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 present an in vivo model for specific protection of normal hepatocytes from damage by the highly specific hepatotoxin galactosamine. The idea is based on the fact that normal, unlike malignant, hepatocytes possess unique cell-surface receptors that can bind and internalize galactose terminal (asialo)glycoproteins by receptor-mediated endocytosis. A targetable carrier-antagonist conjugate was formed by coupling asialofetuin to the galactosamine antagonist uridine monophosphate. Intravenous injection of the antagonist conjugate resulted in specific uptake by the liver. Rats treated with carrier-antagonist conjugate together with a toxic dose of galactosamine developed significantly less hepatotoxicity than did controls. We conclude that a galactosamine antagonist can be targeted to liver, resulting in specific protection of hepatocytes from galactosamine toxicity in vivo. Because hepatoma cells lack asialoglycoprotein receptor activity, this "targeted rescue" may be of value in the differential protection of normal cells in the treatment of hepatocellular carcinoma.
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PMID:Targeted protection of hepatocytes from galactosamine toxicity in vivo. 169 13

Asialofetuin-tacked liposomes (AF-liposomes) encapsulating interferon (IFN)-gamma were bound and internalized into a human hepatoma cell line, HepG2 cells, selectively through asialoglycoprotein receptor, but not non-tacked liposomes (N-liposomes). AF-liposomal IFN-gamma was more effective for inhibition of viral DNA replication in hepatitis B virus (HBV)-producing clone from HepG2 cells transfected with HBV-DNA than N-liposomal IFN-gamma. AF-liposomes may increase the therapeutic potential of IFN-gamma through asialoglycoprotein receptor in treating HBV-infected hepatocytes.
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PMID:Specific uptake of asialofetuin-tacked liposomes encapsulating interferon-gamma by human hepatoma cells and its inhibitory effect on hepatitis B virus replication. 170 30

One proposed function of the asialoglycoprotein receptor in hepatocytes is to mediate the endocytosis of galactose and N-acetylgalactosamine-exposing glycoproteins. Recently we defined a pool of intracellular H1 subunits of the asialoglycoprotein receptor (ASGPR) in the human hepatoma cell line HepG2 which appeared not to be involved in endocytosis (Stoorvogel, W., Geuze, H. J., Griffith, J. M., Schwartz, A. L., and Strous, G. J. (1989) J. Cell Biol. 108, 2137-2148). In addition, a pool of stably phosphorylated intracellular ASGPR has been detected (Fallon, R. J., and Schwartz, A. L. (1988) J. Biol. Chem. 263, 13159-13166). In the current study we integrate these findings and provide evidence for the existence of two types of intracellular nonexchangeable compartments containing ASGPR. A transiently phosphorylated pool of ASGPR shuttles between the plasma membrane and endosomes, via a pathway identical to that of the transferrin receptor. The second pool comprises 20% of the total intracellular ASGPR, is stably phosphorylated at a serine residue, and is located in intracellular compartments devoid of recycling transferrin receptor. We refer to this ASGPR pool as the "silent pool." We furthermore show that the two receptor pools are confined to compartments exhibiting different buoyant densities on sucrose density gradients. ASGPR in the "silent pool" is fully glycosylated, suggesting a post-Golgi sorting mechanism for trafficking to this compartment. Possible functions of the "silent" ASGPR pool are discussed.
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PMID:A pool of intracellular phosphorylated asialoglycoprotein receptors which is not involved in endocytosis. 200 89

Tissue-type plasminogen activator (t-PA) has a short half-life in the circulation because the enzyme is rapidly cleared by the liver. This short review summarizes recent literature concerning mechanisms of uptake and degradation of t-PA in the liver. In vivo studies in rats show that degradation takes place via a lysosomal pathway. Saturation of the uptake system at high t-PA concentrations suggests a receptor-mediated mechanism. Competition experiments with various glycoproteins indicate that the asialoglycoprotein receptor is not involved, but they point to a role for the mannose receptor, which recognizes t-PA via its high mannose-type oligosaccharide on the first kringle domain. Both in vivo and in vitro studies with isolated liver cells demonstrate that parenchymal cells, as well as liver endothelial cells, are involved in the clearance of t-PA. Parenchymal cells, as the hepatoma cell line Hep G2, endocytose t-PA via a still unknown, possibly t-PA specific receptor, while liver endothelial cells catabolize t-PA via the mannose receptor.
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PMID:Receptor-mediated endocytosis of tissue-type plasminogen activator (t-PA) by liver cells. 210 99

