. The B beta fibrinogen subunits are largely degraded 2 hr after synthesis. During this time, approximately half of the A alpha subunits are degraded; the rest are converted to the glycosylated form. The implications of this type of defect with respect to the pathogenesis of fibrinogen storage disease are discussed.
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PMID:Characterization of a chicken hepatoma cell line with a specific defect in fibrinogen secretion. 811 93

The asparagine-linked sugar chains in serum transferrin purified from patients with hepatocellular carcinoma (n = 13), healthy individuals (n = 5) and patients with liver cirrhosis (n = 6) were compared. Sugar chains released with N-glycanase from desialylated and pepsin-digested transferrin were derivatized by reductive pyridylamination. Analysis of the sugar chains by high performance liquid chromatography in combination with exoglycosidase digestion revealed an increase of a biantennary complex-type sugar chain with a fucosylated trimannosyl core; Gal beta 1-4GlcNAc beta 1-2Man alpha 1-6(Gal beta 1-4GlcNAc beta 1-2Man alpha 1-3) Man beta 1-4GlcNAc beta 1-4(Fuc alpha 1-6)GlcNAc in 7 of 13 cancer patients and an increase of a sugar chain with a fucosylated trimannosyl core and bisecting N-acetylglucosamine; Gal beta 1-4GlcNAc beta 1-2Man alpha 1-6(GlcNAc beta 1-4) (Gal beta 1-4GlcNAc beta 1-2Man alpha 1-3)Man beta 1-4GlcNAc beta 1-4(Fuc alpha 1-6)GlcNAc in one of the 13 cancer patients. Further, the fucosylated alteration of the sugar chain was detected also in alpha 1-antitrypsin, hemopexin, alpha 1-acid glycoprotein and alpha 2-HS glycoprotein from one of the patients with increased fucosylated transferrin.
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PMID:Alteration of asparagine-linked glycosylation in serum transferrin of patients with hepatocellular carcinoma. 817 73


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