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)

The gene for glucose-6-phosphatase (G6Pase), the key enzyme in glucose homeostasis, is expressed in a tissue-specific manner in the liver and kidney. To understand the molecular mechanisms regulating liver-specific expression of the G6Pase gene, we characterized G6Pase promoter activity by transient expression assays. The G6Pase promoter is active in HepG2 hepatoma cells, but inactive in JEG3 choriocarcinoma or 3T3 cells. DNA elements essential for optimal and liver-specific expression of the G6Pase gene were contained within nucleotides -234 to +3. Deletion analysis revealed that the G6Pase promoter contained three activation elements (AEs) at nucleotides -234 to -212 (AE-I), -146 to -125 (AE-II), and -124 to -71 (AE-III). AE-I contains binding sites for hepatocyte nuclear factors (HNF) 1 and 4. Electromobility shift and cotransfection assays demonstrated that HNF1alpha, but not HNF4, bound to its cognate site and transactivated G6Pase gene expression. The G6Pase promoter contained five HNF3 motifs, 1 (-180/-174), 2 (-139/-133), 3 (-91/-85), 4 (-81/-75), and 5 (-72/-66), and all five sites bound HNF3gamma with high affinity. Transient expression and cotransfection assays showed that HNF3 site 1 is not required for basal promoter activity, but is essential for HNF3gamma-activated transcription from the G6Pase promoter. We further showed that HNF3 sites 3, 4, and 5 were essential for basal G6Pase promoter activity and transactivation by HNF3gamma. AE-II contains, in addition to a HNF3 motif, a cAMP-response element (CRE) and a C/EBP half-site. The G6Pase(-146/-116) DNA containing AE-II formed multiple protein-DNA complexes with HepG2 nuclear extracts, including HNF3gamma, CRE-binding protein (CREB), C/EBPalpha, and C/EBPbeta. We showed that AE-II mediated transcription activation of the G6Pase gene by cAMP.
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PMID:The role of HNF1alpha, HNF3gamma, and cyclic AMP in glucose-6-phosphatase gene activation. 936 82

Deficiency of glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, causes glycogen storage disease type 1a (GSD-1a), also know as von Gierke disease. Expression of the G6Pase gene is regulated by multiple hormones, including glucocorticoids. The synthetic glucocorticoid dexamethasone increased G6Pase mRNA abundance and gene transcription in H4-IIE hepatoma cells. Transient transfection assays demonstrated that the G6Pase promoter was active in H4-IIE cells only in the presence of dexamethasone. The minimal G6Pase promoter was contained within nucleotides -234/+3, which has two putative glucocorticoid response elements (GREs) at nucleotides -178/-164 (site 1) and -154/-140 (site 2). Electromobility shift and transient transfection assays showed that only GRE site 1 was required for glucocorticoid-activated transcription from the G6Pase promoter. Deletion analysis demonstrated that the DNA elements absolutely essential for glucocorticoid-stimulated transcription from the G6Pase promoter were contained within nucleotides -234/-212, encompassing binding motifs for hepatocyte nuclear factors (HNFs) 1 (-226/-212) and 4 (-231/-220). Electromobility shift and cotransfection assays showed that HNF1alpha bound to its cognate site and mediated transcription activation of the G6Pase gene by glucocorticoids.
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PMID:Hepatocyte nuclear factor 1alpha is an accessory factor required for activation of glucose-6-phosphatase gene transcription by glucocorticoids. 983 6

A 40-year-old man with glycogen storage disease type 1a (von Gierke disease, GSD1a) developed hepatocellular carcinoma (HCC). Cold single-strand conformation polymorphism (SSCP) with 12% glycerol identified the G727T mutation in the glucose-6-phosphatase (G6Pase) gene, which has been reported to be the most common mutation in Japanese GSD1a patients. This case report is the first documentation of HCC in a case with G727T mutation. Given the prevalence of HCC in GSD1a with various germline mutations, analysis is needed to confirm that the germline mutation in this case is really related to hepatocarcinogenesis. DNA analysis of the family pedigree of this case, revealed three individuals with GSD1a and seven heterozygous carriers of the G727T mutation. As the diagnosis of GSD1a in this family was made only after these three patients reached adulthood, DNA diagnosis may help early identification of GSD1a patients and prevention of the progression of the disease. This DNA-based diagnosis permits prenatal diagnosis in at-risk patients and may facilitate screening and counselling of patients clinically suspected of having this disease.
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PMID:Case report: Hepatocellular carcinoma in type 1a glycogen storage disease with identification of a glucose-6-phosphatase gene mutation in one family. 1038 64

