Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Phosphorylation of glucocorticoid receptors is increased by hormone binding and has been implicated in transcriptional regulation. We performed a phosphoamino acid analysis and identified the phosphorylated regions of the glucocorticoid receptor with respect to its functional domains before and after hormone activation. Receptor was isolated by immunoprecipitation from [32P]orthophosphate-labeled FTO 2B rat hepatoma cells grown in the absence or presence of glucocorticoids. The receptor contained mainly phosphoserine, with little phosphothreonine and no phosphotyrosine. Partial proteolysis of receptor from hormone-treated or control cells revealed a similar phosphopeptide pattern. Chemical cleavage with hydroxylamine and cyanogen bromide or digestion with trypsin and chymotrypsin localized the majority of receptor phosphorylation sites to a transactivation domain amino-terminal of the DNA-binding domain. Phosphorylation of this region, termed tau 1/enh2, was increased 2-3-fold by hormone treatment. The DNA-binding domain itself is weakly phosphorylated; no phosphorylation was found in the hormone-binding domain. Phosphorylated regions were also identified in receptor deletion mutants stably transfected into CV-1 monkey kidney cells. Hormone-independent phosphorylation was observed with a strong constitutively active mutant lacking the hormone-binding domain. No phosphorylation was detected in a mutant lacking the amino-terminal region, which showed only weak, hormone-dependent activity. These results support the idea that phosphorylation is important for the strength of the glucocorticoid receptor as a transcriptional regulator.
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PMID:Hormone-dependent phosphorylation of the glucocorticoid receptor occurs mainly in the amino-terminal transactivation domain. 210 36

The intracellular basic helix-loop-helix (bHLH) dioxin receptor mediates signal transduction by dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin). In analogy to nuclear receptors that are members of the steroid hormone receptor superfamily the dioxin receptor is a ligand-inducible transcriptional regulator that directly binds to response elements within regulated genes. The most commonly studied dioxin receptor ligands are dioxin itself and structurally related environmental contaminants. A physiological ligand has not yet been identified. Interestingly, however, indolo[3,2-b]carbazole, a compound formed from precursors in the diet, has been shown to bind the murine dioxin receptor with high affinity in vitro. In the present study we show that this compound and its methylated derivative 5,11-dimethylindolo[3,2-b]carbazole very potently activated transcription from a dioxin or xenobiotic response element (XRE)-driven reporter gene in both murine and human hepatoma cells. This effect was not observed in mutant, dioxin-resistant hepatoma cells which are either deficient in expression of dioxin receptor or the bHLH receptor partner factor Arnt. In vitro indolocarbazoles induced XRE binding activity by the human dioxin receptor-Arnt complex in a dose-dependent manner. Thus, both dioxin- and indolocarbazole-activated forms of dioxin receptor regulate target gene expression by the same mechanism involving recruitment of the bHLH factor Arnt and recognition of the XRE element. Finally, the indolo[3,2-b]carbazole-activated human dioxin receptor appeared to generate more stable complexes with the XRE target sequence relative to those produced by the dioxin-activated receptor form, indicating interesting mechanistic differences between different classes of dioxin receptor ligands in their abilities to modulate human dioxin receptor function.
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PMID:Regulation of human dioxin receptor function by indolocarbazoles, receptor ligands of dietary origin. 810 94

