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)

Transferrin (Tf), the iron-transport protein, plays an essential role in the central nervous system development, plasticity, and aging. As a first step toward elucidating the role of each transcription factor involved in the regulation of Tf gene expression, we have recently shown that similar promoter elements direct cell-type specific transcription in oligodendrocytes, epithelial choroid plexus cells, and in the neuronal cell line B103. Here we have analyzed the regulatory elements that control the level of expression of the Tf gene in neuronal cells. Transient expression experiments in B103 cells revealed that the -164/+1 promoter region is stimulated by a position-dependent -1140/-1000 upstream region. DNase I footprinting, gel retardation assays, and antibody reactivity data allowed us to characterize the nuclear factors interacting with this region. The upstream region I-binding protein (URI-BP) belongs to the steroid/retinoid receptor family, while URII-BP is a member of the nuclear factor I (NF-I) family. Interestingly, no enhancer nor silencer activity is detected in B103 cells. This contrasts with our findings in hepatoma cells, where the activity of the -125/+1 promoter can be repressed by a -1000/-819 upstream negative-acting region and stimulated by the -3600/-3300 enhancer. We demonstrate that the negative-acting region presents the characteristics of a silencer that interacts with a nuclear protein present in liver and absent in B103 cells. Similarly, B103 cells lack a nuclear protein able to bind to an essential site of the enhancer. This shows that in B103 cells, the inactivity of the silencer and the enhancer regions results from the absence of at least one essential nuclear protein.
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PMID:Distinct positive and negative regulatory elements control neuronal and hepatic transcription of the human transferrin gene. 871 15

A polyclonal antibody was raised against a recombinant ligand binding domain construct of the human retinoid X receptor (RXR) alpha. This antibody reacted with an endogenous 54 kDa nuclear protein from human hepatoma-derived HuH7 cells in immunoblot analyses. Immunoblotting of nuclear proteins from human hepatocellular carcinomas (HCCs) and their surrounding tissues revealed the presence of a 44 kDa RXR distinct from the 54 kDa RXR and a dramatic decrease in the relative amounts of 44 kDa RXR to 54 kDa RXR in all HCCs compared with normal tissue. In vitro shift and intracellular conversion from 54 kDa RXR to 44 kDa species were observed with the nuclear extracts of HuH7 cells. Furthermore, transfection of hRXR alpha cDNA into HuH7 cells resulted in the increase of 54 kDa RXR, whereas transfected mouse hepatocytes accumulated 44 kDa RXR. These results strongly indicated that 44 kDa RXR was a physiological proteolytic fragment of 54 kDa RXR and that post-translational metabolism of RXR was impaired in HCC and the HuH7 hepatoma-derived cell line.
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PMID:Aberrant metabolism of retinoid X receptor proteins in human hepatocellular carcinoma. 889 19

Previously we described (Dong et al., 1990) a nuclear protein (mol. wt. 112 kD) which is expressed abundantly in hepatoma cells and also in hepatocyte cells committed to carcinogenesis. In this report, we further characterize its chemical properties and cellular localization in normal and hepatoma cells. 112 kD hepatoma-associate nonhistone protein is not a cytokeratin-related protein as described by Fukuda et al. (1991). Protein purification experiments revealed that 112 kD protein is a dimer of 56 kD polypeptide present in normal rat liver nuclei. Intranuclear distribution pattern indicated that 112 kD nonhistone protein localizes exclusively in hepatoma nuclear matrix. The data from this study suggest that dimerization of 56 kD nonhistone protein is involved in nuclear matrix reorganization during neoplastic transformation.
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PMID:Nonhistone protein reorganization in normal and hepatoma cells. 893 42

