UMLS:C0019204 - FACTA Search

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

The high mobility group (HMG) I proteins are small, non-histone chromosomal proteins that promote gene activation during development and within rapidly dividing cells. They do so by facilitating enhanceosome formation on inducible genes, via both protein/DNA and protein/protein interactions. The HMG I-C gene is tightly regulated, normally being expressed exclusively during embryonic development. However, HMG I-C expression is also observed frequently in a number of tumor types, and this expression has been shown to contribute to the malignant transformation process. With the aim of dissecting pathways that lead to aberrant expression of HMG I-C in tumor cells, we have analyzed HMG I-C gene regulation in the human hepatoma cell line PLC/PRF/5. One of the two HMG I-C transcripts detected in this cell line originates from a novel downstream initiation site at nucleotide -161 relative to the first methionine. Transcription from the downstream initiation site is mediated by a PRE located between nt -222 and -217. We show here that the Sp1 and Sp3 transcription factors interact with the PRE and transactivate the HMG I-C promoter in a cooperative fashion. This study provides the first characterization of this downstream HMG I-C promoter.
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PMID:A novel downstream positive regulatory element mediating transcription of the human high mobility group (HMG) I-C gene. 1047 23

The mouse cytosolic aldehyde dehydrogenase ALDH3A1 (encoded by the Aldh3a1 gene) has previously been shown in cell culture to be markedly inducible by 2,3,7,8,-tetrachlorodibenzo-p-dioxin (TCDD; dioxin), downregulated by the metabolism of functional CYP1A1/1A2 enzymes, and upregulated by a gene on Chr 7 that leads to endogenous oxidative stress. In order to study the regulation of Aldh3a1 gene expression, we isolated two overlapping genomic sequences from a B6/CBA mouse genomic library that included the entire Aldh3a1 gene, along with considerable 5' and 3' flanking sequences. The Aldh3a1 gene was shown to span approximately 10 kb and comprise 11 exons including a noncoding first exon. The sequence of 3.18 kb upstream of exon 1 reveals numerous consensus transcription factor-binding sites, some of which were shown to be important in the positive and negative control of Aldh3a1 gene expression; these include seven aromatic hydrocarbon response elements (AHREs), an electrophile response element (EPRE), and AP-1, C/EBP beta, c/EBP alpha, NF-kappaB, Sp1, and NF-1 putative binding sites. Deletion fusion constructs containing regions of the Aldh3a1 gene 5' flanking sequence, ligated to chloramphenicol experiments suggested that the 5' flanking region of the gene contains a strong promoter, at least four functional AHREs appear to act cooperatively in causing dioxin-mediated upregulation, and a putative negative regulatory element (NRE) controls basal gene expression independent of dioxin inducibility. The dioxin-mediated upregulation of Aldh3a1 expression in mouse hepatoma Hepa-1c1c7 cell cultures was shown to depend exclusively on the aromatic hydrocarbon receptor. acetyltransferase (CAT) or luciferase (LUC) reporter genes, were studied. Transient transfection experiments suggested that the 5' flanking region of the gene contains a strong promoter, at least four functional AHREs appear to act cooperatively in causing dioxin-mediated upregulation, and a putative negative regulatory element (NRE) controls basal gene expression independent of dioxin inducibility. The dioxin-mediated upregulation of Aldh3a1 expression in mouse hepatoma Hepa-1c1c7 cell cultures was shown to depend exclusively on the aromatic hydrocarbon receptor.
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PMID:Mouse cytosolic class 3 aldehyde dehydrogenase (Aldh3a1): gene structure and regulation of constitutive and dioxin-inducible expression. 1059 37

