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)

5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) is a commonly used pharmacological agent to study physiological effects which are similar to those of exercise. However, signal transduction pathways by which AICAR elicits downstream effects in liver are poorly understood. We report here that AICAR not only activated AMPK but also phosphorylated/deactivated glycogen synthase kinase-3 alpha/beta (GSK-3alpha/beta) and dephophorylated/activated glycogen synthase (GS) in a time-dependent manner in human hepatoma HepG2 cells. The signal connection between AICAR and GSK-3 is indirect and involves activation of Raf-1/MEK/p42/44(MAPK)/p90(RSK) signaling cascade as pharmacologic inhibition of MEK significantly reduced phosphorylation/deactivation of GSK-3 and consequent dephosphorylation/activation of GS. Moreover, silencing the expression of p90(RSK), a substrate of p42/44(MAPK), attenuated AICAR-dependent GSK-3 phosphorylation, implicating this kinase as a key mediator of AICAR signaling to GSK-3. Furthermore, consistent with the involvement of Raf-1 kinase cascade, AICAR-induced low-density lipoprotein (LDL) receptor expression in a p42/44(MAPK)-dependent manner. Finally, AICAR requires AMPK-alpha2-dependent and -independent pathways to activate Raf-1 kinase cascade as suppression of AMPKalpha2 activity, and not of AMPKalpha1, partially blocked AICAR-dependent p42/44(MAPK) activation and GSK-3 phosphorylation/deactivation. Collectively, these results highlight Raf-1 signaling cascade as the critical mediator of AICAR action on glucose and lipid metabolism in HepG2 cells.
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PMID:AICAR positively regulate glycogen synthase activity and LDL receptor expression through Raf-1/MEK/p42/44MAPK/p90RSK/GSK-3 signaling cascade. 1794 90

Lafora progressive myoclonus epilepsy (LD) is a fatal autosomal recessive neurodegenerative disorder characterized by the presence of glycogen-like intracellular inclusions called Lafora bodies. LD is caused by mutations in two genes, EPM2A and EPM2B, encoding respectively laforin, a dual-specificity protein phosphatase, and malin, an E3 ubiquitin ligase. Previously, we and others have suggested that the interactions between laforin and PTG (a regulatory subunit of type 1 protein phosphatase) and between laforin and malin are critical in the pathogenesis of LD. Here, we show that the laforin-malin complex downregulates PTG-induced glycogen synthesis in FTO2B hepatoma cells through a mechanism involving ubiquitination and degradation of PTG. Furthermore, we demonstrate that the interaction between laforin and malin is a regulated process that is modulated by the AMP-activated protein kinase (AMPK). These findings provide further insights into the critical role of the laforin-malin complex in the control of glycogen metabolism and unravel a novel link between the energy sensor AMPK and glycogen metabolism. These data advance our understanding of the functional role of laforin and malin, which hopefully will facilitate the development of appropriate LD therapies.
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PMID:Regulation of glycogen synthesis by the laforin-malin complex is modulated by the AMP-activated protein kinase pathway. 1802 86

AM251, a cannabinoid antagonist, has various biological activities. In this study, we found that AM251 suppressed the viability of hepatoma HepG2 cells and also increased phosphorylation of JNK (c-jun N-terminal kinase) and ATF3 (activating transcription factor 3). In addition, AM251 phosphorylated AMPK (AMP-activated protein kinase) in a time and dose-dependent manner. Inhibition of AMPK blocked AM251-induced JNK/ATF3 phosphorylation. Expression of AMPK or treatment with AICAR (5-aminoimidazole-4-carboxy-amide-1-d-ribofuranoside), an AMPK activator, activated the JNK/ATF3 pathways. Together, these results suggest that AM251 may have anti-tumor effects in hepatoma through activation of the AMPK-JNK-ATF3 signal pathway.
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PMID:AM251 suppresses the viability of HepG2 cells through the AMPK (AMP-activated protein kinase)-JNK (c-Jun N-terminal kinase)-ATF3 (activating transcription factor 3) pathway. 1840 47

5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a phylogenetically conserved serine/threonine protein kinase. AMPK may inhibit cell growth and proliferation and also regulates apoptosis. 5'-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) is a cell-permeable AMPK activator. Activation of AMPK with AICAR has been shown to induce apoptosis of the rat hepatoma cell line FTO2B cells and almost completely inhibited HepG2 cells growth. In this study, a HepG2 cell line, which was transfected with a vector containing human CYP2E1 cDNA (E47 cells), was treated with AICAR. Cell proliferation was blocked, and apoptosis and necrosis were elevated as assessed by cellular morphology, DNA content assay, and lactate dehydrogenase leakage. AICAR treatment significantly increases CYP2E1 activity (20-fold) and expression (5.5-fold) in E47 cells. Iodotubericidin, which inhibits the conversion of AICAR to its activated form AICAR monophosphate, the antioxidants trolox and MnTMPyP, and 4-methylpyrazole, an inhibitor of CYP2E1, all can protect the E47 cells from AICAR-induced necrosis. Production of intracellular reactive oxygen species was increased by AICAR treatment in E47 cells. The cytotoxicity mechanism of AICAR in E47 cells is suggested to include AMPK activation, p53 phosphorylation, p21 expression, overexpression of CYP2E1, and intracellular ROS accumulation.
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PMID:Overexpression of CYP2E1 induces HepG2 cells death by the AMP kinase activator 5'-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR). 1847 82