Factor B (Bf) is a constituent of the alternative pathway of complement activation encoded within the major histocompatibility complex. Transcription of the murine gene from two initiation sites generates two Bf mRNA species differing in size and tissue distribution. Striking genetic, tissue-specific differences in Bf mRNA levels at extrahepatic sites (kidney and intestine) among mouse strains correlate with a DNA sequence polymorphism in the 5'-flanking region of the gene and differential nuclear protein binding at the Bf upstream transcriptional initiation site (UIS). To ascertain the functional consequences of this polymorphism in the Bf promoter, we analyzed the effects of strain-specific sequences in the Bf 5' region on the expression of a chloramphenicol acetyltransferase (CAT) reporter gene transfected in human and mouse hepatoma cells. The CAT activity and mRNA level produced when transcription was driven by the sequence of strains with high extrahepatic expression were reduced to background levels when the sequence specific to the low expressor strains was used. Eighty percent of this difference was accounted for by a point substitution that affects DNA-protein interaction at the UIS, the sequence of higher affinity conferring higher expression. Hepatocyte nuclear factor 4 (HNF-4), derived from HepG2, mouse liver and kidney or cell-free translation of HNF-4 RNA, is the nuclear protein that preferentially binds to the high expressor UIS. Bf-CAT is not expressed in cells that lack HNF-4 (CV-1). However, co-transfection of HNF-4 into CV-1 cells drives Bf-CAT expression and reproduces the differences derived from the substitution that affect HNF-4 binding in vitro. These data show that interaction of HNF-4 with polymorphic variants of the upstream Bf promoter is the major determinant of strain-specific extrahepatic factor B expression.
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PMID:Constitutive expression of murine complement factor B gene is regulated by the interaction of its upstream promoter with hepatocyte nuclear factor 4. 893 72

After insulin receptor activation, many cytoplasmic enzymes, including mitogen-activated protein (MAP) kinase, MAP kinase kinase (MEK) and casein kinase II (CKII) are activated, but exactly how insulin signalling progresses to the nucleus remains poorly understood. In Chinese hamster ovary cells overexpressing human insulin receptors [CHO(Hirc)], MEK, CKII and the MAP kinases ERK I and ERK II can be detected by immunoblotting in the nucleus, as well as in the cytoplasm, in the unstimulated state. Nuclear localization of MAP kinase is also observed in 3T3-F442A adipocytes, NIH-3T3 cells and Fao hepatoma cells, whereas MEK is found in the nucleus only in Fao and CHO cells. Insulin treatment for 5-30 min induces a translocation of MEK from the cytoplasm to the nucleus, whereas the MAP kinases and CKII are not translocated into the nucleus in response to insulin during this period. However, nuclear MAP kinase and CKII activities increase by 2-3-fold within 1-10 min after stimulation with insulin. By using gel-shift assays, it has been shown that insulin also stimulates nuclear protein binding to an AP-1 site with kinetics similar to MEK translocation and MAP kinase and CKII activation. Treatment of the extracts in vitro with protein phosphatase 2A or treatment of the intact cells with 5, 6-dichloro-1-beta-d-ribofuranosylbenzimidazole, a cell-permeable inhibitor of CKII, almost completely blocks the insulin-induced DNA-binding activity, whereas incubation of cells with a MEK inhibitor produces only a slight decrease. These results suggest that insulin signalling results in the activation of serine kinases in the nucleus via two pathways: (1) insulin stimulates the nuclear translocation of some kinases, such as MEK, which might directly phosphorylate nuclear protein substrates or activate other nuclear kinases, and (2) insulin activates nuclear kinases without translocation. The latter is true of CKII, which seems to regulate the binding of nuclear proteins to the AP-1 site, possibly by phosphorylation of AP-1 transcription factors.
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PMID:Insulin regulation of mitogen-activated protein kinase kinase (MEK), mitogen-activated protein kinase and casein kinase in the cell nucleus: a possible role in the regulation of gene expression. 916 93

