UMLS:C0019204 - FACTA Search

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Query: UMLS:C0019204 (hepatocellular carcinoma)
71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Extracellular signal-regulated kinase (ERK) plays a central role in regulating cell growth, differentiation, and apoptosis. We previously found that 2-(2-mercaptoethanol)-3-methyl-1,4-napthoquinone or Compound 5 (Cpd 5), is a Cdc25A protein phosphatase inhibitor and causes prolonged, strong ERK phosphorylation which is triggered by epidermal growth factor receptor (EGFR) activation. We now report that Cpd 5 can directly cause ERK phosphorylation by inhibiting Cdc25A activity independently of the EGFR pathway. We found that Cdc25A physically interacted with and de-phosphorylated phospho-ERK both in vitro and in cell culture. Inhibition of Cdc25A activity by Cpd 5 resulted in ERK hyper-phosphorylation. Transfection of Hep3B human hepatoma cells with inactive Cdc25A mutant enhanced Cpd 5 action on ERK phosphorylation, whereas over-expression of Cdc25A attenuated this Cpd 5 action. Furthermore, endogenous Cdc25A knock-down by Cdc25A siRNA resulted in a constitutive-like ERK phosphorylation and Cpd 5 treatment further enhanced it. In EGFR-devoid NR6 fibroblasts and MEK (ERK kinase) mutated MCF7 cells, Cpd 5 treatment also resulted in ERK phosphorylation, providing support for the idea that Cpd 5 can directly act on ERK phosphorylation by inhibiting Cdc25A activity. These data suggest that phospho-ERK is likely another Cdc25A substrate, and Cpd 5-caused ERK phosphorylation is probably regulated by both EGFR-dependent and EGFR-independent pathways.
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PMID:Cdc25A and ERK interaction: EGFR-independent ERK activation by a protein phosphatase Cdc25A inhibitor, compound 5. 1567 48

Metformin is thought to decrease blood glucose levels by reducing hepatic glucose output. To elucidate the pharmacological action of metformin on hepatic glucose production, we examined its effect on the gene expression of glucose-6-phosphatase (G6Pase), a key enzyme of gluconeogenesis, in H4IIE rat hepatoma cell line by RT-PCR and quantitative real-time PCR. Metformin suppressed dexamethasone/cAMP-induced expression of G6Pase mRNA in a dose dependent manner, its maximum effect being observed at 2 mM (79.3% inhibition, P<0.05). Pretreatment with the PI3-kinase inhibitor wortmannin, the MEK-1 inhibitor PD98059 or the protein kinase C inhibitor GF109203X had no effect on suppressed G6Pase expression by metformin. Moreover, metformin did not stimulate Akt phosphorylation. In the present study, we demonstrate that metformin suppresses G6Pase mRNA expression by a mechanism that is independent of the activation of PI3-kinase, Akt, MAP kinase and protein kinase C pathway in hepatocytes.
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PMID:Metformin-induced suppression of glucose-6-phosphatase expression is independent of insulin signaling in rat hepatoma cells. 1570 36

In the present work, insulin's regulation of expression of activating transcription factor 3 (ATF-3), the putative transcription factor proline-rich induced protein (Pip)92, and insulin-inducible gene-1 (Insig-1) (an ER resident protein involved in regulation of sterol-responsive element-binding protein 1 activation) have been examined in a liver-derived cell line (rat H4IIE hepatoma cells). We report that: 1) insulin-induced transcription of ATF-3, Pip92, and Insig-1 required MEK-ERK activation; 2) insulin-induced transcription of ATF-3 and Pip92 reached maximum levels within 15 min and was blocked by wortmannin but not LY294002; 3) in contrast, the maximum level of insulin-induced transcription of Insig-1 was delayed and was not blocked by either wortmannin or LY294002; 4) insulin activated ERK1/2 in two distinct phases, a rapid peak and a later plateau; 5) the delayed plateau phase of insulin-induced ERK1/2 activation was partially phosphatidylinositol 3-OH-kinase dependent; and 6) however, the rapid, insulin-induced peak of ERK1/2 activation was blocked by wortmannin but not LY294002.
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PMID:Blockade of rapid versus prolonged extracellularly regulated kinase 1/2 activation has differential effects on insulin-induced gene expression. 1573 59

