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)

HIV pseudotypes bearing native hepatitis C virus (HCV) glycoproteins (strain H and Con1) are infectious for the human hepatoma cell lines Huh-7 and PLC/PR5. Infectivity depends on coexpression of both E1 and E2 glycoproteins, is pH-dependent, and can be neutralized by mAbs mapping to amino acids 412-447 within E2. Cell-surface expression of one or all of the candidate receptor molecules (CD81, low-density lipoprotein receptor, scavenger receptor class B type 1, and dendritic cell-specific intercellular adhesion molecule 3 grabbing nonintegrin) failed to confer permissivity to HIV-HCV pseudotype infection. However, HIV-HCV pseudotype infectivity was inhibited by a recombinant soluble form of CD81 and a mAb specific for CD81, suggesting that CD81 may be a component of a receptor complex.
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PMID:Hepatitis C virus glycoproteins mediate pH-dependent cell entry of pseudotyped retroviral particles. 1276 83

Green tea has been shown to lower plasma cholesterol, associated with up-regulation of the low-density lipoprotein receptor (LDLR) although the responsible molecular mechanism is unknown. Previously, we reported that ester bond-containing green tea polyphenols (GTPs), such as (-)-epigallocatechin-3-gallate [(-)-EGCG], potently inhibit the tumor cellular proteasome activity, which may contribute to the cancer-preventative effect of green tea. In the current study, we hypothesize that the proteasome is a heart disease-associated molecular target of GTPs. We have shown that ester bond-containing GTPs, including (-)-EGCG, potently inhibit the proteasomal activity in intact hepatocellular carcinoma HepG2 and cervical carcinoma HeLa cells, as evident by accumulation of ubiquitinated proteins and three natural proteasome targets (p27, IkappaB-alpha and Bax). (-)-EGCG selectively inhibits the chymotrypsin-like, but not trypsin-like, activity of the proteasome. Associated with proteasome inhibition by ester bond-containing GTPs, there was a significant, time- and concentration-dependent increase in levels of the cleaved, activated, but not the precursor, form of sterol regulatory element-binding protein 2 (SREBP-2), an essential factor for LDLR transcription. Subsequently, LDL receptor expression was increased dramatically in HepG2 and HeLa cells treated with (-)-EGCG. Our results suggest that ester bond-containing GTPs inhibit ubiquitin/proteasome-mediated degradation of the active SREBP-2, resulting in up-regulation of LDLR. This identified molecular mechanism may be related to the previously reported cholesterol-lowering and heart disease-preventative effects of green tea.
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PMID:Direct inhibition of the ubiquitin-proteasome pathway by ester bond-containing green tea polyphenols is associated with increased expression of sterol regulatory element-binding protein 2 and LDL receptor. 1515 50

The proximal region -234 to (+58 bp) of low-density lipoprotein receptor (LDLR) is responsible for its up-regulation by sterol regulatory element binding protein (SREBP). However, the mechanism of sterol-independent repression of LDLR has not been determined yet. In this study, we observed that there was an early induction and a later repression of LDLR by phorbol ester (PMA) in SK-Hep1 hepatocarcinoma cells and investigated the mechanisms through which PMA repressed LDLR transcription. SK-Hep1 cells were exposed to PMA and LDLR mRNA was evaluated by RT-PCR and Northern blot analysis. The effect of phorbol ester on LDLR transcriptional activity was studied using transient transfection of LDLR promoter-luciferase constructs. Overexpression of N-SREBP-2, a dominant positive SREBP2, did not reverse the PMA-repressed LDLR promoter activity. Serial deletion of LDLR promoter revealed that the region between -1,563 and -1,326 was responsible for the repression. The pretreatment with SB202190, an inhibitor for p38 mitogen-activated protein kinase pathway (p38-MAPK), but not other signaling inhibitors, reversed the PMA-induced repression. The 24 h-treatment with PMA efficiently arrested the SK-Hep1 cell cycle at G0/G1 as demonstrated by FACS analysis and decreased the 3H-thymidine incorporation. The PMA-induced repression of LDLR transcription may be exerted by the factor(s), not SREBP2, induced or modified by p38-MAPK-mediated signaling pathway and associated with cell cycle blockage.
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PMID:Inhibition of low density lipoprotein receptor expression by long-term exposure to phorbol ester via p38 mitogen-activated protein kinase pathway. 1614 74