The retinoblastoma (RB) tumor suppressor is a nuclear phosphoprotein important for cell growth control and able to bind specifically to viral oncoproteins such as the SV40 large tumor antigen (T-ag). Human RB possesses a bipartite nuclear localization sequence (NLS) consisting of two clusters of basic amino acids within amino acids 860-877, also present in mouse and Xenopus homologs, which resembles that of nucleoplasmin. The T-ag NLS represents a different type of NLS, consisting of only one stretch of basic amino acids. To compare the nuclear import kinetics conferred by the bipartite NLS of RB to those conferred by the T-ag NLS, we used beta-galactosidase fusion proteins containing the NLSs of either RB or T-ag. The RB NLS was able to target beta-galactosidase to the nucleus both in vivo (in microinjected cells of the HTC rat hepatoma line) and in vitro (in mechanically perforated HTC cells). Mutational substitution of the proximal basic residues of the NLS abolished nuclear targeting activity, confirming its bipartite character. Nuclear accumulation of the RB fusion protein was half-maximal within about 8 min in vivo, maximal levels being between 3-4-fold those in the cytoplasm, which was less than 50% of the maximal levels attained by the T-ag fusion protein, while the initial rate of nuclear import of the RB protein was also less than half that of T-ag. Nuclear import conferred by both NLSs in vitro was dependent on cytosol and ATP and inhibited by the nonhydrolyzable GTP analog GTPgammaS. Using an ELISA-based binding assay, we determined that the RB bipartite NLS had severely reduced affinity, compared with the T-ag NLS, for the high affinity heterodimeric NLS-binding protein complex importin 58/97, this difference presumably representing the basis of the reduced maximal nuclear accumulation and import rate in vivo. The results support the hypothesis that the affinity of NLS recognition by NLS-binding proteins is critical in determining the kinetics of nuclear protein import.
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PMID:Kinetic characterization of the human retinoblastoma protein bipartite nuclear localization sequence (NLS) in vivo and in vitro. A comparison with the SV40 large T-antigen NLS. 926 57

We have shown previously that insulin positively regulates transcription of the rat calmodulin (CaM) I gene. This activation occurs concomitantly with the activation of the low-Km adenosine 3':5'-cyclic phosphate phosphodiesterase (PDE), which appears to be coregulated with CaM. Rat hepatoma H-411E cells were transfected with plasmids containing various lengths of the putative CaM promoter coupled to a luciferease reporter and were challenged with insulin. We demonstrate that insulin-stimulated transcription of CaM I gene is mediated by a 392-bp 5'-flanking region of the CaM I gene, encompassing 185 bp downstream and 207 bp upstream of the start site of transcription. The CaM I promoter contains three potential Sp1 sites, located at -114 through -109 [(3), +], -77 through -72 [(2), -] and at +53 through +58 [(1), +]. The gel mobility shift assays demonstrated that nuclear protein(s) associate with all three sp1 sites. We present data demonstrating the relative importance of the three Sp1 sites for the insulin effect: prCaM I 1835, 3.8x, delta 1081; prCaM I 392, 5.3x, delta 1055; prCaM I 180, 3.7x, delta 462; prCaM I 237, 1.6x, delta 478; prCaM I 139, 2.6x, delta 182; prCaM I 130, 2.1x, delta 194; and prCaM I 1463, negligible activity. In summary, the maximal insulin stimulation of CaM gene expression is seen when the promoter region contains at least two Sp1 sites.
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PMID:Insulin stimulates rat calmodulin I gene transcription through activation of Sp1. 928 46

