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)

We have identified in plasma membrane fractions isolated from rat hepatocarcinoma AS-30D ascites cells three glycoproteins of 125 kDa, 115 kDa and 105 kDa (gp125, gp115 and gp105) which become adenylylated using ATP as substrate, most readily in the presence of EDTA. The gp115 becomes also phosphorylated. The adenylylation of these tumor glycoproteins was much lower than that of a group of analogous adenylylatable glycoproteins (gp130, gp120-gp110 dimer and gp100) present in normal rat liver plasma membrane. The tumor glycoproteins were reversibly O-adenylylated at threonine residues, as was the case for their normal rat liver counterparts. The tumor gp115, and the gp120-gp110 dimer from normal rat liver were both isolated using either ATP-affinity chromatography and/or AMP-affinity chromatography. The gp120-gp110 dimer from normal rat liver was identified as the plasma cell differentiation antigen-1 (PC-1 protein), an ecto-5' phosphodiesterase/nucleotide-pyrophosphatase (5'-PDE/NPPase). The gp115 from tumor cells also exhibited Zn2+ stimulated 5'-PDE and NPPase activities in alkaline conditions, although it appears to be distinct from the PC-1 protein. We have determined that the gp115 is an ecto-enzyme that catalyzes the hydrolysis of extracellular ATP, since its adenylylation and phosphorylation were detected in intact cells using extracellularly added [alpha-32P]ATP or [gamma-32P]ATP, respectively, in the absence of any permeabilizing agent.
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PMID:Characterization of a new plasma membrane-associated ecto-5'-phosphodiesterase/nucleotide-pyrophosphatase from rat hepatocarcinoma AS-30D cells. 1151 84

We have identified in plasma membrane fractions isolated from rat hepatocarcinoma AS-30D ascites cells three glycoproteins of 125 kDa, 115 kDa and 105 kDa (gp125, gp115 and gp105) which become adenylylated using ATP as substrate, most readily in the presence of EDTA. The gp115 becomes also phosphorylated. The adenylylation of these tumor glycoproteins was much lower than that of a group of analogous adenylylatable glycoproteins (gp130, gp120-gp110 dimer and gp100) present in normal rat liver plasma membrane. The tumor glycoproteins were reversibly O-adenylylated at threonine residues, as was the case for their normal rat liver counterparts. The tumor gp115, and the gp120-gp110 dimer from normal rat liver were both isolated using either ATP-affinity chromatography and/or AMP-affinity chromatography. The gp120-gp110 dimer from normal rat liver was identified as the plasma cell differentiation antigen-1 (PC-1 protein), an ecto-5' phosphodiesterase/ nucleotide-pyrophosphatase (5'-PDE/NPPase). The gp115 from tumor cells also exhibited Zn2+-stimulated 5'-PDE and NPPase activities in alkaline conditions, although it appears to be distinct from the PC-1 protein. We have determined that the gp115 is an ecto-enzyme that catalyzes the hydrolysis of extracellular ATP, since its adenylylation and phosphorylation were detected in intact cells using extracellularly added [alpha-32P]ATP or [gamma-32P]ATP, respectively, in the absence of any permeabilizing agent.
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PMID:Characterization of a new plasma membrane-associated ecto-5'-phosphodiesterase/nucleotide-pyrophosphatase from rat hepatocarcinoma AS-30D cells. 1157 96

Retinoids induce apoptosis and differentiation of hepatocellular carcinoma (HCC) cells and are used clinically in the chemoprevention of HCC. We have shown previously that hepatocarcinogenesis is accompanied by accumulation of full-length retinoid X receptor alpha (RXRalpha), although the underlying mechanisms and biological implications have remained unclear. The present studies were based on the finding that the accumulated full-length RXRalpha was phosphorylated at serine/threonine residues both in all human HCC tissues examined and in human HCC-derived HuH7 cells. Phosphorylation at serine 260 of RXRalpha, a consensus site of mitogen-activated protein kinase, was closely linked to its retarded degradation, low transactivating activity, and the promotion of cancer cell growth. There was no genomic mutation in the RXRalpha gene, and abrogation of phosphorylation by mitogen-activated protein kinase-specific inhibitors restored the degradation of RXRalpha in an RXR ligand-dependent manner. These results suggest that phosphorylation of RXRalpha may interfere with its metabolism and signaling in human HCC, which could lead to growth promotion of these tumors.
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PMID:Phosphorylation of retinoid X receptor alpha at serine 260 impairs its metabolism and function in human hepatocellular carcinoma. 1160 11

