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 initial phase of inflammation is accompanied by dramatic changes in the concentrations of certain plasma proteins. Interleukin-6 (IL-6) is an important inducer of these acute phase proteins at the transcriptional level. The recently cloned nuclear factor NF-IL6, a potent trans-acting regulator of IL-6 gene expression, has a region that is highly homologous to the liver-specific transcriptional factor C/EBP. Both factors recognize the same nucleotide sequence. In this study the recombinant NF-IL6 was shown to interact with the IL-6-responsive elements (IL-6REs) identified in the promoter region of several acute phase protein genes whose activity increases during the acute phase reaction. Furthermore, in competition experiments, formation of all the DNA-protein complexes by the IL-6RE and IL-6-treated hepatoma cell extracts was specifically decreased by adding either the 14-bp NF-IL6 binding motif identified in the IL-6 promoter or the antibody against the recombinant NF-IL6. NF-IL6 was expressed at a minor level in mouse liver, but was dramatically induced after stimulation with IL-6. In contrast, the amount of C/EBP mRNA decreased considerably after IL-6 stimulation. These results indicate that the NF-IL6 that regulated IL-6 expression was also involved in regulation of expression of the acute phase protein genes. The ability of NF-IL6 to replace C/EBP may explain the positive and negative acute phase responses induced by IL-6.
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PMID:Reciprocal expression of NF-IL6 and C/EBP in hepatocytes: possible involvement of NF-IL6 in acute phase protein gene expression. 171 Jan 43

The nuclear factor NF-IL6 had been suggested to be responsible for the IL-6-mediated induction of several acute-phase proteins. To obtain evidence for the involvement of NF-IL6 in the induction of acute-phase proteins, we introduced the NF-IL6 gene and its truncated mutant (delNFIL6) gene into a hepatoma cell line Hep3B. Then, we examined the effect of the overproduced NF-IL6 and delNFIL6 on the expression of haptoglobin, fibrinogen and albumin. As a result, basal production as well as induction of haptoglobin by IL-6 were augmented by the expression of NF-IL6, whereas delNFIL6 blocked the production of haptoglobin, fibrinogen and albumin.
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PMID:Augmentation of haptoglobin production in Hep3B cell line by a nuclear factor NF-IL6. 171 80

Human cytosolic aldehyde dehydrogenase 1 (ALDH1) plays a role in the biosynthesis of retinoic acid that is a modulator for gene expression and cell differentiation. Northern blot analysis showed that liver tissue, pancreas tissue, hepatoma cells, and genital skin fibroblast cells expressed high levels of ALDH1. Sequence analysis showed that the 5'-flanking region contains a number of putative regulatory elements, such as NF-IL6, HNF-5, GATA binding sites, and putative response elements for interleukin-6, phenobarbital and androgen, in addition to a noncanonical TATA box (ATAAA) and a CCAAT box. Functional characterization of the 5'-regulatory region of the human ALDH1 gene was carried out by a fusion to the chloramphenicol acetyltransferase gene. A construct containing 2.6 kilobase pairs of the 5'-flanking region was efficiently expressed in hepatoma Hep3B cells, but not in erythroleukemic K562 cells or in fibroblast LTK- cells, which do not express ALDH1. Within this region, we define a minimal promoter (-91 to +53) that contains positive regulatory elements. The study using site-directed mutagenesis demonstrated that the CCAAT box region is the major cis-acting element involved in basal ALDH1 promoter activity in Hep3B cells. Gel mobility shift assays showed that NF-Y and other octamer factors bound CCAAT box and an octamer motif sequence, but not GATA site existing in the minimal promoter region. Two additional DNA binding activities associated with the minimal promoter were found in the nuclear extract from Hep3B cells, but not from K562 cells. These results offer the possible molecular mechanism of the cell type-specific expression of ALDH1 gene.
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PMID:The transcriptional regulation of human aldehyde dehydrogenase I gene. The structural and functional analysis of the promoter. 761 57

