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)

Insulin inhibits the expression of multiple genes in the liver containing an insulin response sequence (IRS) (CAAAA(C/T)AA), and we have reported that protein kinase B (PKB) mediates this effect of insulin. Genetic studies in Caenorhabditis elegans indicate that daf-16, a forkhead/winged-helix transcription factor, is a major target of the insulin receptor-PKB signaling pathway. FKHR, a human homologue of daf-16, contains three PKB sites and is expressed in the liver. Reporter gene studies in HepG2 hepatoma cells show that FKHR stimulates insulin-like growth factor-binding protein-1 promoter activity through an IRS, and introduction of IRSs confers this effect on a heterologous promoter. Insulin disrupts IRS-dependent transactivation by FKHR, and phosphorylation of Ser-256 by PKB is necessary and sufficient to mediate this effect. Antisense studies indicate that FKHR contributes to basal promoter function and is required to mediate effects of insulin and PKB on promoter activity via an IRS. To our knowledge, these results provide the first report that FKHR stimulates promoter activity through an IRS and that phosphorylation of FKHR by PKB mediates effects of insulin on gene expression. Signaling to FKHR-related forkhead proteins via PKB may provide an evolutionarily conserved mechanism by which insulin and related factors regulate gene expression.
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PMID:Phosphorylation of serine 256 by protein kinase B disrupts transactivation by FKHR and mediates effects of insulin on insulin-like growth factor-binding protein-1 promoter activity through a conserved insulin response sequence. 1035 76

The insulin response element (IRE) in the IGFBP-1 promoter, and in other gene promoters, contains a T(A/G)TTT motif essential for insulin inhibition of transcription. Studies presented here test whether FKHR may be the transcription factor that confers insulin inhibition through this IRE motif. Immunoblots using antiserum to the synthetic peptide FKHR413-430, RNase protection, and Northerns blots show that FKHR is expressed in HEP G2 human hepatoma cells. Southwestern blots, electromobility shift assays, and DNase I protection assays show that Escherichia coli-expressed GST-FKHR binds specifically to IREs from the IGFBP-1, PEPCK and TAT genes; however, unlike HNF3beta, another protein proposed to be the insulin regulated factor, GST-FKHR does not bind the insulin unresponsive G/C-A/C mutation of the IGFBP-1 IRE. When HEP G2 cells were cotransfected with FKHR expression vectors and with IGFBP-1 promoter plasmids containing either native or mutant IREs, FKHR expression induced a 5-fold increase in activity of the native IGFBP-1 promoter but no increase in activity of promoter constructs containing insulin unresponsive IRE mutants. These data suggest that FKHR, and/or a related family member, is the important T(G/A)TTT binding protein that confers the inhibitory effect of insulin on gene transcription.
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PMID:FKHR binds the insulin response element in the insulin-like growth factor binding protein-1 promoter. 1038 7

An unusual case of a massive liver tumour composed of rhabdomyosarcoma with a small focus of hepatocellular carcinoma in a 52-year-old man is presented. He had hepatitis B virus (HBV) surface antigen in his serum. Macroscopically, a large tumour with satellite nodules occupied the right lobe of the cirrhotic liver. Microscopically, the tumours were composed of small and short spindle-shaped undifferentiated cells, mixed with desmin-positive round rhabdomyoblasts and elongated striated muscle cells, strongly suggestive of rhabdomyosarcoma of the liver. Elevated levels of alpha-fetoprotein in the serum led us to examine the liver tumour closely in multiple sections, which disclosed a hepatocellular carcinoma component measuring 2 cm in diameter within the massive tumour. Immunohistochemically, the hepatocellular carcinoma cells were alpha-fetoprotein positive. There was neither a tumour capsule, nor distinct demarcation, and cytokeratin-positive clusters of undifferentiated cells were intermingled with the hepatocellular carcinoma and rhabdomyosarcoma at the border. The invading tumour outside the liver and metastatic tumours were pure rhabdomyosarcomas. It is suggested that the present case should be diagnosed as rhabdomyosarcoma transformed from hepatocellular carcinoma.
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PMID:Sarcomatoid hepatocellular-carcinoma showing rhabdomyoblastic differentiation in the adult cirrhotic liver. 1039 85