Gap junctional intercellular communication facilitates liver homeostasis and growth control in the liver. The major gap junction protein expressed by hepatocytes is connexin32 (Cx32) and non-parenchymal hepatic cells do not express this gene. We investigated the regulation of Cx32 transcription by trans-activating factors in liver cells. Transient transfection assays using deletions of the rat Cx32 promoter (nt -753 to -33) linked to the luciferase gene were performed in MH1C1 rat hepatoma cells that express endogenous Cx32 compared with WB-F344 rat liver epithelial cells that do not. The basal promoter element was located within nt -134 to -33 and was 1.4-fold more active in MH1C1 cells than WB-F344 cells whereas the entire promoter fragment (nt -754 to -33) was four-fold more active in MH1C1 cells. Specific nuclear protein-DNA complexes that bound to Sp1 consensus sites within the basal promoter were formed using nuclear extracts from both types of cells. Additional promoter sequences increased promoter activity more strongly in MH1C1 cells than WB-F344 cells and this was correlated with the binding of hepatocyte nuclear factor-1 (HNF-1) to two HNF-1 consensus sites centered at -187 and -736. Expression of HNF-1 and binding to these elements was only observed with MH1C1 cells. Other specific protein-DNA complexes were formed, however, that included YY-1- and NF-1-containing complexes, but these were not related to promoter activity. Dexamethasone increased Cx32 promoter activity and expression in MH1C1 cells, but had little effect in WB-F344 cells and did not alter protein-DNA complex formation. These data suggest that Sp1 is responsible for Cx32 promoter basal activity, that HNF-1 determines the cell-specific expression of Cx32, and that dexamethasone increases Cx32 expression through other mechanisms.
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PMID:Liver cell-specific transcriptional regulation of connexin32. 1076 May 74

ATP citrate-lyase (ACL) is a key enzyme supplying acetyl-CoA for fatty acid and cholesterol synthesis. Its expression is drastically up-regulated when an animal is fed a low fat, high carbohydrate diet after prolonged fasting. In this report, we describe the role of sterol regulatory element-binding proteins (SREBPs) in the transactivation of the rat ACL promoter. ACL promoter activity was markedly stimulated by the overexpression of SREBP-1a and, to a lesser extent, by SREBP-2 in Alexander human hepatoma cells. The promoter elements responsive to SREBPs were located within the 55-base pair sequences from -114 to -60. The gel mobility shift assay revealed four SREBP-1a binding sites in this region. Of these four elements, the -102/-94 region, immediately upstream of the inverted Y-box, and the -70/-61 region, just adjacent to Sp1 binding site, played critical roles in SREBPs-mediated stimulation. The mutation in the inverted Y-box and the coexpression of dominant negative nuclear factor-Y (NF-Y) significantly attenuated the transactivation by SREBP-1a, suggesting that NF-Y binding is a prerequisite for SREBPs to activate the ACL promoter. However, the multiple Sp1 binding sites did not affect the transactivation of the ACL promoter by SREBPs. The binding affinity of SREBP-1a to SREs of the ACL promoter also was much higher than that of SREBP-2. The transactivation potencies of the chimeric SREBPs, of which the activation domains (70 amino acids of the amino terminus) were derived from the different species of their carboxyl-terminal region, were similar to those of SREBPs corresponding to their carboxyl termini. Therefore, it is suggested that the carboxyl-terminal portions of SREBPs containing DNA binding domains are important in determining their transactivation potencies to a certain promoter.
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PMID:The roles of sterol regulatory element-binding proteins in the transactivation of the rat ATP citrate-lyase promoter. 1080

Our previous finding that insulin induces apolipoprotein AI (apoAI) transcription points to the participation of intracellular signaling. This finding prompted us to ask whether two classical G-protein-coupled signaling pathways requiring activated protein kinase A (PKA) or kinase C (PKC) may also regulate apoAI. Therefore, human hepatoma, Hep G2 cells stably transfected with pAI.474-CAT, a reporter construct spanning -474 to -7 of apoAI DNA fused to chloramphenicol acetyltransferase (CAT) were treated with 10 microm forskolin (FSK) or 50 nm phorbol dibutyrate (PDBu) to activate PKA and PKC, respectively. Results showed that the apoAI promoter activity increased 4-5-fold following 24 h of treatment with either FSK or PDBu. Induction by either agent was blocked with actinomycin D but not the protein synthesis inhibitor, cycloheximide. The PKA inhibitor, PKI 14-22 amide, abrogated induction by FSK, 100 microm 8-bromo-cAMP, or 100 ng/ml cholera toxin, but it had no effect on activation via PKC. Similarly, PDBu induction was attenuated by 2 microm of the PKC inhibitor, GF109203X, but it did not affect FSK activity. Next we used deletional constructs to show that the actions of FSK and PDBu required the insulin-responsive core element (IRCE). This motif matched the consensus binding site for the transcription factor, Sp1. The binding of Sp1 to the IRCE was confirmed by gel-retardation and supershift analysis. Site-directed mutagenesis of the IRCE eliminated Sp1 action and induction by FSK or PDBu. Whereas overexpression of Sp1 enhanced basal and FSK or PDBu induced promoter activity, transfection of an antisense oligomer against Sp1 mRNA attenuated both parameters. In summary, activation of PKA or PKC increases apoAI promoter activity. The activity of both signaling pathways is mediated by the IRCE, a motif that binds the transcription factor, Sp1.
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PMID:Activation of apolipoprotein AI gene expression by protein kinase A and kinase C through transcription factor, Sp1. 1082 13