The mammalian aromatic hydrocarbon (Ah) receptor is a soluble protein involved in the regulation of gene expression by halogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Little is known, however, about the presence and properties of this receptor in nonmammalian species. In these studies, we sought evidence for an Ah receptor in the liver or liver-equivalent of diverse species of invertebrate and vertebrate animals. Velocity sedimentation analysis of hepatic cytosol labeled with [3H]TCDD gave equivocal results with three species of marine fish. In subsequent studies, photoaffinity labeling with 2-azido-3-[125I]iodo-7,8-dibromodibenzo-p-dioxin was used to identify the Ah receptor. Specific labeling (labeling that could be displaced by an excess of unlabeled ligand) was observed in seven species of teleost and elasmobranch fish, including winter flounder (Pleuronectes americanus), killifish (Fundulus heteroclitus), scup (Stenotomus chrysops), rainbow trout (Oncorhynchus mykiss), brown trout (Salmo trutta), and dogfish (Mustelus canis and Squalus acanthias). Specific labeling was also found in cytosolic fractions prepared from PLHC-1 fish hepatoma cells and livers of a turtle (Chrysemys picta) and a cetacean, the beluga whale Delphinapterus leucas. The fish Ah receptor was sensitive to conditions of tissue preparation; inclusion of proteinase inhibitors in the homogenization buffer stabilized the receptor in some species. There was heterogeneity in the apparent molecular mass of the largest specifically labeled band in each species; these ranged from 105 to 146 kDa, slightly larger on average than mammalian Ah receptors (95-130 kDa). In contrast to the results obtained with teleost and elasmobranch fish, no specifically labeled polypeptides were detectable in cytosol from two agnathan fish species (hagfish Myxine glutinosa and sea lamprey Petromyzon marinus), the tunicate Ciona intestinalis, or any of nine other invertebrate species representing eight classes in four phyla. Overall these results suggest that the Ah receptor evolved at least 450 million years ago, prior to the divergence of bony and cartilaginous fishes. Although the exact relationship between receptor presence and dioxin responsiveness in these species is uncertain, our data predict that the invertebrate species examined in this study, which appear to lack an Ah receptor protein like that seen in mammals and fish, may be less sensitive than vertebrates to the effects of environmental contaminants that act through this transcriptional regulator.
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PMID:Photoaffinity labeling of the Ah receptor: phylogenetic survey of diverse vertebrate and invertebrate species. 816 Dec 8

For an approach of gene therapy for hepatocellular carcinoma (HCC), transcriptional regulatory sequence (TRS) of either alpha-fetoprotein (AFP) or albumin has been used for targeting cancer cells. To examine the feasibility of using TRSs of these genes for possible gene therapy of HCCs, the cellular distribution of AFP and albumin gene transcripts was studied in 25 cases of surgically removed human HCCs. AFP gene expression was observed in HCC nodules of 13 cases. The expression in HCC was heterogeneous, and the distribution of the transcripts was mostly sparse and spotty. The higher the serum AFP levels, the larger population of the AFP-expressing HCC cells tended to reflect. In noncancerous liver, a slight AFP expression was found by Northern blot analysis, but the transcripts were not detected in the liver sections. In contrast, albumin expression was found in all HCCs as well as in noncancerous hepatocytes. In HCC, the transcripts for albumin were distributed in cancer cells, and the expression varied with nodules. There were more albumin-expressing cancer cells than the AFP-expressing cells. Albumin expression was retained even in poorly differentiated HCC, although the intensity of the signal was not as strong as in more-differentiated HCCs. Metastatic HCC nodules revealed transcripts for both AFP and albumin genes, and those were clearly recognized in the lung tissue. These results suggest that, for gene therapy for HCCs, neither AFP nor albumin are ideal options for targeting HCC cells. AFP-TRS may be used as a transcriptional regulator in selected cases in which AFP gene expression is observed in the cancer nodules. The serum AFP level appears to be an important indicator in selecting cases. Albumin-TRS in conjunction with retroviral vector might be used in limited cases such as HCCs with no AFP expression. However, careful consideration must be taken, because albumin is constitutively expressed in normal hepatocytes, and AFP-expressing nonmalignant progenitor cells possibly exist.
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PMID:Expression of alpha-fetoprotein and albumin genes in human hepatocellular carcinomas: limitations in the application of the genes for targeting human hepatocellular carcinoma in gene therapy. 946 63

Apoptosis is a morphologically and biochemically distinct form of cell death which can be triggered by a variety of extracellular agents both during normal developments and in adult pathological states. However, the molecular mechanism of apoptotic cell death due to hypoxia has not been clearly elucidated. In this study, we investigated critical factors involved in hypoxia-induced apoptosis using HepG2, a human hepatocellular carcinoma cell line, as an experimental model. We found that 24 h of exposure of HepG2 cells to hypoxia induced apoptosis, for which de novo protein synthesis was required. Apoptosis was demonstrated by DNA fragmentation and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Hypoxia-induced apoptosis was associated with a marked induction of c-jun and c-fos messenger RNAs. Electromobility shift assay showed the increased DNA binding activity of AP-1 during hypoxia, suggesting that AP-1 may be involved in the induction of cell death by acting as a transcriptional regulator. A purine analogue, 6-thioguanine (6-TG), significantly blocked the induction of apoptosis by hypoxia. Moreover, the inductive effect of hypoxia on c-jun expression was also inhibited by 6-TG, whereas the levels of c-fos mRNA and its protein were rather strongly increased. Iodoacetamide (IAA), a non-specific inhibitor of ICE family proteases, also has an inhibitory effect on hypoxia-induced apoptosis. These results suggest that the 6-TG-sensitive protein kinase(s)-dependent signaling pathway may be involved in the apoptotic response of HepG2 cells exposed to hypoxia by increasing the level of c-jun and c-fos and the activity of AP-1 and/or by activating ICE family protease(s).
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PMID:Hypoxia-induced apoptosis in human hepatocellular carcinoma cells: a possible involvement of the 6-TG-sensitive protein kinase(s)-dependent signaling pathway. 956 54