Fifteen years after the discovery of hepatitis C virus (HCV) in 1989, much remains to be learnt about the cell biology of this virus. Using the serum from a patient containing HCV RNA in high titer as a source, a Singapore strain of genotype 1b was recovered and characterized. This full-length HCV genome was then constructed into a tetracycline-inducible vector using the pSTAR plasmid. Transfection of hepatoma cell lines with this HCV genome under tetracycline induction indicated that chemokines (RANTES and monocyte chemoattractant protein-1) were upregulated, possibly contributing to the induction of immune responses. Using the yeast two-hybrid system to discover protein-protein interactions, nonstructural region NS3 was found to interact with itself, forming a dimer that increased helicase activity but was not essential for its activity, thereby disqualifying it as a suitable target of drug actions. The significance of the interaction between core and NS5A is unclear, and the cleavage of NS5A is related to the development of apoptosis. However, the interaction of p68 and NS56B appears to be important because the knockdown of p68 reduced the viral replication. Finally, a new cell model using chimeric CD81 linked to the cytoplasmic domain of either a low-density lipoprotein receptor or a transferrin receptor led to productive infection of HCV that had been recovered from infected serum. These studies allow us to examine the pathogenesis of HCV infection in more detail.
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PMID:Use of an in vitro model and yeast two-hybrid system to investigate the pathogenesis of hepatitis C. 1616 88

Hepatitis C virus (HCV) infection correlates with human immune disorders characterized by abnormal activation and proliferation of lymphocytes. Interaction of HCV major envelope protein E2 with susceptible cells occurs at an early stage of the viral infection. HCV tropism for susceptible cells may elicit cellular signaling events implicated in the viral pathogenicity, and E2 protein is known to be responsible for the tropism. We documented previously that HCV E2 protein was capable of activating extracellular signal-regulated kinase (ERK) in human hepatoma Huh-7 cells. Here, ERK and p38 mitogen-activated protein kinase (MAPK) signaling pathways were investigated in human T lymphoma cell line Molt-4 in response to HCV E2 protein. Binding of HCV E2 protein to Molt-4 cells was detectable, and such interaction was a determinant for recognition and delivery of the E2 signal to intracellular pathways. Activation of ERK and p38 MAPK was specifically induced following the HCV E2-cell interaction. CD81 and low-density lipoprotein receptor (LDLR), proposed cellular receptors for HCV, were expressed naturally on Molt-4 cells. CD81 and LDLR were shown to mediate HCV E2-induced activation of ERK and p38 MAPK. In CD81-deficient U937 cells, levels of ERK and p38 MAPK activation and cell proliferation induced by HCV E2 protein were lower than those in Molt-4 cells. Furthermore, cell proliferation and secretion of interferon-gamma and interleukin-10 by Molt-4 cells were promoted by HCV E2 protein. Therefore, ERK and p38 MAPK signaling pathways were up-regulated by HCV E2 protein without synergetic stimulation, which was accompanied by alterations of cell behavior.
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PMID:Up-regulation of ERK and p38 MAPK signaling pathways by hepatitis C virus E2 envelope protein in human T lymphoma cell line. 1679 13

Liver X receptor (LXR) agonists have the potential to treat atherosclerosis based on their ability to enhance reverse cholesterol transport. However, their side effects, such as induction of liver lipogenesis and triglyceridemia, may limit their pharmaceutical development. In contrast to the nonsteroidal LXR agonist N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide (T0901317), 3alpha, 6alpha, 24-trihydroxy-24, 24-di(trifluoromethyl)-5beta-cholane (ATI-829), a novel potent synthetic steroidal LXR agonist, was a poor inducer of sterol regulatory element-binding protein 1c expression in hepatoma HepG2 cells, whereas both compounds increased ABCA1 expression in macrophage THP-1 cells. In male low-density lipoprotein receptor-deficient mice, ATI-829 selectively activated LXR target gene expression in mouse intestines and macrophages but not in the liver. A significant increase in liver triglyceride and plasma triglyceriderich small very low-density lipoprotein (VLDL) was observed in T0901317 but not ATI-829-treated mice. Compared with vehicle-treated mice, atherosclerosis development was significantly inhibited in the innominate artery after treatment with either compound. However, in the aortic root, inhibition of atherosclerosis was only observed in the right (right coronary artery-associated sinus) but not the left coronary-related sinus (left coronary artery-associated sinus; LC) of mice treated with either compound. Lesions in the innominate artery were less complex after treatment with either compound and contained mostly macrophage foam cells. In contrast, LC lesions were more complex and had a large collagen-positive fibrous cap and less macrophage foam cell area after treatment with either compound. The T0901317-induced hypertriglyceridemia was accompanied by an increase in small triglyceride-rich VLDL that may influence LXR agonist-mediated antiatherosclerotic effects at certain vascular sites. ATI-829, by selectively activating LXR in certain tissues without inducing hypertriglyceridemia, is a good candidate for drug development.
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PMID:Antiatherosclerotic effects of a novel synthetic tissue-selective steroidal liver X receptor agonist in low-density lipoprotein receptor-deficient mice. 1872 76