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

Glucocorticoids stimulate gluconeogenesis by increasing the rate of transcription of genes that encode gluconeogenic enzymes such as phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase. Previous studies have shown that hepatic nuclear factor 3 (HNF3) is required as an accessory factor for several glucocorticoid-stimulated genes, including PEPCK. Here, we show that adenovirus-mediated expression of an HNF3beta protein with a deleted C-terminal transactivation domain (HNF3betaDeltaC) reduces the glucocorticoid-induced expression of the PEPCK and glucose-6-phosphatase genes in H4IIE hepatoma cells. Furthermore, expression of this truncated HNF3 protein results in a proportionate reduction of glucocorticoid-stimulated glucose production from lactate and pyruvate in these cells. The expression of HNF3betaDeltaN, in which the N-terminal transactivation domain is deleted, does not exhibit any of these effects. These results provide direct evidence that members of the HNF3 family are required for proper regulation of hepatic gluconeogenesis. Modulation of the function of the HNF3 family of proteins might be used to reduce the excessive hepatic production of glucose that is an important pathophysiologic feature of diabetes mellitus.
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PMID:The molecular physiology of hepatic nuclear factor 3 in the regulation of gluconeogenesis. 1079 60

Insulin regulates the rate of expression of many hepatic genes, including PEPCK, glucose-6-phosphatase (G6Pase), and glucose-6-phosphate dehydrogenase (G6PDHase). The expression of these genes is also abnormally regulated in type 2 diabetes. We demonstrate here that treatment of hepatoma cells with 5-aminoimidazole-4-carboxamide riboside (AICAR), an agent that activates AMP-activated protein kinase (AMPK), mimics the ability of insulin to repress PEPCK gene transcription. It also partially represses G6Pase gene transcription and yet has no effect on the expression of G6PDHase or the constitutively expressed genes cyclophilin or beta-actin. Several lines of evidence suggest that the insulin-mimetic effects of AICAR are mediated by activation of AMPK. Also, insulin does not activate AMPK in H4IIE cells, suggesting that this protein kinase does not link the insulin receptor to the PEPCK and G6Pase gene promoters. Instead, AMPK and insulin may lie on distinct pathways that converge at a point upstream of these 2 gene promoters. Investigation of the pathway by which AMPK acts may therefore give insight into the mechanism of action of insulin. Our results also suggest that activation of AMPK would inhibit hepatic gluconeogenesis in an insulin-independent manner and thus help to reverse the hyperglycemia associated with type 2 diabetes.
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PMID:5-aminoimidazole-4-carboxamide riboside mimics the effects of insulin on the expression of the 2 key gluconeogenic genes PEPCK and glucose-6-phosphatase. 1086 40

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

Reduced glucose-6-phosphatase, increased GGT activity and reduction of cytochrome P-450 content are considered to be markers of chemical hepatocarcinogenesis in rats. The significance of these changes were studied in certain human liver lesions; adenoma, focal nodular hyperplasia and hepatocellular carcinoma all developed in non-cirrhotic livers. Enzymes showed normal values in 4 out of 5 adenomas, in 2/13 FNH and in 4/18 HCC samples. The decreased cP-450 content in HCC proved to be the most consistent alteration (12/18). Only 3 HCC samples possessed changes off all enzymes. These data suggest that at least those enzymes which are used as markers in rat chemical hepatocarcinogenesis have little or no biological significance in human liver tumors, primarily due to the intertumoral heterogeneity of enzyme activity. Such heterogeneity was observed in the peritumoral "normal" liver tissue, too.
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PMID:Marker Enzymes of Rat Chemical Hepatocarcinogenesis in Human Liver Tumors. 1117 85

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

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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