Chronic griseofulvin (GF) feeding induces preneoplastic foci followed by hepatocellular carcinoma in the mouse liver. Our previous study suggested that GF-induced hepatocellular proliferation had a different mechanism from that of peroxisome proliferator (PP)-induced direct hyperplasia. The GF-induced hepatocellular proliferation was mediated through activation of immediate early genes such as Fos, Jun, Myc, and NFKB. In contrast, PP-induced direct hyperplasia does not involve activation of any of these immediate early genes. It has been shown that nuclear hormone receptors including peroxisome proliferator activated receptors (PPARs) and retinoid x receptors (RXRs) play important roles in mediating the pleiotropic effects of PPs. To examine the possible roles of PPARs and RXRs during non-PP-induced hepatocellular proliferation and the interaction between PP and non-PP-induced proliferation, we have studied the expression of the PPAR and RXR genes in the GF model using northern blot hybridizations and gel retardation assays. The data showed that the expression of PPARalpha and RXRalpha genes was down-regulated in the livers containing preneoplastic nodules and in the liver tumors induced by GF. The mRNA down-regulation was accompanied by a decrease in the amount of nuclear protein-bound to peroxisome proliferator and retinoic acid responsive elements. Down-regulation was also associated with the suppressed expression of the PPARalpha/RXRalpha target genes (i.e., acyl-Co oxidase and cytochrome P450 4A1) and the catalase gene. The RXR-gamma gene was also down-regulated, but the RARalpha, beta, and gamma and PPARbeta and gamma genes were up-regulated. These results indicated that the hepatocarcinogenesis induced by GF is accompanied by suppression of the PPARalpha/RXRalpha-mediated direct hyperplasia pathway. The differential expression of these nuclear hormone receptors reveals a new aspect for understanding the individual roles and intercommunication of PPAR, RXR, and RAR isoforms in the liver.
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PMID:Inhibition of PPAR alpha/RXR alpha-mediated direct hyperplasia pathways during griseofulvin-induced hepatocarcinogenesis. 954 66

We have studied the DNA binding activities of transcription factors in the liver of Long-Evans Cinnamon (LEC) rats, an animal model of Wilson's disease. Owing to a genetic defect, this strain of rats accumulates excessive copper in the liver and develops severe hepatitis and hepatocellular carcinoma. We found that the DNA binding activity of the serum response factor (SRF) was higher in the liver of LEC rats (approximately 2-fold) than in that of Wistar rats. There was a close correlation between the intensity of the activity and the concentrations of copper in the nuclear protein. The DNA binding activity of Sp1, on the other hand, showed similar levels in both LEC and Wistar rats. SRF may play an important role in the development of hepatocellular carcinoma in LEC rats by mediating the proto-oncogene c-fos induction. We suggest that the copper in nuclear protein may be involved in the activation of SRF.
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PMID:Activation of serum response factor in the liver of Long-Evans Cinnamon (LEC) rat. 957 Mar 63

Protein C inhibitor (PCI) is the plasma inhibitor of activated protein C, which is the main protease of the anticoagulant protein C pathway. In this study the transcriptional regulation of human PCI gene in the human hepatoma cell line, HepG2, was characterized by evaluating the transient expression of a luciferase reporter gene. The 5' flanking region (residues -1587 to +2) of the PCI gene showed an adequate transcriptional activity, the maximum transcriptional activity being in a region between residues -452 and -94, which contains an Sp1-binding site, two AP2-binding sites and an inverted AP2-binding site. Transient expression assays with various deletion mutants and site-directed mutants showed that the Sp1-binding site (residues -302 to -294) has a potent promoter activity and that the upstream AP2-binding site (residues -350 to -343) has a potent enhancer activity; no activity was detected in the inverted (residues -413 to -404) and downstream (residues -136 to -127) AP2-binding sites. In addition, a region of the PCI gene (residues -452 to -414) containing the STATx-binding site, the A-activator (AA)-binding site, and the interferon alpha (IFN-alpha) response element, and another region of the PCI gene (residues -176 to -147) containing the GATA-1 and the IFN-gamma response element showed potent silencer activities. Gel mobility-shift assays with various DNA fragments indicated that the Sp1-binding site, the upstream AP2-binding site, the AA-binding site and the IFN-gamma response element interact with nuclear protein(s) of HepG2 cells. These findings suggest that the Sp1-binding site is the promoter, the AP2-binding site (residues -350 to -343) the enhancer, and both the AA-binding site and the IFN-gamma response element are the silencers of human PCI gene expression in HepG2 cells.
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PMID:Regulation of the human protein C inhibitor gene expression in HepG2 cells: role of Sp1 and AP2. 960 Oct 89

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