Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously shown that a membrane-associated P36 from rat liver was in vitro phosphorylated at His residue(s) with a phosphoric amide bond (FEBS Lett., 319:75-79, 1993), and the activity was solubilized and partially purified (J. Biol. Chem., 269:9030-9037, 1994). The present study demonstrates that the P36 histidyl phosphorylation occurs in rat hepatoma cells under normal conditions. Phosphorylation and dephosphorylation of histidine as well as those of serine, threonine and tyrosine residues may also play an important role in animal cells.
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PMID:Histidyl phosphorylation of P36 in rat hepatoma Fao cells in vitro and in vivo. 799 29

Mutations in the p53 gene are frequent genetic alterations in human hepatocellular carcinoma. We have examined 38 hepatocellular carcinoma cases from Taiwan for the presence of p53 alterations in exons 5-8 of the gene using the single-stranded conformational polymorphism method and direct sequencing of polymerase chain reaction products. Using the single-stranded conformational polymorphism method, we found mutations in 16 (42.1%) cases. Twelve mutations were found in exon 5, three in exon 7, and one in exon 8. No mutations were found in exon 6. Sequencing of polymerase chain reaction products showed that all mutations in exon 5 were clustered at codon 166 and were T/A transversions resulting in an amino acid change from serine to threonine, identifying a new hot-spot for point mutations in the p53 gene. The mutations in exon 7 were all at codon 249, and were G/T transversions leading to an amino acid change of arginine to serine. Finally, the mutation at exon 8 was a G-to-T transversion at codon 286 leading to a stop codon. These data indicate that mutations of the p53 gene may be important in the development of human hepatocellular carcinoma and that, in contrast to other tumors, the mutations of the p53 gene in hepatocellular carcinomas can be clustered in a specific codon of the gene.
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PMID:A new mutational hot-spot in the p53 gene in human hepatocellular carcinoma. 805 96

The glycoprotein tissue-type plasminogen activator (t-PA) is subject to hepatic clearance in humans. Here, the interaction of t-PA with a well-differentiated hepatoma cell line (HepG2) was examined. Suspended HepG2 cells bound 125I-t-PA in a specific, saturable, and reversible fashion through a Ca(2+)-dependent, active site-independent mechanism. Binding isotherms indicated a high affinity system with a single class of saturable binding sites (Kd 39 nM; maximum binding capacity 493,000 sites per cell). Bound t-PA was rapidly degraded at 37 degrees C in a manner inhibited by lysosomotropic agents or metabolic inhibitors. Pretreatment of t-PA with monoclonal antibodies against the EGF/fibronectin finger domain, but not kringle 2 or kringle 1, reduced total binding by 86%. Binding of 125I-t-PA to HepG2 cells was inhibited by monosaccharides fucose and galactose and by the neoglycoprotein fucosyl-albumin. Enzymatic removal of alpha-fucose residues, but not alpha-galactose, high mannose, or complex oligosaccharide from 125I-t-PA, reduced specific binding by 60 +/- 5%. Binding was also inhibited by high, but not low, molecular weight urokinase, which contains an EGF-based threonine-linked alpha-fucose homologous to that of t-PA. These data suggest that EGF-associated O-linked alpha-fucose may mediate t-PA binding and degradation by HepG2 cells. This mechanism may be relevant to other proteins with analogous structures.
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PMID:alpha-Fucose-mediated binding and degradation of tissue-type plasminogen activator by HepG2 cells. 811 82

The transcription factor LFB1 (HNF1) involved in the expression of liver-specific genes is characterized by a serine/threonine-rich activation domain whose transactivation potential differs between mammals and Xenopus. Exchanging the activation domain between the Xenopus and rat LFB1, we produced chimeric transactivators whose activities are primarily determined by the origin of the activation domain. By replacing the serine/threonine-rich activation domain of LFB1 with the acidic activation domain of VP16, we generated transcription factors that act as dominant positive interfering mutants on endogenous LFB1 in differentiated hepatoma cells. As these LFB1/VP16 chimeras show no self-squelching as observed with wild-type LFB1 and increase the activity of saturating LFB1, we postulate that acidic and serine/threonine-rich activation domains use different targets of the basal transcription machinery. Stable transfection of various LFB1 derivatives, including those containing the VP16 transactivation domain, into the dedifferentiated C2 hepatoma cell resulted in cell clones stably expressing LFB1 function. However, as in none of these clones the chromosomal albumin genes are activated, we conclude that the presence of functional LFB1 may not be sufficient to reactivate liver-specific functions lost in dedifferentiated hepatoma cells.
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PMID:Chimeric liver transcription factors LFB1 (HNF1) containing the acidic activation domain of VP16 act as positive dominant interfering mutants. 839 59