Interleukin-6 (IL-6) is known to be a major mediator of the acute-phase response in liver. We show here that IL-6 triggers the rapid activation of a nuclear factor, termed acute-phase response factor (APRF), both in rat liver in vivo and in human hepatoma (HepG2) cells in vitro. APRF bound to IL-6 response elements in the 5'-flanking regions of various acute-phase protein genes (e.g., the alpha 2-macroglobulin, fibrinogen, and alpha 1-acid glycoprotein genes). These elements contain a characteristic hexanucleotide motif, CTGGGA, known to be required for the IL-6 responsiveness of these genes. Analysis of the binding specificity of APRF revealed that it is different from NF-IL6 and NF-kappa B, transcription factors known to be regulated by cytokines and involved in the transcriptional regulation of acute-phase protein genes. In HepG2 cells, activation of APRF was observed within minutes after stimulation with IL-6 or leukemia-inhibitory factor and did not require ongoing protein synthesis. Therefore, a preexisting inactive form of APRF is activated by a posttranslational mechanism. We present evidence that this activation occurs in the cytoplasm and that a phosphorylation is involved. These results lead to the conclusions that APRF is an immediate target of the IL-6 signalling cascade and is likely to play a central role in the transcriptional regulation of many IL-6-induced genes.
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PMID:Acute-phase response factor, a nuclear factor binding to acute-phase response elements, is rapidly activated by interleukin-6 at the posttranslational level. 767 52

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

Pancreatic secretory trypsin inhibitor (PSTI) has been suggested to be an acute-phase reactant in humans and to be induced by inflammatory cytokines such as the interleukins IL-1 and IL-6. We report that PSTI is synthesized in hepatoma cells and that the gene expression is augmented by IL-6. The start points (tsp) for basal and augmented transcription are exactly the same as the tsp in normal pancreas. Analysis of the PSTI gene revealed that a 40-bp DNA fragment located between kb -3.84 and -3.80 carries the element responsible for both transcriptional activity and IL-6-induced gene expression. This 40-bp fragment contains TTGNNGNAATG, the consensus sequence for the NF-IL6-binding site, which is also known as the IL-6-responsive element that is conserved among various acute-phase genes. The basal activity was augmented by another sequence that lies between kb -4.0 and -3.9.
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PMID:Identification of the IL-6-responsive element in an acute-phase-responsive human pancreatic secretory trypsin inhibitor-encoding gene. 769 87

Mouse serum amyloid A proteins (SAA) are encoded by multiple genes and the expression of these SAA genes is highly induced during inflammation. We demonstrate that the expression of one of SAA genes (SAA3) is induced by interleukin-1 (IL-1), and that other inflammatory cytokines such as IL-6 and leukemia inhibitory factor, while they themselves are without any effects, enhanced IL-1 induced SAA3 gene expression. The results of mutational analysis on the SAA3 promoter indicate that both the NF-kappa B and C/EBP transcription factor-binding motifs are essential for cytokine-induced SAA3 gene expression in Hep3B cells. To study further roles of NF-kappa B and C/EBP transcription factor family members in SAA3 gene activation, expression vectors for NF-kappa B subunits (p50 and p65) and C/EBP family members (C/EBP-alpha and NFIL-6, also called C/EBP-beta) were co-transfected into Hep3B hepatoma and F9 embryonic carcinoma cells. The results show that, while the expression of p65 alone strongly transactivated a SAA3 gene, p50 did not induce a significant transactivation, and NFIL-6 and C/EBP-alpha induced only a marginal transactivation when expressed alone. However, the co-expression of p50 or p65 with C/EBP family members did result in the efficient induction of SAA3 gene expression, indicating that the synergy between NF-kappa B and C/EBP transcription factor families is essential for SAA3 gene expression during inflammation.
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PMID:NF-kappa B and C/EBP transcription factor families synergistically function in mouse serum amyloid A gene expression induced by inflammatory cytokines. 795 7