Kanadaptin (kidney anion exchanger adaptor protein) has recently been identified as a protein with binding activity to the cytoplasmic domain of the kidney Na(+)-independent Cl(-)/HCO(-)(3) anion exchanger 1 (kAE1). Since it is widely expressed in tissues devoid of kAE1, however, kanadaptin is likely to have additional cellular roles. This is supported by its multidomain structure, and possession of three clusters of basic amino acids exhibiting similarity to known nuclear localization sequences (NLSs). In the present study, we use immunofluorescence and subcellular fractionation approaches to demonstrate that kanadaptin is localized within the nuclei of various epithelial and non-epithelial cultured cell types. The role of the different NLSs is examined in transfection studies using plasmids encoding full-length kanadaptin with or without green fluorescent protein (GFP) as a fusion tag, as well as truncation derivatives thereof. Strong nuclear localization of fusion proteins containing amino acids 140-230 of kanadaptin, which include the sequence AVSRKRKA(193) (NLS1) was observed. Substitution of Arg(191) with a threonine residue resulted in a cytoplasmic location of the expressed protein, while NLS1 proved sufficient to target an otherwise cytoplasmically localized beta-galactosidase-GFP fusion protein to the nucleus. Using a direct binding assay we show that a fusion protein containing kanadaptin amino acids 1-231 (but not the Thr(191) substituted derivative) is recognized with nM affinity by the conventional NLS-binding importin alpha/beta heterodimer. Nuclear import studies on microinjected and permeabilized rat hepatoma cells demonstrated functionality of the NLS in nuclear targeting, with inhibition by antibodies demonstrating the requirement of both importin alpha and beta for nuclear import of kanadaptin. That kanadaptin possesses a functional importin-alpha/beta-recognized NLS explains the nuclear localization of kanadaptin in various cultured cell types, and opens up the possibility that kanadaptin may have a signalling role in the nucleus.
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PMID:Signal- and importin-dependent nuclear targeting of the kidney anion exchanger 1-binding protein kanadaptin. 1177

Eukaryotic initiation factor 2- (eIF2-) associated glycoprotein p67 blocks eIF2alpha phosphorylation by kinases, and its N-terminal 1-97 amino acid segment can induce efficient translation. To investigate whether glycosylation at the serine/threonine clusters at this region is important in protein synthesis, we selected (27)TSST(30) and (60)SGTS(63) clusters for further analysis. By site-directed mutagenesis, (27)TSST(30) and (60)SGTS(63) clusters were substituted with (27)AAGA(30) and (60)AGAA(63) amino acid residues in full-length p67, and their EGFP fusions were constitutively expressed in rat tumor hepatoma cells (KRC-7). The (60)AGAA(63) mutant blocked eIF2alpha phosphorylation less than either wild-type p67 or the (27)AAGA(30) mutant. The (60)AGAA(63) mutant also showed a low level of protein synthesis rate, a lower level of glycosylation, increased turnover rate, and weaker binding to eIF2alpha. These results suggest that glycosylation within the (60)SGTS(63) sequence of p67 plays an important role in its stability and thus its regulation of protein synthesis by modulating the phosphorylation of the alpha-subunit of eIF2.
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PMID:A glycosylation site, 60SGTS63, of p67 is required for its ability to regulate the phosphorylation and activity of eukaryotic initiation factor 2alpha. 1273 87

The cyclin-dependent kinase (Cdk)-associated protein phosphatase (KAP) is a human dual-specificity protein phosphatase that dephosphorylates Cdk2 on a conserved threonine residue, T160, in a cyclin dependent manner. Several aberrant KAP transcripts with characteristic deletion regions have been identified in hepatocellular carcinoma tissues. In this report, we demonstrated that multiple aberrant KAP transcripts were also present in a hepatoblastoma cell line (HepG2), albeit harboring a totally different set of deletions. By performing yeast two-hybrid and co-immunoprecipitation experiments, a KAP-Cdk2 interaction domain located in the amino acid 1-34 region was identified. This interaction domain was different from the major protein interface deduced from crystal structure analysis. Using a yeast three-hybrid system, it was shown that the presence of a truncated KAP mutant encoding this interaction domain abolished the wild-type KAP-Cdk2 interaction. In conclusion, a previously unidentified KAP-Cdk2 interaction domain was discovered. Truncated KAP mutants containing this domain interfered with the wild-type KAP-Cdk2 interaction.
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PMID:Abolishment of the interaction between cyclin-dependent kinase 2 and Cdk-associated protein phosphatase by a truncated KAP mutant. 1274 75