Apolipoprotein A-V (apoA-V) has a close interrelationship with plasma triglyceride (TG). Since the discovery of the apoA-V gene in 2001, we have learned that single nucleotide polymorphisms in this gene correlate with altered plasma TG levels in humans, while genetically engineered mice manifest unique TG phenotypes. Studies of recombinant apoA-V protein have revealed that it is composed of two independently folded structural domains. The C-terminal domain possesses high lipid binding affinity, while the N-terminal domain adopts a helix bundle molecular architecture. A sequence element with high positive charge character, between residues 185 and 228, functions in binding of apoA-V to heparan sulfate proteoglycans as well as to members of the low-density lipoprotein receptor family and glycosylphosphatidylinositol high-density lipoprotein binding protein1. These interactions may be related to the capacity of this protein to regulate TG levels. ApoA-V is poorly secreted from transfected cultured hepatoma cell lines and is present in plasma at exceedingly low levels. Studies of apoA-V intracellular trafficking revealed an association with cytosolic lipid droplets. Thus, it is conceivable that apoA-V may also modulate TG metabolism within the cell. Much remains to be learned about this fascinating yet confounding member of the class of exchangeable apolipoproteins.
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PMID:The ins (cell) and outs (plasma) of apolipoprotein A-V. 1905 Mar 14

Hepatitis C virus (HCV) is an enveloped, single-stranded RNA virus, belonging to the Flaviviridae family. HCV infection is a major cause of chronic hepatitis worldwide, leading to steatosis, liver cirrosis and hepatocellular carcinoma. Significant advances in understanding the mechanisms of HCV infection have been made since the development of a cell culture system reproducing the complete HCV cell cycle in vitro. HCV represents a new paradigm in interactions between the virus and its target cell, the human hepatocyte, due to the central role of lipoproteins in the HCV life cycle. Very low density lipoproteins are required for virus particle assembly and secretion. Upon the release, the infectious virus circulates in the blood as triglyceride-rich particles and infects cells using lipoprotein-receptor dependent mechanisms. HCV cell entry is a multi-step process: heparan sulphate and/or low-density lipoprotein receptor are cell surface factors mediating an initial virus attachment; subsequent virus interaction with tetraspanin CD81 and the human scavenger receptor SR-BI, the main HCV receptors, triggers virus movement to the tight junctions and its uptake via Claudin-1 and occludin. Another originality of HCV is that initiation of productive infection requires dynamic microtubules. Whereas other viruses use kinesin or dynein-dependent transport, HCV exploits mechanisms driven by microtubule polymerization to efficiently infect its target cell, in which virus nucleocapsid protein might play a particular role. An improved of understanding of the cellular events involved in HCV cell entry and transport, leading to the initiation of productive HCV infection, may reveal novel targets for anti-viral interventions.
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PMID:Mechanism of cell infection with hepatitis C virus (HCV)--a new paradigm in virus-cell interaction. 1982 91

Hepatitis C virus (HCV) infection represents a serious public health problem worldwide. Development of new therapeutics against HCV has been hampered by the lack of a small-animal model. Until now, it has been unclear which host factors influence the HCV infection. It was known that human CD81 (hCD81) or low-density lipoprotein receptor (hLDLR), the putative HCV receptors, induce concentration of viral particles on the cell surface. In this study, recombinant plasmids containing hCD81 or hLDLR genes were transfected to mouse hepatoma Hepa 1-6 cells and transgenic cell lines expressing hCD81 (hCD81/1-6 cell line) or hLDLR (hLDLR/1-6 cell line) on their surface have been established. HCV infection of these cell lines showed that the virus was bound, entered the cell, and replicated inside the cell. This finding is essential for the development of mouse model for the study of HCV replication in vivo.
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PMID:Hepatitis C virus infection of mouse hepatoma cell expressing human CD81 or LDLR. 1994

Entry of hepatitis C virus (HCV) into hepatocytes is a multi-step process that involves a number of different host cell factors. Following initial engagement with glycosaminoglycans and the low-density lipoprotein receptor, it is thought that HCV entry proceeds via interactions with the tetraspanin CD81, scavenger receptor class B type I (SR-BI), and the tight-junction proteins claudin-1 (CLDN1) and occludin (OCLN), culminating in clathrin-dependent endocytosis of HCV particles and their pH-dependent fusion with endosomal membranes. Physiologically, SR-BI is the major receptor for high-density lipoproteins (HDL) in the liver, where its expression is primarily controlled at the post-transcriptional level by its interaction with the scaffold protein PDZK1. However, the importance of interaction with PDZK1 to the involvement of SR-BI in HCV entry is unclear. Here we demonstrate that stable shRNA-knockdown of PDZK1 expression in human hepatoma cells significantly reduces their susceptibility to HCV infection, and that this effect can be reversed by overexpression of full length PDZK1 but not the first PDZ domain of PDZK1 alone. Furthermore, we found that overexpression of a green fluorescent protein chimera of the cytoplasmic carboxy-terminus of SR-BI (amino acids 479-509) in Huh-7 cells resulted in its interaction with PDZK1 and a reduced susceptibility to HCV infection. In contrast a similar chimera lacking the final amino acid of SR-BI (amino acids 479-508) failed to interact with PDZK1 and did not inhibit HCV infection. Taken together these results indicate an indirect involvement of PDZK1 in HCV entry via its ability to interact with SR-BI and enhance its activity as an HCV entry factor.
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PMID:The SR-BI partner PDZK1 facilitates hepatitis C virus entry. 2094 66


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