Membranes from the human hepatoma cell line HepG2 mediate the phosphorylation on tyrosine of the asialoglycoprotein receptor. Manganese was the preferred divalent for phosphorylation although magnesium was effective at an 8-fold higher concentration. Calcium was ineffective at promoting phosphorylation and zinc was inhibitory. The protein kinase inhibitor staurosporine blocked asialoglycoprotein receptor phosphorylation on tyrosine in nanomolar concentrations (IC50 = 70 nM). In contrast another protein kinase C inhibitor, H7, was not inhibitory, suggesting that the effect of staurosporine was not mediated by protein kinase C inhibition. Concentrations of staurosporine that inhibit receptor phosphorylation by greater than 90% did not inhibit the phosphorylation of other protein substrates identified on SDS-polyacrylamide gels. These data suggest that staurosporine selectively and directly inhibits a membrane-associated tyrosine protein kinase.
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PMID:Staurosporine inhibits a tyrosine protein kinase in human hepatoma cell membranes. 216 72

The interactions between H1 and H2, the two polypeptides comprising the human asialoglycoprotein receptor (ASGP-R), were investigated by immunofluorescence and lateral mobility measurements combined with antibody-mediated cross-linking and immobilization. Immunofluorescence microscopy revealed two ASGP-R populations on the cell surface, one homogeneously distributed and the other in micropatches. This was observed both in stably transfected NIH 3T3 lines expressing H1 and/or H2, and in the human hepatoma cell line HepG2. In transfected cells expressing both polypeptides (the 1-7-1 line), H1 and H2 were colocalized in the same micro aggregates. Moreover, enhancement of the patching of, e.g., H1 by IgG-mediated crosslinking was accompanied by copatching of H2. To quantify H1-H2 complex formation, the lateral diffusion of H1 and H2 was measured at 12 degrees C (to avoid internalization) by fluorescence photobleaching recovery. H1 (or H2) was immobilized by crosslinking with specific IgG molecules; the other chain was labeled with fluorescent monovalent Fab' fragments, and is lateral mobility was measured. In HepG2 cells, immobilization of either H1 or H2 led to an equal immobilization of the other, indicating that all the mobile H1 and H2 are in stable heterooligomers. In 1-7-1 cells, immobilization of H2 immobilized H1 to the same degree, but immobilization of H1 reduced the mobile fraction of H2 only by 2/3. Thus, in 1-7-1 cells all surface H1 molecules are associated with H2, but 1/3 of the H2 population is independent of H1. From these data and from measurements of the relative surface densities of H1 and H2, conclusions are drawn regarding the oligomeric structure and stoichiometry of the ASGP-R.
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PMID:Oligomeric structure of the human asialoglycoprotein receptor: nature and stoichiometry of mutual complexes containing H1 and H2 polypeptides assessed by fluorescence photobleaching recovery. 221 17

The fate of intravascular IgA which is produced in large quantities in humans and many animal species was investigated in vivo and in vitro with emphasis on the monomeric form of IgA. The site(s) of the catabolism of intravenously injected mouse monomeric IgA labeled with a residualizing tracer (dilactitol - 125I tyramine) was studied in mice. The greatest in vivo uptake of monomeric IgA was observed in the liver. In contrast to identically labeled IgG, liver accounted for more internal catabolism of monomeric IgA than all other tissues (spleen, muscle, skin, and kidney) combined. Although both parenchymal and nonparenchymal liver cells internalized monomeric IgA, hepatocytes were far more active. The uptake of monomeric IgA was primarily mediated by the asialoglycoprotein receptor. In humans, the particulate fraction of liver homogenates and a human hepatoma cell line (Hep G2) bound human IgA proteins of various molecular forms. Inhibition of the binding by desialylated glycoproteins, requirement for the presence of calcium, and the molecular properties of the IgA-binding protein from the plasma membrane of Hep G2 cells indicated that the binding was primarily mediated by the asialoglycoprotein receptor. IgA proteins bound by Hep/G2 cells were internalized and catabolized to low molecular weight fragments.
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PMID:The role of the liver in catabolism of mouse and human IgA. 265 14