We have cloned a cDNA for a novel GC box-binding protein designated BTEB2 from a human placenta cDNA library using rat BTEB cDNA (Imataka et al. (1992). EMBO J. 11,3663-3671. as a hybridization probe. BTEB2 consists of 219 amino acids and contains three contiguous zinc finger motifs at its C-terminus. The zinc finger domains showed 59% and 64% sequence similarity to those of Sp1 and BTEB, respectively. Adjacent to the N-terminal of the zinc finger motifs, a short sequence rich in basic amino acids is conserved between BTEB2 and Sp1. Furthermore, This basic sequence concurs with the N-terminal half of the consensus sequence for basic domains of the proteins containing both helix-loop-helix and leucine zipper motifs. The other region of BTEB2 is notably rich in proline, serine, threonine, and alanine residues. BTEB2 expressed in Escherichia coli showed DNA-binding activity whose specificity was closely similar to that of Sp1. Cotransfection experiments using Hepa-1 cells (a mouse hepatoma cell line) with a BTEB2 expression plasmid and GC box-containing reporter plasmids revealed that BTEB2 apparently activated the expression of the CAT activity. Moreover, when BTEB2 was fused to GAL4 DNA-binding domain, the chimeric protein could enhance the transcription through promoters containing GAL4-binding sites. Analysis of the BTEB2 mRNA by RNA blot analysis demonstrated that the mRNA was expressed specifically in testis and placenta with different sizes, 20S and 28S, respectively, among various organs examined.
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PMID:cDNA cloning and transcriptional properties of a novel GC box-binding protein, BTEB2. 847 2

The effect has been studied of various media, hormones and of amino acids on the membrane potential of rat hepatoma cells in culture measured by microelectrode impalement. Cells in Eagle's minimal essential medium plus 5% serum had a value which varied daily from about 5-8 mV, inside negative. The membrane potential of rat hepatocytes was measured to be 8.7 +/- 0.2 mV, inside negative. The membrane potential of the hepatoma cells was decreased by insulin and increased by glucagon. Membrane potential was unaffected by change of medium to Hanks' or Earle's balanced salt solutions or deprivation of serum. It was, however, reduced in cells in phosphate-buffered saline and by reduction of pH. The former effect was shown to be due to the higher [Na+] of phosphate-buffered saline as opposed to the other media. Addition of alanine, glycine, serine, proline and methylaminoisobutyrate all reduced membrane potential by 2-3 mV. Smaller decreases were seen with methionine, leucine and phenylalanine, but none with glutamine, threonine, BCH (2-aminonorborane-2-carboxylic acid) and D-alanine. The results are compared with the effects of similar conditions on aminoisobutyrate uptake. Whilst there was a correlation under some conditions there was not under others. It is concluded that for the hepatoma cells factors additional to the membrane potential must exert some influence on the capacity for amino acid transport.
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PMID:Membrane potential of rat hepatoma cells in culture: influence of factors affecting amino acid transport. 856 68

Wortmannin is an inhibitor of phosphatidylinositol (PI) 3'-kinase, a cellular kinase activated by docking to phosphotyrosyl residues of insulin receptor substrate-1 (IRS-1) that can also phosphorylate serine residues on IRS-1 in vitro. After treatment of hepatoma cells with 100 nM wortmannin, the tyrosine phosphorylation of IRS-1 in response to insulin was increased by 38.3 +/- 3.3% while its phosphoserine/threonine content was reduced by 19%. Treatment with 1 microM wortmannin further increased IRS-1 tyrosine phosphorylation to 180% of control, while under these conditions, tyrosine phosphorylation of the IR substrate p52 Shc was reduced to less than 50% of control. Thus, alteration of the serine phosphorylation of IR substrates by a wortmannin-sensitive kinase may regulate post-insulin receptor signaling pathways by differential modulation of their insulin-stimulated tyrosine phosphorylation.
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PMID:Differential regulation of insulin-stimulated tyrosine phosphorylation of IRS-1 and SHC by Wortmannin in intact cells. 866 Mar 83

