Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 elongated mutant of alpha 2-plasmin inhibitor (alpha 2 PI) designated as alpha 2 PI-Nara is caused by a frameshift mutation found near the 3' end of the coding region of the alpha 2 PI gene. To elucidate the mechanism by which this molecular abnormality leads to alpha 2 PI deficiency in plasma, we transfected an expression plasmid for alpha 2 PI-Nara into a monkey kidney cell line COS-7 or human hepatoma cell line HepG2 synthesizing alpha 2 PI, and analyzed the secretory process of the expressed alpha 2 PI-Nara by radioimmunoprecipitation followed by sodium dodecyl sulfate polyacrylamide gel electrophoresis and fluorography. The results obtained showed that the recombinant alpha 2 PI-Nara was retained within the cells for prolonged periods as an endoglycosidase H-sensitive precursor form, and only a small portion of the recombinant protein was secreted into the medium as a neuraminidase-sensitive mature form. These results suggest that instead of being secreted from the cells, most of the alpha 2 PI-Nara undergoes degradation within the cells while its transport is retarded in the intracellular secretory pathway; thus, alpha 2 PI-Nara should lead to the alpha 2 PI deficiency primarily by causing a block in the intracellular transport from the endoplasmic reticulum to the Golgi complex.
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PMID:Impaired secretion of mutant alpha 2-plasmin inhibitor (alpha 2 PI-Nara) from COS-7 and HepG2 cells: molecular and cellular basis for hereditary deficiency of alpha 2-plasmin inhibitor. 168 97

A cDNA clone encoding 55-kDa multifunctional, thyroid hormone binding protein of rabbit skeletal muscle sarcoplasmic reticulum was isolated and sequenced. The cDNA encoded a protein of 509 amino acids, and a comparison of the deduced amino acid sequence with the NH2-terminal amino acid sequence of the purified protein indicates that an 18-residue NH2-terminal signal sequence was removed during synthesis. The deduced amino acid sequence of the rabbit muscle clone suggested that this protein is related to human liver thyroid hormone binding protein, rat liver protein disulfide isomerase, human hepatoma beta-subunit of prolyl 4-hydroxylase and hen oviduct glycosylation site binding protein. The protein contains two repeated sequences Trp-Cys-Gly-His-Cys-Lys proposed to be in the active sites of protein disulfide isomerase. Northern blot analysis showed that the mRNA encoding rabbit skeletal muscle form of the protein is present in liver, kidney, brain, fast- and slow-twitch skeletal muscle, and in the myocardium. In all tissues the cDNA reacts with mRNA of 2.7 kilobases in length. The 55-kDa multifunctional thyroid hormone binding protein was identified in isolated sarcoplasmic reticulum vesicles using a monoclonal antibody specific to the 55-kDa thyroid hormone binding protein from rat liver endoplasmic reticulum. The mature protein of Mr 56,681 contains 95 acidic and 61 basic amino acids. The COOH-terminal amino acid sequence of the protein is highly enriched in acidic residues with 17 of the last 29 amino acids being negatively charged. Analysis of hydropathy of the mature protein suggests that there are no potential transmembrane segments. The COOH-terminal sequence of the protein, Arg-Asp-Glu-Leu (RDEL), is similar to but different from that proposed to be an endoplasmic reticulum retention signal; Lys-Asp-Glu-Leu (KDEL) (Munro, S., and Pelham, H.R.B. (1987) Cell 48, 899-907). This variant of the retention signal may function in a similar manner to the KDEL sequence, to localize the protein to the sarcoplasmic or endoplasmic reticulum. The positively charged amino acids Lys and Arg may thus interchange in this retention signal.
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PMID:Molecular cloning of cDNA encoding a 55-kDa multifunctional thyroid hormone binding protein of skeletal muscle sarcoplasmic reticulum. 169 92

As resolved by electrophoresis in non-reducing SDS gels, transferrin newly made in Hep G2 cells migrates as a very diffuse set of species. During a subsequent 1-h chase all transferrin polypeptides are converted to a single, rapidly migrating species. These changes in gel mobility are due to alterations in the pattern of disulfide bonding, are not caused by carbohydrate processing, and occur while the protein is in the rough endoplasmic reticulum. Cyclosporin A causes an approximately 10-min lag in transferrin folding, after which folding resumes at the normal rate. Cyclosporin A also retards transferrin maturation from the endoplasmic reticulum and its secretion, at concentrations that do not affect secretion of other hepatoma proteins. Neither FK506 nor rapamycin affect transferrin folding. We conclude that an initial stage in transferrin folding is accelerated by an endoplasmic reticulum peptidyl-proline isomerase that is inhibited by cyclosporin A.
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PMID:Cyclosporin A inhibits an initial step in folding of transferrin within the endoplasmic reticulum. 171 45