Transforming growth factor-beta (TGF-beta) inhibits cell cycle progression, in part through up-regulation of gene expression of the p21(WAF1/Cip1) (p21) cell cycle inhibitor. Previously we have reported that the intracellular effectors of TGF-beta, Smad3 and Smad4, functionally cooperate with Sp1 to activate the human p21 promoter in hepatoma HepG2 cells. In this study we show that Smad3 and Smad4 when overexpressed in HaCaT keratinocytes lead to activation of the p21 promoter. Activation requires the binding sites for the ubiquitous transcription factor Sp1 on the proximal promoter. Induction of the endogenous HaCaT p21 gene by TGF-beta1 is further enhanced after overexpression of Smad3 and Smad4, whereas dominant negative mutants of Smad3 and Smad4 and the inhibitory Smad7 all inhibit p21 induction by TGF-beta1 in a dose-dependent manner. We show that Sp1 expressed in the Sp1-deficient Drosophila SL-2 cells binds to the proximal p21 promoter sequences, whereas Smad proteins do not. In support of this finding, we show that DNA-binding domain mutants of Smad3 and Smad4 are capable of transactivating the p21 promoter as efficiently as wild type Smads. Co-expression of Smad3 with Smad4 and Sp1 in SL-2 cells or co-incubation of phosphorylated Smad3, Smad4, and Sp1 in vitro results in enhanced binding of Sp1 to the p21 proximal promoter sequences. We demonstrate that Sp1 physically and directly interacts with Smad2, Smad3, and weakly with Smad4 via their amino-terminal (Mad-Homology 1) domain. Finally, by using GAL4 fusion proteins we show that the glutamine-rich sequences in the transactivation domain of Sp1 contribute to the cooperativity with Smad proteins. In conclusion, Smad proteins play important roles in regulation of the p21 gene by TGF-beta, and the functional cooperation of Smad proteins with Sp1 involves the physical interaction of these two types of transcription factors.
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PMID:Role of Smad proteins and transcription factor Sp1 in p21(Waf1/Cip1) regulation by transforming growth factor-beta. 1087 24

Persistent infection by hepatitis B virus (HBV) and exposure to chemical carcinogens correlates with the prevalence of hepatocellular carcinoma in endemic areas. The precise nature of the interaction between these factors is not known. Glutathione S-transferases (GST) are responsible for the cellular metabolism and detoxification of a variety of cytotoxic and carcinogenic compounds by catalysis of their conjugation with glutathione. Diminished GST activity could enhance cellular sensitivity to chemical carcinogens. We have investigated GST isozyme expression in hepatocellular HepG2 cells and in an HBV-transfected subline. Total GST activity and selenium-independent glutathione peroxidase activity are significantly decreased in HBV transfected cells. On immunoblotting, HBV transfected cells demonstrate a significant decrease in the level of GST Alpha class. Cytotoxicity assays reveal that the HBV transfected cells are more sensitive to a wide range of compounds known to be detoxified by GST Alpha conjugation. Although no significant difference in protein half-life between the two cell lines was found, semi-quantitative reverse transcription-polymerase chain reaction shows a reduced amount of GST Alpha mRNA in the transfected cells. Because the HBV x protein (HBx) seems to play a role in HBV transfection, we also demonstrated that expression of the HBx gene into HepG2 cells decreased the amount of GST Alpha protein. Transient transfection experiments using both rat and human GST Alpha (rGSTA5 and hGSTA1) promoters in HepG2 cells show a decreased CAT activity upon HBx expression, supporting a transcriptional regulation of both genes by HBx. This effect is independent of HBx interaction with Sp1. Treatment with oltipraz, an inducer of GST Alpha, partially overcomes the effect of HBx on both promoters. Promoter deletion studies indicate that oltipraz works through responsive elements distinct from AP1 or NF-kappaB transcription factors. Thus, HBV infection alters phase II metabolizing enzymes via different mechanisms than those modulated by treatment with oltipraz.
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PMID:Modulation of glutathione S-transferase alpha by hepatitis B virus and the chemopreventive drug oltipraz. 1093 96