Because overexpression of the glucose-6-phosphatase catalytic subunit (G-6-Pase) in both type 1 and type 2 diabetes may contribute to the characteristic increased rate of hepatic glucose production, we have investigated whether the insulin response unit (IRU) identified in the mouse G-6-Pase promoter is conserved in the human promoter. A series of human G-6-Pase-chloramphenicol acetyltransferase (CAT) fusion genes was transiently transfected into human HepG2 hepatoma cells, and the effect of insulin on basal CAT expression was analyzed. The results suggest that the IRU identified in the mouse promoter is conserved in the human promoter, but that an upstream multimerized insulin response sequence (IRS) motif that is only found in the human promoter appears to be functionally inactive. The G-6-Pase IRU comprises two distinct promoter regions, designated A and B. Region B contains an IRS, whereas region A acts as an accessory element to enhance the effect of insulin, mediated through region B, on basal G-6-Pase gene transcription. We have previously shown that the accessory factor binding region A is hepatocyte nuclear factor-1, and we show here that the forkhead protein FKHR is a candidate for the insulin-responsive transcription factor binding region B.
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PMID:Conservation of an insulin response unit between mouse and human glucose-6-phosphatase catalytic subunit gene promoters: transcription factor FKHR binds the insulin response sequence. 1048 Jun 25

Primary hepatic tumours in children represent an heterogeneous group of neoplasms. Malignant tumours are more common (60% of primary liver tumours), but account for only 1.2-5% of all paediatric neoplasms. There are two main types of malignant tumour, those of epithelial origin, hepatoblastoma (HB) and hepatocellular carcinoma (HCC), and the rarer mesenchymal tumours, e.g. rhabdomyosarcoma and undifferentiated sarcoma, (Weinberg AG, Finegold, MJ. Primary hepatic tumours of childhood. Hum Pathol 1983, 14, 512-532). Vascular tumours e.g. haemangioendotheliomas are the most common of the benign tumours followed by mesenchymal hamartoma and the rare hepatic adenoma and focal nodular hyperplasia. This article will concentrate on the malignant epithelial tumours.
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PMID:Liver tumours. 1053 78

The forkhead rhabdomyosarcoma transcription factor (FKHR) is a promising candidate to be the transcription factor that binds to the insulin response element of the insulin-like growth factor-binding protein-1 (IGFBP-1) promoter and mediates insulin inhibition of IGFBP-1 promoter activity. Cotransfection of mouse FKHR increased IGFBP-1 promoter activity 2-3-fold in H4IIE rat hepatoma cells; insulin inhibited FKHR-stimulated promoter activity approximately 70%. A C-terminal fragment of mouse FKHR (residues 208-652) that contains the transcription activation domain fused to a Gal4 DNA binding domain potently stimulated Gal4 promoter activity. Insulin inhibited FKHR fragment-stimulated promoter activity by approximately 70%. Inhibition was abolished by coincubation with the phosphatidylinositol-3 kinase inhibitor, LY294002. The FKHR 208-652 fragment contains two consensus sites for phosphorylation by protein kinase B (PKB)/Akt, Ser-253 and Ser-316. Neither site is required for insulin inhibition of promoter activity stimulated by the FKHR fragment, and overexpression of Akt does not inhibit FKHR fragment-stimulated Gal4 promoter activity. These results suggest that insulin- and phosphatidylinositol-3 kinase-dependent phosphorylation of another site in the fragment by a kinase different from PKB/Akt inhibits transcription activation by the fragment. Phosphorylation of this site also may be involved in insulin inhibition of transcription activation by full-length FKHR, but only after phosphorylation of Ser-253 by PKB/Akt.
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PMID:Insulin inhibits the activation of transcription by a C-terminal fragment of the forkhead transcription factor FKHR. A mechanism for insulin inhibition of insulin-like growth factor-binding protein-1 transcription. 1070 99

Glucose-6-phosphatase plays an important role in the regulation of hepatic glucose production, and insulin suppresses glucose-6-phosphatase gene expression. Recent studies indicate that protein kinase B and Forkhead proteins contribute to insulin-regulated gene expression in the liver. Here, we examined the role of protein kinase B and Forkhead proteins in mediating effects of insulin on glucose-6-phosphatase promoter activity. Transient transfection studies with reporter gene constructs demonstrate that insulin suppresses both basal and dexamethasone/cAMP-induced activity of the glucose-6-phosphatase promoter in H4IIE hepatoma cells. Both effects are partially mimicked by coexpression of protein kinase Balpha. Coexpression of the Forkhead transcription factor FKHR stimulates the glucose-6-phosphatase promoter activity via interaction with an insulin response unit (IRU), and this activation is suppressed by protein kinase B. Coexpression of a mutated form of FKHR that cannot be phosphorylated by protein kinase B abolishes the regulation of the glucose-6-phosphatase promoter by protein kinase B and disrupts the ability of insulin to regulate the glucose-6-phosphatase promoter via the IRU. Mutation of the insulin response unit of the glucose-6-phosphatase promoter also prevents the regulation of promoter activity by FKHR and protein kinase B but only partially impairs the ability of insulin to suppress both basal and dexamethasone/cAMP-stimulated promoter function. Taken together, these results indicate that signaling by protein kinase B to Forkhead proteins can account for the ability of insulin to regulate glucose-6-phosphatase promoter activity via the IRU and that other mechanisms that are independent of the IRU, protein kinase B, and Forkhead proteins also are important in mediating effects of in insulin on glucose-6-phosphatase gene expression.
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PMID:Regulation of glucose-6-phosphatase gene expression by protein kinase Balpha and the forkhead transcription factor FKHR. Evidence for insulin response unit-dependent and -independent effects of insulin on promoter activity. 1096 Apr 73