mRNA levels and enzyme activities of the serine/threonine protein phosphatases (EC 3.1.3.16) type 1 (PP1) and 2A (PP2A) in drug-resistant rat ascites hepatoma cells were examined and compared with those in the parental drug-sensitive cell lines, under drug-free conditions. The mRNA levels of PP1 alpha were much higher in all the hepatomas, either sensitive or resistant, compared with normal liver. The mRNA level of PP2C alpha was decreased in the drug-resistant hepatomas compared with the parental drug-sensitive hepatomas, whereas mRNA levels of PP1 alpha, PP1 gamma 1 and PP2A alpha in resistant hepatomas showed diverse deviations, which are not drug-resistance-specific. However, both spontaneous and potential PP1 activities in particulate fractions of the resistant hepatomas were markedly increased compared with those of the sensitive hepatomas and normal rat liver. Western blot analysis showed that the resistant hepatomas contained larger amounts of PP1 alpha in both cytosolic and particulate fractions than the sensitive hepatomas and rat liver. In both groups of hepatomas, spontaneous and potential activities of PP2A were kept lower than those in normal rat liver, but there was no difference between drug-sensitive and -resistant hepatomas. These results suggest an involvement of PP1 in development of drug-resistant phenotype.
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PMID:mRNA levels and enzyme activities of protein phosphatases in drug-resistant rat ascites hepatomas. 886 62

The rat CYP2D5 P-450 gene is activated in the liver during postnatal development. We previously showed that liver-specific transcription of the CYP2D5 gene is dictated by a proximal promoter element, termed 2D5, that is composed of a binding site for Sp1 or a related factor, and an adjacent cryptic C/EBP (CCAAT/enhancer-binding protein) site. Despite the fact that both C/EBP alpha and C/EBP beta are expressed abundantly in liver, only C/EBP beta is capable of stimulating the 2D5 promoter in HepG2 hepatocarcinoma cells. In addition, activation of the 2D5 promoter by C/EBP beta is completely dependent on the presence of the Sp1 site. Domain switch experiments reveal that C/EBP beta proteins containing either the leucine zipper or the activation domain of C/EBP alpha are unable to stimulate the 2D5 promoter yet are fully capable of transactivating an artificial promoter bearing a high-affinity C/EBP site. Thus, the leucine zipper and the activation domain of C/EBP beta are absolutely required to support transactivation of the 2D5 promoter. Using Drosophila cells that lack endogenous Sp1 activity, we show that the serine/threonine- and glutamine-rich activation domains A and B of Sp1 are required for efficient cooperatively with C/EBP beta. Furthermore, analysis of c/ebp beta-deficient mice shows that mutant animals are defective in expression of a murine CYP2D5 homolog in hepatic cells, confirming the selective ability of C/EBP beta to activate this liver-specific P-450 gene in vivo. Our findings illustrate that two members of a transcription factor family can achieve distinct target gene specificities through differential interactions with a cooperating Sp1 protein.
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PMID:The ability of C/EBP beta but not C/EBP alpha to synergize with an Sp1 protein is specified by the leucine zipper and activation domain. 912 52

In this study we have investigated the molecular mechanism by which sodium butyrate modulates gene expression when added to cultured cells. As a model system we used hepatoma tissue culture cells in which sodium butyrate treatment increases histone H1(0) mRNA level and decreases c-myc mRNA level. Because we observed that stimulation of histone H1(0) gene expression could take place in the absence of protein neosynthesis, we hypothesized that sodium butyrate induced a post-translational modification of a factor involved in the transcription process. Using different types of well known kinase and phosphatase inhibitors, we studied the implication of kinase or phosphatase activity in this pathway. Interestingly, cell treatment with potent serine-threonine-phosphatase inhibitors, calyculin A or okadaic acid, prevented the regulation of both histone H1(0) and c-myc gene expressions by sodium butyrate. On the other hand, the tyrosine phosphatase inhibitor, vanadate, or the protein kinase C inhibitor, staurosporine, did not significantly modify sodium butyrate effects. Using protein phosphatase 1 and 2A for in vitro assays, we found a 45% increase of phosphatase activity after cell treatment by sodium butyrate, possibly due to a protein phosphatase 1-type protein phosphatase. These data strongly suggest that signaling pathway(s) triggered by sodium butyrate to modulate gene expression involve(s) a serine-threonine-phosphatase activity.
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PMID:The effects of sodium butyrate on transcription are mediated through activation of a protein phosphatase. 930 63


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