Aflatoxin B1 (AFB1) induced mutation of the p53 gene at codon 249 (p53mt249) is critical during the formation of hepatocellular carcinoma (HCC) following hepatitis B virus (HBV) infection. p53mt249 markedly increases insulin-like growth factor II (IGF-II) transcription largely from promoter 4, accumulating the fetal form of IGF-II. Modulation of the transcription factor binding to IGF-II P4 by wild-type p53 and p53mt249 was identified. Wild-type p53 inhibited binding of transcription factors Sp1 and TBP on the P4 promoter, while p53mt249 enhanced the formation of transcriptional complexes through enhanced DNA-protein (Sp1 or TBP) and protein-protein (Sp1 and TBP) interactions. p53mt249 stimulates transcription factor Sp1 phosphorylation which might be a cause of increased transcription factor binding on the P4 promoter while wild-type p53 does not. Transfection of hepatocytes with p53mt249 impaired induction of apoptosis by the HBV-X protein and TNF-alpha. Therefore, the blocking of apoptosis through enhanced production of IGF-II should provide a favorable opportunity for the selection of transformed hepatocytes. These results explain the molecular basis for the genesis of HCC by p53mt249 which was found to be induced by a potent mutagen, AFB1.
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PMID:Activation of the insulin-like growth factor II transcription by aflatoxin B1 induced p53 mutant 249 is caused by activation of transcription complexes; implications for a gain-of-function during the formation of hepatocellular carcinoma. 1094 25

Fructose-1,6-bisphosphatase (FBPase; EC 3.1.3.11), an important gluconeogenic enzyme, catalyses the hydrolysis of fructose 1, 6-bisphosphate to fructose 6-phosphate and P(i). Enzyme activity is mainly regulated by the allosteric inhibitors fructose 2, 6-bisphosphate and AMP. Although some observations about hormonal regulation of the enzyme have been published, the FBPase promoter has not been studied in detail. Here we report an in vitro characterization of the FBPase promoter with respect to the elements that are required for basal promoter activity. Transient transfection of H4IIE rat hepatoma cells, combined with site-directed mutagenesis, demonstrated that an enhancer box, three GC-boxes and a nuclear factor kappaB (NF-kappaB)-binding element are important for hepatic FBPase promoter activity. These elements are found in the region located between -405 to +25 bp relative to the transcription start site. Electrophoretic-mobility-shift assays and supershift analysis confirmed that upstream stimulatory factor 1 (USF1)/USF2, specificity protein 1 (Sp1)/Sp3 and NF-kappaB respectively bind to these sites. The present study provides the basis for a more comprehensive screening for mutations in FBPase-deficient patients and for further studies of the transcriptional regulation of this gene.
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PMID:Characterization of the human liver fructose-1,6-bisphosphatase gene promoter. 1102 24

The ATP-binding cassette transporter G1 (ABCG1) was recently identified as a regulator of macrophage cholesterol and phospholipid transport. This transporter together with ABCA1 belongs to a group of sterol-sensitive ABC proteins which are induced by lipid loading or specific oxysterols. We report here the genomic structure of ABCG1 along with the 5' flanking sequence using library screening and BLAST search analysis. The ABCG1 gene spans more than 70 kb and contains 15 exons. The exon size is between 30 and 1081 bp and the introns range in size from 137 bp to more than 45 kb. All exon-intron boundaries display the canonical GT/AG sequences. Using promoter-luciferase reporter assays in the myeloid cell lines THP-1 and RAW246.7 and the hepatoma cell line HepG2 we could demonstrate the functionality of the ABCG1 promoter and the minimal sequence requirements for gene expression. The TATA-less proximal promoter contains multiple Sp1 binding sites and a consensus sequence for sterol regulatory element binding protein.
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PMID:Genomic organization and characterization of the promoter of the human ATP-binding cassette transporter-G1 (ABCG1) gene. 1107 82

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