Growth hormone (GH) and insulin are important regulators of cellular and whole body metabolism as well as somatic growth and body composition. Studies have indicated complex feedback effects of GH on insulin action and of insulin on GH signaling pathways. Previous studies in our laboratory have shown that GH induction of signal transducers and activators of transcription (STAT)5B tyrosine phosphorylation is inhibited by prolonged insulin treatment, probably via downregulation of GHR. Here, we find that in rat H4IIE hepatoma cells GH-induced tyrosine phosphorylation of two other STATs (STAT3 and STAT1) was also greatly reduced following prolonged insulin pretreatment compared with that induced by GH alone. In the present work, total STAT5B and STAT1 protein levels were not altered by prolonged insulin treatment. However, prolonged insulin treatment (16 h; 10 or 100 nM) resulted in a 30-40% reduction of total STAT3 protein, with little change at 0.1 and 1.0 nM insulin. Thus, there is a selective reduction of total STAT3 protein levels by insulin, but only at high concentration of insulin. Basal tyrosine phosphorylated (PY)-STAT3 was also significantly reduced by prolonged insulin treatment, and to a greater extent than total STAT3 protein levels. The inhibitory effect of insulin on total STAT3 protein and basal PY-STAT3 levels was dependent on activation of the MEK-ERK pathway, rather than the PI3K pathway. In contrast, the MEK-ERK pathway did not play a major role in insulin's inhibition of GH-induced PY-STAT3 and PY-STAT1. The present studies indicate that prolonged hyperinsulinemia, such as that found in some obese patients or patients with Type 2 diabetes mellitus, may have profound effects on GH signaling via STAT3 and STAT1.
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PMID:Prolonged insulin treatment inhibits GH signaling via STAT3 and STAT1. 1574 7

The potent tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA) induces activator protein-1 (AP-1) transcription factors, early response genes involved in a diverse set of transcriptional regulatory processes, and protein kinase C (PKC) activity. This work was designed to explore the signal transduction pathways involved in TPA regulation of 5-aminolevulinate synthase (ALAS) gene expression, the mitochondrial matrix enzyme that catalyzes the first and rate-limiting step of heme biosynthesis. We have previously reported that TPA causes repression of ALAS gene, but the signaling pathways mediating this effect remain elusive. The present study investigates the role of different cascades often implicated in the propagation of phorbol ester signaling. To explore this, we combined the transient overexpression of regulatory proteins involved in these pathways and the use of small cell permeant inhibitors in human hepatoma HepG2 cells. In these experimental conditions, we analyzed TPA action upon endogenous ALAS mRNA levels, as well as the promoter activity of a fusion reporter construct, harboring the TPA-responsive region of ALAS gene driving chloramphenicol acetyl transferase gene expression. We demonstrated that the participation of alpha isoform of PKC, phosphatidylinositol 3-kinase (PI3K), extracellular-signal regulated kinase (ERK1/2), and c-Jun N-terminal kinase (JNK) is crucial for the end point response. Remarkably, in this case, ERK activation is achieved in a Ras/Raf/MEK-independent manner. We also propose that p90RSK would be a convergent point between PI3K and ERK pathways. Furthermore, we elucidated the crosstalk among the components of the cascades taking part in TPA-mediated ALAS repression. Finally, by overexpression of a constitutively active p90RSK and the coactivator, cAMP-response element protein (CREB)-binding protein (CBP), we reinforced our previous model, that implies competition between AP-1 and CREB for CBP.
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PMID:Repression of 5-aminolevulinate synthase gene by the potent tumor promoter, TPA, involves multiple signal transduction pathways. 1579 41

The transcription factor nuclear factor-kappa B (NF-kappaB) subunit p65 is phosphorylated by IkappaB kinase (IKK) at S536 in transactivation domain (TAD) 1. In this study, we investigate the presence of IKK sites in TAD2 of p65. Recombinant IKKbeta, but not IKKalpha, phosphorylated a GST-p65 substrate in which TAD1 was deleted. Mutational analysis revealed S468 as the only IKK site in TAD2. S468 phosphorylation occurred rapidly after TNF-alpha and IL-1beta in T cell, B cell, cervix carcinoma, hepatoma, breast cancer, and astrocytoma lines and in primary hepatic stellate cells as well as peripheral blood mononuclear cells. S468-phosphorylated p65 coimmunoprecipitated with IkappaBalpha, indicating that p65 is phosphorylated while bound to IkappaBalpha. Dominant negative IKKbeta or pharmacological IKK inhibition blocked S468 phosphorylation after TNF-alpha or IL-1beta, whereas dominant negative IKKalpha or inhibitors of MEK, p38, JNK, PI-3 kinase, or GSK-3 had no effect. p65S468A-reconstituted p65-/- mouse embryonic fibroblasts (MEFs) showed a small, but significant, elevation of NF-kappaB-driven luciferase activity and RANTES mRNA levels after TNF-alpha and IL-1beta in comparison to wtp65-reconstituted MEFs. p65 nuclear translocation was not altered in p65S468A-expressing MEFs. In conclusion, our results indicate that 1) IKKbeta phosphorylates multiple p65 sites, 2) IKKbeta phosphorylates p65 in an IkappaB-p65 complex, and 3) S468 phosphorylation slightly reduces TNF-alpha- and IL-1beta-induced NF-kappaB activation.
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PMID:IKKbeta phosphorylates p65 at S468 in transactivaton domain 2. 1604 71

The tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) is a well-known activator of both protein kinase C (PKC) and mitogen activated protein kinase (MAPK) signal cascade triggering a lot of effects in many non-tumor and tumor cells. We have reported activation of PKCalpha isozyme was specifically required for TPA-induced ERK (MAPK) signaling that mediated gene expressions of the CDK inhibitors p15(INK4b) and p16 (INK4a) leading to growth inhibition of hepatoma cell HepG2. We further investigated the upstream signal molecule linking PKCalpha to ERK. In the Ras activation assay, HepG2 cell exhibited substantial amount of Ras activity. Treatment of the cell with 50nM TPA for 10min slightly inhibited Ras activity by about 10-20%. Pretreatment of the cell with 10microM manumycin A, which abolish basal Ras activity, did not prevent TPA-triggered ERK phosphorylation. Immunoprecipitation coupled with kinase assay demonstrated that MEK-1 activity was strongly induced by treatment of TPA for 5-30min in HepG2. In contrast, c-Raf activity was not significantly induced by TPA within 5-15min. Consistently, Western blot of Phospho(ser-218/222)-MEK demonstrated that phosphorylation of MEK-1 was greatly induced by 50nM TPA, which can be prevented by the PKC inhibitor Bisindolylmaleimides II. Moreover, pretreatment of the MEK1/2 inhibitor, but not c-Raf inhibitor prevented the TPA-induced ERK phosphorylation, gene expression of p15(INK4b) and p16 (INK4a) and growth inhibition of HepG2. In addition, transient expression of a dominant negative Raf mutant in HepG2 did not prevent these effects of TPA. Constitutive expression of an active PKCalpha mutant in HepG2 enhanced phosphorylation of both MEK and ERK accompanied with induction of gene expression of p16(INK4a) and growth inhibition of HepG2. In contrast, Ras and Raf activity were not increased by expression of active PKCalpha. Taken together, we conclude that PKCalpha may activate MEK, independently of Raf and Ras, to trigger sustained ERK (MAPK) signaling and cell cycle arrest of HepG2 induced by TPA.
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PMID:Protein kinase C alpha trigger Ras and Raf-independent MEK/ERK activation for TPA-induced growth inhibition of human hepatoma cell HepG2. 1616 61

Previous studies identified the putative SCAP ligands including compound GW707 as a new class of up-regulators of LDL receptor (LDLR) transcription by activation of the sterol-regulatory element binding proteins (SREBP). These compounds increase LDLR expression in hepatoma cells in vitro and lower plasma LDL-c in hamsters. However, it is unknown, what signaling pathways are utilized by these agents that lead to the activation of LDLR transcription. Here, we report that the ERK signaling cascade is critically involved in GW707-mediated induction of LDLR expression. We show that: a) blocking ERK activation with U0126, the inhibitor of ERK upstream kinase MEK, completely abolishes the inducing effects of GW707 on LDLR promoter activity, LDLR mRNA expression, and DiI-LDL uptake in HepG2 cells; b) treating HepG2 cells with GW707 induces a dose-dependent conversion of SREBP-2 from the 125 kDa precursor form to the 68 kDa activated form and U0126 does not inhibit this cleavage process, but U0126 significantly reduces the total amount of SREBP-2 protein in GW707-treated cells without affecting the expression levels of other proteins involving in SREBP processing; and c) inhibition of ERK signaling pathway has no effects on the promoter activity or mRNA expression of SREBP-2. Collectively, these new findings establish an important role of ERK signaling pathway in SCAP ligand-induced transcription of LDLR and imply that the protein synthesis or turnover rate of SREBP-2 may be regulated by ERK.
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PMID:Blockage of the ERK signaling pathway abrogates the SCAP ligand-induced transcriptional activation of the LDL receptor gene in HepG2 cells. 1621 Dec 44

Growth hormone (GH) plays an important role in growth and metabolism by signaling via at least three major pathways, including STATs, ERK1/2, and phosphatidylinositol 3-kinase/Akt. Physiological concentrations of insulin promote growth probably by modulating liver GH receptor (GHR) levels in vivo, but the possible effects of insulin on GH-induced post-GHR signaling have yet to be studied. We hypothesized that short-term insulin, similar to the fluctuations that occur following feeding, affects GH-induced post-GHR signaling. Our present studies suggest that, in rat H4IIE hepatoma cells, insulin (4 h or less) selectively enhanced GH-induced phosphorylation of MEK1/2 and ERK1/2, but not GH-induced activation of STAT5 and Akt. Although insulin pretreatment altered GH-induced formation of Shc.Grb2.SOS complex, it did not significantly affect GH-induced activation of other signaling intermediates upstream of MEK/ERK, including JAK2, Ras, and Raf-1. Immunofluorescent staining indicated that insulin pretreatment facilitated GH-induced cell membrane translocation of MEK1/2. Insulin pretreatment also increased the amount of MEK association with its scaffolding protein, KSR. In summary, short-term insulin treatment of cultured, liver-derived cells selectively sensitized GH-induced MEK/ERK phosphorylation independent of JAK2, Ras, and Raf-1, but likely resulted from increased cell membrane translocation of MEK1/2. These findings suggest that insulin may be necessary for sensitization of cells to GH-induced ERK1/2 activation and provides a potential cellular mechanism by which insulin promotes growth.
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PMID:Insulin enhances growth hormone induction of the MEK/ERK signaling pathway. 1627 59