A case of a right ovarian tumor in a 64-year-old patient showing high blood levels of alpha-fetoprotein (AFP) is reported. Histologically, the tumor resembled hepatocellular carcinoma with hyaline globules. Localization of AFP was detected by the immunoperoxidase method. Electron microscopically, the rough-surfaced endoplasmic reticulum had developed into a meshwork, and the mitochondria were present within this meshwork. Because a transition from adenocarcinoma to a region resembling hepatocellular carcinoma was observed, this tumor was considered to originate as a common epithelial carcinoma. In the blood, 67% of the AFP was bound with concanavalin A (Con A), and the fraction pattern obtained by lentil agglutinin affinity chromatography (LCA) was of the germ cell type. From these results, the current case may be labeled clinicopathologically a hepatoid carcinoma of the ovary as described by Ishikura and Scully.
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PMID:Hepatoid carcinoma of the ovary: a case report. 171 89

Numerous hepatic cell lineage pathways have been proposed for the development of hepatocarcinogensis induced by chemical carcinogens in rats. The roles of bile ductule cells and hepatocytes in the development of carcinogenesis were investigated using light and electron microscopic procedures to detect differences in morphology and in the phenotypic expression of antigens that are associated with each cell type. In early stages of hepatocarcinogenesis (4-10 weeks after initiation of feeding of a choline-deficient ethionine containing diet), both bile ductulelike (BDL) cells and hepatocytes were seen in mitosis. At the light microscope level, BDL cells showed intense cytoplasmic pyronin (RNA) staining and were positive for the antigens defined by monoclonal antibody 270.38 (bile ductule cells and "oval" cell marker) and glutathione-S-transferase (Yp isoform), whereas hepatocytes were positive for the antigens defined by monoclonal antibodies 270.26 and 258.26 (liver parenchymal cell markers), catalase activity (peroxisome marker) and adenosine triphospatase activity (bile canalicular marker). The authors frequently encountered BDL cells and hepatocytes in close proximity. Ultrastructural examination showed extensive plasma membrane appositions between a subset of BDL cells and hepatocytes. Desmosome structures, tight junctions, microvilli interdigitations and ATPase-positive bile canalicularlike structures were present along the contiguous plasma membrane domains of BDL cells and hepatocytes. Many of the BDL cells attached to hepatocytes were also attached to other BDL cells that had retained a basal lamina. In many cases, BDL cells connected to both hepatocytes and other BDL cells were no longer completely surrounded by basal lamina and had acquired a dual polarity as a consequence of their sharing apical and lateral membrane domains with both BDL cells and hepatocytes. BDL cells showed increased numbers of microperoxisomes (catalase positive organelles) and numerous free ribosomes. Hepatocytes showed a prominent development of the smooth endoplasmic reticulum, a feature prominent in hepatocytes within hyperplastic nodules. Since BDL cells and hepatocytes proliferate and BDL cells and hepatocytes develop intercellular junction sites, the authors propose that both cell types in early stages of carcinogenesis have the capacity to enter the cell lineage pathway leading to the development of hepatocarcinoma. Furthermore, the finding that BDL cells and hepatocytes form multiple attachment sites at the level of the plasma membrane, suggests the possibility that at some stage convergence of separate hepatic cell pathways may occur.
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PMID:Characterizations of and interactions between bile ductule cells and hepatocytes in early stages of rat hepatocarcinogenesis induced by ethionine. 175 May 8

Dramatic cellular changes that occur during hepatocarcinogenesis are associated with major alterations in extracellular matrix formation and in the relationships between cells and their microenvironment. We have studied the expression of laminin, the major noncollagenous glycoprotein of basement membrane, and the laminin receptor 32 kD laminin-binding protein in two rat (Faza 967 and HTC) and two human (HepG2 and HBGC2) hepatoma cell lines that express a variety of liver-specific functions. Laminin was found in the rough endoplasmic reticulum of these cells when the indirect immunoperoxidase method and electron microscopic examination were used. Radiolabeled laminin, immunoprecipitated from both media and cell extracts, was resolved by electrophoresis on sodium dodecyl sulfate gel in two major polypeptides that comigrated with the A and B subunits from Engelbreth-Holm-Swarm tumor laminin. Immunoblot analysis showed that the Mr = 400,000 polypeptide did not correspond to the A subunit of laminin. Northern blot analyses demonstrated large amounts of B1 and B2 mRNAs but no A chain mRNA. We conclude that the tumor cells produce the laminin B chains only. In contrast, normal adult hepatocytes from either man or rat lacked laminin mRNAs, whereas in 1-day primary culture, B chain mRNAs became detectable. The steady-state level of 32 kD laminin-binding protein mRNA was 10-fold and threefold higher in rat hepatoma cells than in freshly isolated and 1-day cultured normal rat hepatocytes, respectively. In human hepatocytes, the steady-state levels of 32 kD laminin-binding protein mRNAs varied depending on the donor and never reached the level of the human hepatoma cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Expression of laminin and its receptor LBP-32 in human and rat hepatoma cells. 184 49