A major action of insulin is to regulate the transcription rate of specific genes. The expression of these genes is dramatically altered in type 2 diabetes. For example, the expression of two hepatic genes, glucose-6-phosphatase and PEPCK, is normally inhibited by insulin, but in type 2 diabetes, their expression is insensitive to insulin. An agent that mimics the effect of insulin on the expression of these genes would reduce gluconeogenesis and hepatic glucose output, even in the presence of insulin resistance. The repressive actions of insulin on these genes are dependent on phosphatidylinositol (PI) 3-kinase. However, the molecules that lie between this lipid kinase and the two gene promoters are unknown. Glycogen synthase kinase-3 (GSK-3) is inhibited following activation of PI 3-kinase and protein kinase B. In hepatoma cells, we find that selectively reducing GSK-3 activity strongly reduces the expression of both gluconeogenic genes. The effect is at the level of transcription and is observed with induced or basal gene expression. In addition, GSK-3 inhibition does not result in the subsequent activation of protein kinase B or inhibition of the transcription factor FKHR, which are candidate regulatory molecules for these promoters. Thus, GSK-3 activity is required for basal activity of each promoter. Inhibitors of GSK-3 should therefore reduce hepatic glucose output, as well as increase the synthesis of glycogen from L-glucose. These findings indicate that GSK-3 inhibitors may have greater therapeutic potential for lowering blood glucose levels and treating type 2 diabetes than previously realized.
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PMID:Inhibition of GSK-3 selectively reduces glucose-6-phosphatase and phosphatase and phosphoenolypyruvate carboxykinase gene expression. 1133 36

Glutamate cysteine ligase (GCL; also referred to as gamma-glutamylcysteine synthetase, GCS) catalyzes the rate-limiting step of glutathione synthesis. The GCL holoenzyme is composed of a catalytic (GCLC; also called GCS(h)) and a modifier (GCLM; also called GCS(l)) subunit, each encoded by a unique gene. Wild-type and mutant promoter/luciferase reporter transgenes containing the promoter region of each GCL subunit gene were transfected into A549 (lung carcinoma), HEK 293 (transformed embryonic kidney), HepG2 (hepatocellular carcinoma), and RD (skeletal muscle rhabdomyosarcoma) cells to examine potential cell-type related differences in transcriptional regulation. In A549, HepG2, and RD cells, maximal basal expression of the GCLC transgene required the full-length (-3802 bp) promoter. Maximal expression in HEK 293 cells was uniquely directed by cis-elements contained within the -2752 to -1286 bp fragment of the promoter. No differences in GLCM promoter function were detected among these 4 cell lines. GCL subunit induction in each cell line by pyrrolidine dithiocarbamate (PDTC), phenethyl isothiocyanate (PEITC), and beta-naphthoflavone (beta-NF) was examined by RNAse protection assays. Although both genes were similarly induced in HepG2 cells by beta-NF, PDTC, and PEITC, neither was induced by beta-NF in A549, HEK 293, and RD cells. PDTC and PEITC induced GCLM to a much greater extent than GCLC in HEK 293 cells and failed to induce GCLC in RD cells. Neither subunit was induced by any of the agents in A549 cells. These studies indicate that the GCL subunit genes are independently regulated and display cell-type specific differences in both basal and inducible expression.
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PMID:Cell-type specific differences in glutamate cysteine ligase transcriptional regulation demonstrate independent subunit control. 1135 35

The insulin responsive H4IIEC3 rat hepatoma cell line (H4 cells) was used in order to determine the role of the transcription factor FKHR in the regulation of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). Both PEPCK and G6Pase contain putative FKHR binding sites in their promoter sequence. Using a retroviral expression system, we stably overexpressed FKHR in H4-cells. FKHR was phosphorylated in a PI 3-kinase- and Akt-dependent manner, and was translocated from the nucleus to the cytoplasm in response to insulin. Furthermore, overexpression of FKHR markedly increased the expression of the catalytic subunit of G6Pase (basal about 2.5-fold, dexamethasone/cAMP stimulated about fivefold, respectively). In contrast, both basal and dexamethasone/cAMP-induced levels of PEPCK mRNA were unaffected by FKHR-overexpression. These data suggest a specific function for FKHR in the regulation of hepatic gluconeogenesis at the level of G6Pase, but not PEPCK gene expression.
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PMID:Differential regulation of endogenous glucose-6-phosphatase and phosphoenolpyruvate carboxykinase gene expression by the forkhead transcription factor FKHR in H4IIE-hepatoma cells. 1146 35


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