SAMe (S-adenosylmethionine) is the main methyl donor group in the cell. MAT (methionine adenosyltransferase) is the unique enzyme responsible for the synthesis of SAMe from methionine and ATP, and SAMe is the common point between the three principal metabolic pathways: polyamines, transmethylation and transsulfuration that converge into the methionine cycle. SAMe is now also considered a key regulator of metabolism, proliferation, differentiation, apoptosis and cell death. Recent results show a new signalling pathway implicated in the proliferation of the hepatocyte, where AMPK (AMP-activated protein kinase) and HuR, modulated by SAMe, take place in HGF (hepatocyte growth factor)-mediated cell growth. Abnormalities in methionine metabolism occur in several animal models of alcoholic liver injury, and it is also altered in patients with liver disease. Both high and low levels of SAMe predispose to liver injury. In this regard, knockout mouse models have been developed for the enzymes responsible for SAMe synthesis and catabolism, MAT1A and GNMT (glycine N-methyltransferase) respectively. These knockout mice develop steatosis and HCC (hepatocellular carcinoma), and both models closely replicate the pathologies of human disease, which makes them extremely useful to elucidate the mechanism underlying liver disease. These new findings open a wide range of possibilities to discover novel targets for clinical applications.
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PMID:S-adenosylmethionine and proliferation: new pathways, new targets. 1879 49

AMP-activated protein kinase (AMPK) responds to oxidative stress. Previous work has shown that ethanol treatment of cultured hepatoma cells and of mice inhibited the activity of AMPK and reduced the amount of AMPK protein. Ethanol generates oxidative stress in the liver. Since AMPK is activated by reactive oxygen species, it seems paradoxical that ethanol would inhibit AMPK in the hepatoma cells. In an attempt to understand the mechanism whereby ethanol inhibits AMPK, we studied the effect of ethanol on AMPK activation by exogenous hydrogen peroxide. The effects of ethanol, hydrogen peroxide, and inhibitors of protein phosphatase 2A (PP2A) [either okadaic acid or PP2A small interference RNA (siRNA)] on AMPK phosphorylation and activity were examined in rat hepatoma cells (H4IIEC3) and HeLa cells. In H4IIEC3 cells, hydrogen peroxide (H(2)O(2), 1 mM) transiently increased the level of phospho-AMPK to 1.5-fold over control (P < 0.05). Similar findings were observed in HeLa cells, which do not express the upstream AMPK kinase, LKB1. H(2)O(2) markedly increased the phosphorylation of LKB1 in H4IIEC3 cells. Ethanol significantly inhibited the phosphorylation of PKC-zeta, LKB1, and AMPK caused by exposure to H(2)O(2). This inhibitory effect of ethanol required its metabolism. More importantly, the inhibitory effects of ethanol on H(2)O(2)-induced AMPK phosphorylation were attenuated by the presence of the PP2A inhibitor, okadaic acid, or PP2A siRNA. The inhibitory effect of ethanol on AMPK phosphorylation is exerted through the inhibition of PKC-zeta and LKB1 phosphorylation and the activation of PP2A.
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PMID:Effect of ethanol on hydrogen peroxide-induced AMPK phosphorylation. 1883 48

AMP-activated protein kinase (AMPK) is an intracellular fuel sensor that plays a key role in regulating fatty acid synthesis in liver. Sterol regulatory element-binding protein (SREBP)-1c is a master regulator of hepatic lipogenic gene expression. It has long been documented that AMPK activation suppresses hepatic SREBP-1 mRNA and nuclear SREBP-1 protein. But the mechanism remains undefined. In this study we investigated the molecular mechanisms by which AMPK downregulates hepatic SREBP-1c mRNA using a novel model cell line McA-RH7777. We found that AMPK is robustly activated in rat hepatoma McA-RH7777 cells treated with two widely used AMPK activators, AICAR and metformin, and AMPK activation sharply suppresses SREBP-1c mRNA and nuclear SREBP-1c protein, but not SREBP-1a mRNA derived from the same gene. These inhibitory effects are reversed by the AMPK inhibitor Compound C or 8-BrAMP, demonstrating the requirement of AMPK in the suppression of SREBP-1c mRNA and nuclear SREBP-1c protein by AICAR and metformin. AMPK does not enhance SREBP-1c mRNA degradation in the presence of the general transcription inhibitor actinomycin D; instead it inhibits SREBP-1c promoter activity in a luciferase reporter assay. AMPK-mediated inhibition of SREBP-1c promoter activity can also be abrogated by the AMPK inhibitor Compound C. Furthermore AMPK activation significantly attenuates the synthetic liver X receptor (LXR) ligand T0901317-induced SREBP-1c promoter activity. AMPK also inhibits cleavage of LXR ligand-induced SREBP-1c precursor. We conclude that AMPK suppresses hepatic SREBP-1c mRNA expression by inhibiting LXR-dependent SREBP-1c transcription via inhibition of endogenous LXR ligand production and by inhibiting SREBP-1c processing in McA-RH7777 cells.
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PMID:AMP-activated protein kinase suppresses LXR-dependent sterol regulatory element-binding protein-1c transcription in rat hepatoma McA-RH7777 cells. 1912 18