The rat UDP glucuronosyltransferase, UGT2B1, is expressed in the liver where it glucuronidates steroids, environmental toxins, and carcinogens. A region between -88 and -111 base pairs upstream from the UGT2B1 gene transcription start site contains a CCAAT enhancer binding protein (C/EBP)-like element and was previously shown by Dnase I footprint analysis to bind to proteins in both rat liver and human hepatoma (HepG2) cell nuclear extracts. In this study, the importance of this region in the regulation of the UGT2B1 gene was assessed by functional and DNA binding assays. Varying lengths of the UGT2B1 gene promoter, with and without the C/EBP-like element, were fused to the chloramphenicol acetyltransferase reporter gene and transfected into HepG2 cells. Transcriptional activity of the UGT2B1 promoter construct containing the C/EBP-like element was strongly elevated in the presence of a cotransfected C/EBPalpha expression vector. In contrast, no change was observed when an expression vector encoding C/EBPbeta was cotransfected with the UGT2B1 promoter constructs. Introduction of point mutations into the C/EBP-like element prevented any C/EBPalpha-mediated increase in chloramphenicol acetyltransferase activity. Gel shift analyses demonstrated that the C/EBP-like element binds a complex of nuclear proteins present in both HepG2 cells and rat liver. The presence of C/EBPalpha in this complex was confirmed by supershift analysis with antiserum to this factor. These data strongly suggest that the liver-enriched factor C/EBPalpha binds to, and activates, the UGT2B1 gene promoter. The importance of C/EBPalpha in the regulation of the homologous mouse UGT2B1 gene was also assessed in vivo. Transcripts homologous to UGT2B1 were detected in the livers of mice containing intact c/ebpalpha and c/ebpbeta genes and in mice containing a homozygous null mutation in the c/ebpbeta gene. In contrast, these transcripts were not detected in mice with a disrupted hepatic c/ebpalpha gene. These data extend the findings with the rat UGT2B1 gene promoter and establish that C/EBPalpha, but not C/EBPbeta, is an essential transcriptional regulator of the homologous UGT2B1 gene in the mouse.
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PMID:C/EBPalpha is a regulator of the UDP glucuronosyltransferase UGT2B1 gene. 961 4

Triglyceride-rich remnant lipoproteins are considered as major risk factors contributing to the pathogenesis of atherosclerosis. Because apolipoprotein (apo) C-III is a major determinant of plasma triglyceride and remnant lipoprotein metabolism, it is important to understand how the expression of this gene is regulated. In the present study, we identified the orphan nuclear receptor RORalpha1 as a regulator of human and mouse apo C-III gene expression. Plasma triglyceride and apo C-III protein concentrations in staggerer (sg/sg) mice, homozygous for a deletion in the RORalpha gene, were significantly lower than in wild type littermates. The lowered plasma apo C-III levels were associated with reduced apo C-III mRNA levels in liver and intestine of sg/sg mice. Transient transfection experiments in human hepatoma HepG2, human colonic CaCO2, and rabbit kidney RK13 cells demonstrated that overexpression of the human RORalpha1 isoform specifically increases human apo C-III promoter activity, indicating that RORalpha1 enhances human apo C-III gene transcription. RORalpha1 response elements were mapped by promoter deletion analysis and gel shift experiments to two AGGTCA half-sites located at positions -83/-78 (within the C3P site) and -23/-18 (downstream of the TATA box) in the human apo C-III promoter, with the -23/-18 site exhibiting the highest binding affinity. Transfection of site-directed mutated constructs in HepG2 cells indicated that the RORalpha1 effect is predominantly mediated by the -23/-18 site. This site is conserved in the mouse apo C-III gene promoter. Moreover, RORalpha binds to the equivalent mouse site and activates constructs containing three copies of the mouse site cloned in front of an heterologous promoter. Taken together, our data identify RORalpha as a transcriptional regulator of apo C-III gene expression, providing a novel, physiological role for RORalpha1 in the regulation of genes controlling triglyceride metabolism.
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PMID:Transcriptional regulation of apolipoprotein C-III gene expression by the orphan nuclear receptor RORalpha. 1105 33