gamma-Glutamyl hydrolase (GGH) plays a central role in folate metabolism and antifolate action. Increased GGH activity has been found in rat hepatoma cells resistant to the cancer drug methotrexate (MTX). The aim of this study was to identify polymorphisms in the GGH gene that modulate GGH activity and that may affect methotrexate resistance. Exons of the human gamma-glutamyl hydrolase (hGGH) gene were amplified by polymerase chain reaction (PCR) from breast cancer tissue and leukemia cell lines. Single-stranded conformational polymorphism (SSCP) analysis was performed, and PCR products containing different patterns were cloned and sequenced. Six single nucleotide polymorphisms (SNPs) were identified, at bases -401C>T, -354G>T, -124T>G, +16T>C, +452C>T, and +1102A>G, relative to the A of the translation start codon being considered as +1. The SNP at +16, which changes codon -19 (relative to the start of the mature hGGH protein) in the endoplasmic reticulum targeting sequence of hGGH protein from cysteine to arginine, has previously been identified in this laboratory. The SNP at +452 changes the conserved hGGH protein codon 127 from threonine to isoleucine. The functions of SNPs in the promoter of the hGGH gene were studied by site-directed mutagenesis of a 516-bp region of the hGGH gene promoter in a luciferase reporter vector and transfection into HepG2 and MCF-7 cells. All of the promoter polymorphisms enhanced the production of luciferase compared to the wild-type hGGH gene promoter in HepG2 cells, and -401C>T and -124T>G enhanced luciferase expression in MCF-7 cells, suggesting that polymorphisms in the hGGH gene promoter may increase expression of hGGH protein.
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PMID:Identification of single nucleotide polymorphisms in the human gamma-glutamyl hydrolase gene and characterization of promoter polymorphisms. 1459 82

A potent inhibitor of serine/threonine kinases, staurosporine exerts antiproliferative and apoptotic effects in many cancer cells, although the exact mechanism of its action is still unclear. This study examines the effects of staurosporine on Chang liver cells, an immortalized non-tumor cell line, in comparison with those caused in HuH-6 and HepG2 cells, two human hepatoma cell lines. Our results provide evidence that staurosporine promotes apoptosis in Chang liver cells as observed by flow cytometric analysis and acridine orange/ethidium bromide staining. The effect appeared already after 8 h of treatment and increased with treatment time and dose. After 48 h of exposure to 200 nM staurosporine clear apoptotic signs were observed in about 50% of the cells. Western blotting analysis showed that in Chang liver cells staurosporine induced a marked decrease in the levels of the antiapoptotic factors Bcl-2 (-75%) and Bcl-XL (-50%). Staurosporine also caused loss of mitochondrial transmembrane potential, release of cytochrome c from mitochondria and activation of caspase-3. The involvement of caspases in staurosporine-induced cell death was also suggested by the observation that the addition of z-VAD-fmk, a general inhibitor of caspases, suppressed apoptosis. In HuH-6 and HepG2 cells treatment with staurosporine induced the arrest of cells in G2/M phase of cell cycle. This effect was not modified by z-VAD-fmk and was not accompanied by the appearance of biochemical signs of apoptosis. We conclude that staurosporine induced apoptosis in Chang liver cells by a mitochondria-caspase-dependent pathway which was closely correlated with a decrease in Bcl-2 and Bcl-XL levels, while in HuH-6 and HepG2 hepatoma cells the drug caused only an antiproliferative effect.
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PMID:Staurosporine-induced apoptosis in Chang liver cells is associated with down-regulation of Bcl-2 and Bcl-XL. 1501 Aug 57

Protein phosphorylation is a vital process in the regulation of mammalian cell division and the protein kinases that catalyze the phosphorylation of proteins on serine, threonine and tyrosine residues have been well characterized. In contrast, little is known about the kinases involved in protein histidine phosphorylation, which have been described in various mammalian cells that are highly proliferative. Histone H4 histidine kinase (HHK) activity is highly active in regenerating rat liver. Using a novel and specific assay, we demonstrate that it is active in human fetal liver, essentially absent in adult liver and highly expressed in liver tumours. 'Normal' liver surrounding the HCC contains low to undetectable levels of HHK. In a rodent model of chronic liver injury that leads to HCC, its activity is induced. Two lines of evidence suggest that liver progenitor (oval) cells, which populate the liver at early stages following induction of liver damage are responsible for the increased activity. Purified oval cells, as well as cell lines established from primary cultures of oval cells express high levels of HHK. We propose that the pattern of expression of histone H4 histidine kinase activity justifies its classification as an oncodevelopmental marker and suggest it may be useful as a diagnostic marker for hepatocellular carcinoma as well for identifying preneoplastic lesions.
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PMID:Histone H4 histidine kinase displays the expression pattern of a liver oncodevelopmental marker. 1524 May 7

SNARK is a member of the AMPK subfamily of serine/threonine protein kinases. In this study, we examined the regulation of SNARK activity in kidney (BHK, HEK293), pancreatic beta-cell insulinoma (INS-1), hepatocarcinoma (H4IIE) and keratinocyte (NRKC)-derived cell lines in response to diverse cellular stresses. We show that SNARK activity is regulated by glucose- or glutamine-deprivation, induction of endoplasmic reticulum stress by homocysteine or DTT, elevation of cellular AMP and/or depletion of ATP, hyperosmotic stress, salt stress, ultraviolet B radiation and oxidative stress caused by hydrogen peroxide. Moreover, the regulation of SNARK activity in response to cellular stresses depends greatly upon cell type. Furthermore, SNARK activity is downregulated by metformin in a dose- and time-dependent manner in H4IIE cells. These observations support a role for SNARK as a molecular component of the cellular stress response.
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PMID:Regulation of SNARK activity in response to cellular stresses. 1589 79


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