Alcohol abuse reduces response rates to IFN therapy in patients with chronic hepatitis C. To model the molecular mechanisms behind this phenotype, we characterized the effects of ethanol on Jak-Stat and MAPK pathways in Huh7 human hepatoma cells, in HCV replicon cell lines, and in primary human hepatocytes. High physiological concentrations of acute ethanol activated the Jak-Stat and p38 MAPK pathways and inhibited HCV replication in several independent replicon cell lines. Moreover, acute ethanol induced Stat1 serine phosphorylation, which was partially mediated by the p38 MAPK pathway. In contrast, when combined with exogenously applied IFN-alpha, ethanol inhibited the antiviral actions of IFN against HCV replication, involving inhibition of IFN-induced Stat1 tyrosine phosphorylation. These effects of alcohol occurred independently of i) alcohol metabolism via ADH and CYP2E1, and ii) cytotoxic or cytostatic effects of ethanol. In this model system, ethanol directly perturbs the Jak-Stat pathway, and HCV replication. Infection with Hepatitis C virus is a significant cause of morbidity and mortality throughout the world. With a propensity to progress to chronic infection, approximately 70% of patients with chronic viremia develop histological evidence of chronic liver diseases including chronic hepatitis, cirrhosis, and hepatocellular carcinoma. The situation is even more dire for patients who abuse ethanol, where the risk of developing end stage liver disease is significantly higher as compared to HCV patients who do not drink 12.Recombinant interferon alpha (IFN-alpha) therapy produces sustained responses (ie clearance of viremia) in 8-12% of patients with chronic hepatitis C 3. Significant improvements in response rates can be achieved with IFN plus ribavirin combination 456 and pegylated IFN plus ribavirin 78 therapies. However, over 50% of chronically infected patients still do not clear viremia. Moreover, HCV-infected patients who abuse alcohol have extremely low response rates to IFN therapy 9, but the mechanisms involved have not been clarified.MAPKs play essential roles in regulation of differentiation, cell growth, and responses to cytokines, chemokines and stress. The core element in MAPK signaling consists of a module of 3 kinases, named MKKK, MKK, and MAPK, which sequentially phosphorylate each other 10. Currently, four MAPK modules have been characterized in mammalian cells: Extracellular Regulated Kinases (ERK1 and 2), Stress activated/c-Jun N terminal kinase (SAPK/JNK), p38 MAP kinases, and ERK5 11. Interestingly, ethanol modulates MAPKs 12. However, information on how ethanol affects MAPKs in the context of innate antiviral pathways such as the Jak-Stat pathway in human cells is extremely limited. When IFN-alpha binds its receptor, two receptor associated tyrosine kinases, Tyk2 and Jak1 become activated by phosphorylation, and phosphorylate Stat1 and Stat2 on conserved tyrosine residues 13. Stat1 and Stat2 combine with the IRF-9 protein to form the transcription factor interferon stimulated gene factor 3 (ISGF-3), which binds to the interferon stimulated response element (ISRE), and induces transcription of IFN-alpha-induced genes (ISG). The ISGs mediate the antiviral effects of IFN. The transcriptional activities of Stats 1, 3, 4, 5a, and 5b are also regulated by serine phosphorylation 14. Phosphorylation of Stat1 on a conserved serine amino acid at position 727 (S727), results in maximal transcriptional activity of the ISGF-3 transcription factor complex 15. Although cross-talk between p38 MAPK and the Jak-Stat pathway is essential for IFN-induced ISRE transcription, p38 does not participate in IFN induction of Stat1 serine phosphorylation 1416171819. However, cellular stress responses induced by stimuli such as ultraviolet light do induce p38 MAPK mediated Stat1 S727 phosphorylation 18. In the current report, we postulated that alcohol and HCV proteins modulate MAPK and Jak-Stat pathways in human liver cells. To begin to address these issues, we characterized the interaction of acute ethanol on Jak-Stat and MAPK pathways in Huh7 cells, HCV replicon cells lines, and primary human hepatocytes.
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PMID:Effect of ethanol on innate antiviral pathways and HCV replication in human liver cells. 1632 17

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