Compound K (CK) is a major intestinal metabolite of ginsenosides derived from ginseng radix. Although antidiabetic and antihyperlipidemic activities of CK have been investigated in recent years, action mechanism of CK remains poorly understood. Therefore, we examined whether CK affects the lipid metabolism in insulin-resistant HepG2 human hepatoma cells. In this study, a significant increase in AMP-activated protein kinase (AMPK) was observed when the cells were treated with CK. Activation of AMPK was also demonstrated by measuring the phosphorylation of acetyl-CoA carboxylase (ACC), a substrate of AMPK. CK attenuated gene expression of sterol regulatory element-binding protein 1c (SREBP1c) in time- and dose-dependent manners. Genes for fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD1), well-known target molecules of SREBP1c, were also suppressed. In contrast, gene expressions of peroxisome proliferator-activated receptor alpha (PPAR-alpha) and CD36 were increased. These effects were reversed by treatment of compound C, an AMPK inhibitor. However, there were no differences in gene expressions of SREBP2, hydroxymethyl glutaryl CoA reductase (HMGR), and low-density-lipoprotein receptor (LDLR). Taken together, AMPK mediates CK induced suppression and activation of SREBP1c and PPAR-alpha, respectively, and these effects seem to be one of antidiabetic and/or antihyperlipidemic mechanisms of CK in insulin-resistant HepG2 human hepatoma cells.
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PMID:Compound K, intestinal metabolite of ginsenoside, attenuates hepatic lipid accumulation via AMPK activation in human hepatoma cells. 1918 50

Hepatic apoptosis is elevated in patients with non-alcoholic steatohepatitis and is correlated with the severity of the disease. Long-chain saturated fatty acids, such as palmitate, induce apoptosis in liver cells. The present study examined adiponectin-mediated protection against saturated fatty acid-induced apoptosis in the human hepatoma cell line, HepG2. Cells were cultured in a control media (i.e. without fatty acids) or the same media containing 250 micromol L(-1) of albumin-bound oleate or palmitate for 24 h. The adiponectin concentrations used were: 0, 1, 10 or 100 microg mL(-1) (n = 4-6 per treatment). Palmitate and thapsigargin, but not oleate, activated caspase-3 and decreased cell viability in the absence of adiponectin. Adiponectin reduced palmitate- and thapsigargin-induced activation of caspase-3 and cell death in a dose-dependent manner. Phosphatidylinositol 3-kinase and AMP-activated protein kinase inhibitors abolished the effects of adiponectin. Adiponectin-induced inhibition of palmitate- and thapsigargin-induced apoptosis was not the result of an augmentation in the unfolded protein response or the increased expression of genes encoding the inhibitor of apoptosis proteins, inhibitor of apoptosis protein-2 and X-linked mammalian inhibitor of apoptosis protein. Palmitate and thapsigargin, but not oleate, increased c-Jun NH(2) terminal kinase phosphorylation in the absence of adiponectin. Adiponectin blocked palmitate- and thapsigargin-induced activation of c-Jun NH(2) terminal kinase and reduced apoptosis. These data suggest that adiponectin is an important determinant of saturated fatty acid-induced apoptosis in liver cells and may have implications for fatty acid-mediated liver cell injury in adiponectin-deficient individuals.
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PMID:Full-length adiponectin protects hepatocytes from palmitate-induced apoptosis via inhibition of c-Jun NH2 terminal kinase. 1929 Aug 87

Genomic copy number aberrations and corresponding transcriptional deregulation in the cancer genome have been suggested to have regulatory roles in cancer development and progression. However, functional evaluation of individual genes from lengthy lists of candidate genes from genomic data sets presents a significant challenge. Here, we report effective gene selection strategies to identify potential driver genes based on systematic integration of genome scale data of DNA copy numbers and gene expression profiles. Using regional pattern recognition approaches, we discovered the most probable copy number-dependent regions and 50 potential driver genes. At each step of the gene selection process, the functional relevance of the selected genes was evaluated by estimating the prognostic significance of the selected genes. Further validation using small interference RNA-mediated knockdown experiments showed proof-of-principle evidence for the potential driver roles of the genes in hepatocellular carcinoma progression (i.e., NCSTN and SCRIB). In addition, systemic prediction of drug responses implicated the association of the 50 genes with specific signaling molecules (mTOR, AMPK, and EGFR). In conclusion, the application of an unbiased and integrative analysis of multidimensional genomic data sets can effectively screen for potential driver genes and provides novel mechanistic and clinical insights into the pathobiology of hepatocellular carcinoma.
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PMID:Identification of potential driver genes in human liver carcinoma by genomewide screening. 1936 92


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