A cDNA clone for human catechol-O-methyltransferase (hCOMT; S-adenosyl-L-methionine:catechol O-methyltransferase; EC 2.1.1.6) was isolated from a human hepatoma cell line (Hep G2) cDNA library by hybridization screening with a porcine cDNA probe. The cDNA clone was sequenced and found to have an insert of 1226 nucleotides. The deduced primary structure of hCOMT is composed of 271 amino acid residues with the predicted molecular mass of 30 kDa. At its N terminus it has a hydrophobic segment of 21 amino acid residues that may be responsible for insertion of hCOMT into the endoplasmic reticulum membrane. The primary structure of hCOMT exhibits high homology to the porcine partial cDNA sequence (93%). The deduced amino acid sequence contains two tryptic peptide sequences (T-22, T-33) found in porcine liver catechol-O-methyltransferase (COMT). The coding region of hCOMT cDNA was placed under the control of the cytomegalovirus promoter to transfect human kidney 293 cells. The endogenous COMT activity, which was approximately 9.98 units per mg of protein in the untransfected cells, increased to 206 units per mg of protein upon transfection with a plasmid containing the COMT cDNA. The COMT activity of recombinant protein was inhibited competitively (IC50 = 700 nM) by the selective COMT inhibitor Ro 40-7592. An anti-COMT monoclonal antibody recognized, on immunoblots, a major polypeptide with apparent molecular mass of 29 kDa, in reasonable agreement with the predicted molecular mass. The recombinant hCOMT was shown by immunoblot analysis to be mainly associated with the membrane fraction. RNA blot analysis revealed one COMT mRNA transcript of 1.4 kilobases in Hep G2 poly(A)+ RNA.
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PMID:Human catechol-O-methyltransferase: cloning and expression of the membrane-associated form. 184 21

Hepatitis B virus (HBV) particles are generated by budding of preformed cytoplasmic nucleocapsids into endoplasmic reticulum (ER) membranes containing the three viral envelope proteins (L, M, and S). We have examined the contributions of the envelope proteins to virion assembly by using cultured hepatoma cells transfected with mutant HBV genomes bearing lesions in the envelope coding regions. We show here that HBV nucleocapsids are not released from cells without expression of envelope proteins, implying an active role for these proteins in viral morphogenesis. S and L but not M proteins are necessary for virion production. L protein over-expression inhibits virion release, just as it inhibits the release of subviral hepatitis B surface antigen (HBsAg) particles. Mutant L proteins that are no longer capable of retaining HBsAg particles in the ER still allow virion formation, indicating that this ER retention reaction is not required for viral budding. Myristoylation of L protein is also dispensable for virion formation. A chimeric protein bearing foreign epitopes fused to the S protein can be incorporated into virions when coexpressed with the wild-type envelope proteins. Models for the dependence of virion formation on both L and S proteins are discussed.
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PMID:The role of envelope proteins in hepatitis B virus assembly. 199 57

Using the ketone compound metyrapone (MPON) as a substrate for carbonyl reduction it has been verified for the first time that various permanent cell lines in culture express carbonyl reducing activity. This is even true for the dedifferentiated and fibroblastoid cell line V79, emphasizing the essentiality of this metabolic pathway. MPON reducing enzyme activities are located in the endoplasmic reticulum as well as in the cytoplasm of the cells. Compared to MPON-reductase in rat liver microsomes, no immunological homology to microsomal C2REV7 rat liver hepatoma cell MPON-reductase could be detected, indicating differences in antigenic determinants between the enzymes of the solid organ and respective cells in continuous culture.
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PMID:The occurrence of carbonyl reduction in continuous cell lines emphasizes the essentiality of this metabolic pathway. 203 51

Transport of the lysosomal enzyme cathepsin C was studied in Morris hepatoma 7777 cells. Subcellular fractions obtained after isopyenic centrifugation in sucrose gradients of labelled cell homogenates were sequentially extracted by hypo-osmotic shock, Na2CO3 and Triton X-100. Polypeptides related to cathepsin C were immunoprecipitated and analysed by SDS/PAGE and fluorography. At early times after synthesis and for up to 60 min, precursor polypeptides of cathepsin C are distributed in endoplasmic reticulum and Golgi fractions, in membrane-associated form, as Triton X-100 is necessary for their extraction. At 2 h and later after synthesis, intermediate and mature forms of the enzyme can be totally extracted by hypo-osmotic shock from gradient fractions corresponding to the lysosomes of Morris hepatoma 7777 cells.
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PMID:Transient membrane association of the precursors of cathepsin C during their transfer into lysosomes. 203 58


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