We have developed a system for targeting foreign DNA to hepatocytes in vitro using a soluble DNA carrier that takes advantage of receptor-mediated endocytosis to achieve internalization. The idea is based on the fact that hepatocytes possess a unique receptor that binds and internalizes galactose-terminal (asialo)glycoproteins. To create a targetable carrier system that could bind DNA in a nondeforming manner, we used poly(L-lysine) to bind DNA in a strong but noncovalent interaction. An asialoglycoprotein, asialoorosomucoid (AsOR), was chemically coupled to poly(L-lysine) to form an asialoorosomucoid-poly(L-lysine) conjugate. Various proportions of conjugate to DNA were tested to determine conditions that maximized DNA content in a soluble complex and that limited solubility of complexes. To test the targetable gene delivery system, AsOR-poly(L-lysine) conjugate was complexed to the plasmid pSV2 CAT containing the gene for chloramphenicol acetyltransferase (CAT) driven by an SV-40 promoter. We tested this complex using a model system consisting of human hepatoma cell line Hep G2 [asialoglycoprotein receptor (+)], hepatoma SK-Hep 1, IMR-90 fibroblasts, and uterine smooth muscle [receptor (-)] cells. Each cell line was incubated with 0.2 micron filtered AsOR-poly(L-lysine)-DNA complex or controls consisting of DNA plus AsOR, DNA plus poly(L-lysine), or DNA alone. Cells were assayed for the presence of CAT activity as a measure of gene transformation. SK-Hep 1, IMR-90, and smooth muscle [receptor (-)] cells produced no detectable acetylated chloramphenicol derivatives under any of these conditions.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Evidence for targeted gene delivery to Hep G2 hepatoma cells in vitro. 283 80

In the rat, asialoorosomucoid and rat dimeric immunoglobulin A are both taken up by hepatocytes via receptor-mediated endocytosis. The fate of these two proteins, however, differs significantly. Rat dimeric IgA is taken up into smooth vesicles, transported to the bile canaliculus and secreted intact into the bile, whereas asialoglycoproteins are internalized via coated vesicles and transported to lysosomes for degradation. Recently, several studies both in the rat and in cultured human hepatoma cells have suggested that the receptor for asialoglycoproteins may play a role in the hepatic uptake and processing of human polymeric IgA. Using receptor-binding techniques, we have provided quantitative data for the competition of human monomeric, polymeric and secretory IgA with asialoorosomucoid for its receptor on liver plasma membrane preparations from rat, monkey and man. Some IgA molecules required desialylation with neuraminidase to enhance markedly their efficacy for asialoorosomucoid inhibition. Quantitatively, human IgA molecules showed an affinity for the ASOR receptor similar to that for asialoceruloplasmin. Rat dimeric IgA does not compete for this binding site. We conclude that human IgA can compete with ligands for the asialoglycoprotein receptor of rat, monkey and human liver. This receptor may provide an alternative pathway for the hepatic processing of IgA and IgA immune complexes when secretory component-mediated uptake is not available as in the monkey and man, particularly under pathological conditions where serum IgA concentrations accumulate to abnormally high levels.
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PMID:Hepatic asialoglycoprotein receptor-mediated binding of human polymeric immunoglobulin A. 291 27

Two related polypeptides, H1 and H2, comprise the human asialoglycoprotein receptor (ASGP-R). Stable lines of murine NIH 3T3 fibroblasts expressing H1 alone or H2 alone do not bind or internalize the ligand asialoorosomucoid (ASOR), which contains triantennary oligosaccharides. In contrast, cells expressing H1 and H2 together bind and degrade ASOR with properties indistinguishable from those of the ASGP-R in human hepatoma HepG2 cells. Whether or not H2 is coexpressed, H1 is synthesized as a 40-kDa precursor bearing high-mannose oligosaccharides, processed to its mature 46-kDa form, and transported to the cell surface. In cells expressing only H1, homodimers and -trimers of H1 are formed. In contrast, when expressed in 3T3 cells without H1, H2 is synthesized as its 43-kDa precursor, bearing high-mannose oligosaccharides, but is rapidly degraded. When H1 and H2 are coexpressed in the same cell, the H1 polypeptide "rescues" the H2 polypeptide; H2 is processed to its characteristic 50-kDa mature form and is transported to the surface. We conclude that the human ASGP-R is a multichain heterooligomer, probably a trimer of H1 molecules in noncovalent association with one, two, or three H2 molecules, and that the two polypeptides normally interact early in biosynthesis.
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PMID:The two subunits of the human asialoglycoprotein receptor have different fates when expressed alone in fibroblasts. 291 87


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