To understand the mechanisms by which large increases in serum amyloid A (SAA) occur during the acute phase response, human hepatoma cells were transfected with SAA2 gene reporter plasmids and stimulated with combinations of cytokines. Although interleukin-1 (IL-1) and interleukin-6 (IL-6) stimulated transcription from this promoter individually, addition of both mediators produced a response between two and nine times greater than the expected additive response. This synergistic activation was dependent on the integrity of at least two cis-acting sequences in the SAA2 enhancer. The SAA2 NF-kappa B site was required functionally for the response to both IL-1 and IL-6 alone as well as for synergistic activation; however, IL-6 did not directly induce binding of nuclear proteins to the NF-kappa B sequence. A NF-IL6 site was required for full induction by IL-1 and IL-6, and also mediated strong transactivation by recombinant NF-IL6. Furthermore, transfected NF-IL6 synergized strongly with co-transfected NF-kappa B, particularly with RelA (p65). However synergy between IL-1 and IL-6 was only partly reduced by mutation of the NF-IL6 site, indicating further levels of interaction in addition to the NF-kappa B/NF-IL6 cooperativity.
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PMID:The role of NF-kappa B and NF-IL6 transactivating factors in the synergistic activation of human serum amyloid A gene expression by interleukin-1 and interleukin-6. 824 97

GADD153, a ubiquitously expressed member of the CCAAT/enhancer-binding protein (C/EBP) family is induced by a wide variety of growth-arresting and DNA-damaging agents. Functionally, GADD153 has been postulated to act as a dominant-negative regulator of C/EBPs. Therefore we sought to gain evidence for interactions between GADD153 and other C/EBPs during cellular responses to stress. In this report we have demonstrated that treatment of rat pheochromocytoma PC12 cells with sodium arsenite leads to enhanced expression of C/EBP-beta and GADD153 (growth arrest and DNA damage inducible gene 153) but not other C/EBPs. Coimmunoprecipitation experiments provided evidence for the formation of endogenous GADD153-C/EBP-beta complexes in arsenite-treated cells. Additional experiments were performed to determine the role of such complexes in regulating GADD153 expression. Previous studies in our laboratory demonstrated that the GADD153 promoter contains a C/EBP binding site through which other C/EBPs interact to transactivate GADD153 expression in liver hepatoma cells. Here, we demonstrate that extracts prepared from arsenite-treated PC12 cells likewise show increased amounts of factors capable of binding to the GADD153-C/EBP site and that these complexes are comprised at least in part of C/EBP-beta. Forced expression of C/EBP-beta was found to be capable of transactivating the GADD153 promoter in PC12 cells cotransfected with plasmids expressing a GADD153 reporter gene and C/EBP-beta protein. However, overexpression of GADD153 inhibited the transactivation of the GADD153 promoter by C/EBP-beta. These findings provide evidence for an autoregulatory loop in which stress-induced GADD153 feeds back to attenuate GADD153 expression during the cellular response to stress.
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PMID:Physical and functional association between GADD153 and CCAAT/enhancer-binding protein beta during cellular stress. 866 54

Expression of the albumin gene in the liver is controlled by several liver-enriched transcription factors. However, the mechanisms which contribute to its regulation during pathophysiological states, such as liver regeneration, are still little understood. In the present study we found that during liver regeneration down-regulation of albumin mRNA expression is transcriptionally controlled through a minimal element (nucleotide -170 to +22) of the albumin promoter and is observed mainly during the G1 phase of the cell cycle, while high levels of albumin expression are preserved at later time points. Decreased albumin mRNA levels correlate with a dramatic increase in nuclear expression of C/EBP-beta/LAP, a protein known to bind to the D site of the albumin promoter and also to be involved in cell cycle control. In contrast, nuclear expression of other factors such as HNF-1 or C/EBP-alpha, which also have been shown to transcriptionally control albumin expression, is either unchanged or slightly decreased. We show that pre- and post-translational mechanisms are involved in the higher nuclear expression of C/EBP-beta/LAP as early as 1 h after hepatectomy, which also leads to its increased binding toward the D site of the albumin promoter. Finally, in vitro transcription assays with liver nuclear extracts and recombinant C/EBP-beta/LAP demonstrate that C/EBP-beta/LAP can directly down-regulate transcription mediated by the minimal element of the albumin promoter. Additionally the inhibitory role of C/EBP-beta/LAP on the albumin minimal promoter could be confirmed by transfection experiments in hepatoma cells. These results indicate that C/EBP-beta/LAP, while enhancing transcription of cell cycle-related genes and controlling G1/S phase checkpoint, down-regulates a major liver function, i.e. albumin synthesis, to prepare the hepatocyte for entry into the cell cycle.
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PMID:C/EBP-beta/LAP controls down-regulation of albumin gene transcription during liver regeneration. 870 43


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