Hepatic steatosis and hepatocellular carcinoma (HCC) are common and serious features of hepatitis C virus (HCV) infection, and the core protein has been shown to play distinct roles in the pathogenesis. Here we report the direct interaction of HCV core protein with retinoid X receptor alpha (RXRalpha), a transcriptional regulator that controls many aspects of cell proliferation, differentiation, and lipid metabolism. The core protein binds to the DNA-binding domain of RXRalpha, leading to increase the DNA binding of RXRalpha to its responsive element. In addition, RXRalpha is activated in cells expressing the core protein as well as in the livers of the core-transgenic mice that would develop hepatic steatosis and HCC later in their lives. Using promoter genes of cellular retinol binding protein II (CRBPII) and acyl-CoA oxidase as reporters, we also show that the expression of the core protein enhances the transcriptional activity regulated by the RXRalpha homodimer as well as by the heterodimer with peroxisome proliferator activated receptor alpha. Furthermore, expression of the CRBPII gene is also up-regulated in the livers of HCV core-transgenic mice. In conclusion, these results suggest that modulation of RXRalpha-controlled gene expression via interaction with the core protein contributes to the pathogenesis of HCV infection.
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PMID:Interaction of hepatitis C virus core protein with retinoid X receptor alpha modulates its transcriptional activity. 1191 42

To identify potential biomarkers for the monitoring and risk assessment of benzo[a]pyrene (BaP), the oxidative stress-related DNA damage and p53 modification were investigated in human hepatoma HepG2 cells. Benzo[a]pyrene exposure induced a decrease in the cell viability, but increased the antioxidant enzyme activity as well as the DNA and lipid damage. The p53 protein activation appeared to have been a downstream response to the benzo[a]pyrene-induced DNA damage, suggesting p53 plays important roles in the defense against benzo[a]pyrene-induced genotoxicity. The response of phosphorylated p53 may be more sensitive towards benzo[a]pyrene exposure than normal p53. Following DNA damage, the activation of p53 acts as a transcriptional regulator of several target genes, including, p21 protein; a gene that encodes the Cdk inhibitor and is induced by exposure to benzo[a]pyrene. The p53 mRNA level was increased after the treatment of cells with benzo[a]pyrene, as well as following the induction of p53 protein, suggesting the benzo[a]pyrene-stimulated p53 accumulation may also be transcriptionally induced. The overall results suggest that benzo[a]pyrene leads to serious DNA damage, which leads to the transcription of the p53 gene; that the subsequent p53 protein accumulation up-regulates the cellular p21 protein. Oxidative DNA damage and p53 accumulation seem to be related to benzo[a]pyrene toxicity; however, their potential as biomarkers in environmental monitoring and risk assessment needs to be validated in the context of their specificity and sensitivity.
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PMID:Benzo[a]pyrene-induced DNA damage and p53 modulation in human hepatoma HepG2 cells for the identification of potential biomarkers for PAH monitoring and risk assessment. 1702 27

Nuclear factor-kappaB (NF-kappaB) is a transcriptional regulator of genes involved in immunity, inflammatory response, cell fate, and function. Recent attention has focused on the pathophysiological role of NF-kappaB in the diseased liver. In vivo studies using rodent models of liver disease and cell-targeted perturbation of NF-kappaB activity have revealed complex and multicellular functions in hepatic inflammation, fibrosis, and the development of hepatocellular carcinoma - a process we have termed the "inflammation-fibrosis-cancer axis". This review summarizes the current state of knowledge and provides insight into the vast complexity of the hepatic NF-kappaB signaling system, which should provide a rich source of new therapeutic targets.
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PMID:Nuclear factor-kappaB and the hepatic inflammation-fibrosis-cancer axis. 1766 7


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