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)

Multiple elements in the upstream region of the GAPDH gene play a role in mediating the acute and chronic effect of insulin on GAPDH gene expression. The complexity of this regulation provides many layers of control. In differentiated tissues, the transcriptional response to insulin results from the additive effects of g/TRE, IRE-A and IRE-B. The gTRE may interact with newly synthesized c-fos/c-jun heterodimer to activate GAPDH gene transcription. Studies are underway to determine whether protein synthesis inhibitors affect the regulation of GAPDH. Because there are several elements that mediate the effect, it will be difficult to determine the significance of these findings until each cis-acting factor and its binding protein can be studied in isolation. IRE-A and IRE-B act together to promote a 5- to 8-fold insulin effect on HGAPDH-CAT in H35 hepatoma cells and a 3-fold effect in 3T3 adipocytes. We have succeeded in detecting an insulin-sensitive DNA-binding protein referred to as IREA-BP with an element -480 to -435. Insulin treatment of differentiated 3T3 adipocytes for 1 hr results in a 4-fold increase in the amount of this binding protein, as estimated by the amount of 32P-labelled oligonucleotide retarded on non-denaturing PAGE (11). The effect of insulin on IRP-B is comparable. Furthermore, IREA-BP is induced during the process of fasting and refeeding rats, an important in vivo correlate with our tissue culture models (11). These observations imply that the binding proteins IREA-BP and IRP-B are essential components in the signal transduction pathway of insulin action on GAPDH gene expression in metabolically active tissues such as fat and liver. Differentiation-dependence and tissue-specificity are achieved through multiple regulatory elements and involve pre- and post-translational regulation of multiple transcription factors. IREA-BP is present in preadipocytes but activity in highly induced upon differentiation of preadipocytes to adipocytes. The IRE-B (-408 to -269) DNA binding protein is not detected in 3T3 preadipocytes. A gC/EBP like-protein takes part in the formation of this complex which may explain the inductive effect of differentiation on binding. Finally, footprint and cotransfection studies indicate that the differentiation-dependent protein C/EBP also regulates GAPDH gene transcription through a motif located within one hundred nucleotides of the promoter. We have begun to clone the IRE-A and IRE-B DNA binding proteins. An IRE-A binding protein that footprints the 3' domain of the IRE-A has been cloned.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Multiple insulin-responsive elements regulate transcription of the GAPDH gene. 138 8

Regulation of expression of the genes for the low density lipoprotein receptor (LDLR) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) is of central importance in the control of cholesterol metabolism and thus in influencing the concentration of low density lipoprotein in the plasma. This can be studied by investigating the effects of factors (hormones, drugs, etc.) on the levels of mRNA for these genes. An RNase protection assay is reported for measurement of the levels of mRNA for the LDLR and HMGR. Several probes have been developed for these genes, together with probes for the "housekeeping" genes, beta-actin and glyceraldehyde-3-phosphate dehydrogenase. Various conditions in the assay have been examined and optimised, e.g. conditions for solution hybridization and RNase digestion and the use of "sense" RNA standards. The assay allows accurate measurement of approximately 2 x 10(7) copies of LDLR and HMGR mRNAs, which is equivalent to the number of copies present in approximately 1 x 10(6) human dermal fibroblasts and approximately 5 x 10(5) Hep G2 liver hepatoma cells cultured in 10% fetal calf serum. The average number of copies of mRNA per cell was estimated in fibroblasts and Hep G2 cells under various conditions of regulation of the LDLR and revealed the following: [table: see text] Under the chosen conditions 10 copies per cell was the detection limit for the assay. The effect of these treatments on the number of copies of mRNA per cell for beta-actin and glyceraldehyde-3-phosphate dehydrogenase was also determined.
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PMID:A sensitive RNase protection assay for the quantitation of the mRNAs for the LDL receptor and HMG-CoA reductase in human total RNA. Effects of treatments on cells in culture designed to up- and down-regulate expression of the LDL receptor. 182 10

Glyceraldehyde-3-phosphate dehydrogenase [GAPDH; D-glyceraldehyde-3-phosphate:NAD+ oxidoreductase (phosphorylating), EC 1.2.1.12] mRNA levels are induced by physiologic concentrations of insulin in cultured 3T3-F442A adipocyte and H35 hepatoma cell lines. To examine the mechanism by which insulin regulates GAPDH mRNA levels in these two insulin-sensitive tissues, we have isolated a functional human GAPDH gene. When stably transfected and expressed in 3T3-F442A preadipocytes and H35 hepatoma cells, the intact human GAPDH gene is induced 10-fold by insulin in 3T3-F442A adipocytes and 3-fold by insulin in H35 hepatoma lines, which is similar to the induction obtained with the endogenous gene. A human GAPDH-chloramphenicol acetyltransferase construct, containing sequences -487 to +20 of the human gene fused to the chloramphenicol acetyltransferase gene, is regulated by insulin in stably transfected 3T3 adipocytes and stably or transiently transfected H35 hepatoma cell lines, whereas the Rous sarcoma virus-chloramphenicol acetyltransferase fusion protein is not. Thus, the inductive effect of insulin on human GAPDH gene expression is mediated through cis-acting sequences located between -487 and +20 of the human GAPDH gene.
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PMID:Insulin stimulates glyceraldehyde-3-phosphate dehydrogenase gene expression through cis-acting DNA sequences. 283 30

A recombinant M13 clone (O42) containing a 65 b.p. cDNA fragment from human fetal liver mRNA coding for glyceraldehyde-3-phosphate dehydrogenase has been identified and it has been used to isolate from a full-length human adult liver cDNA library a recombinant clone, pG1, which has been subcloned in M13 phage and completely sequenced with the chain terminator method. Besides the coding region of 1008 b.p., the cDNA sequence includes 60 nucleotides at the 5'-end and 204 nucleotides at the 3'-end up to the polyA tail. Hybridization of pG1 to human liver total RNA shows only one band about the size of pG1 cDNA. A much stronger hybridization signal was observed using RNA derived from human hepatocarcinoma and kidney carcinoma cell lines. Sequence homology between clone 042 and the homologous region of clone pG1 is 86%. On the other hand, homology among the translated sequences and the known human muscle protein sequence ranges between 77 and 90%; these data demonstrate the existence of more than one gene coding for G3PD. Southern blot of human DNA, digested with several restriction enzymes, also indicate that several homologous sequences are present in the human genome.
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PMID:The complete sequence of a full length cDNA for human liver glyceraldehyde-3-phosphate dehydrogenase: evidence for multiple mRNA species. 609 21

Oral vanadate administration has been demonstrated to normalize blood glucose levels in ob/ob and db/db mice and streptozotocin (STZ) diabetic rats. The exact mechanism of this vanadate effect is uncertain, since there are no consistent effects on the insulin receptor tyrosine kinase activity or phosphotyrosine phosphatase activity. We have therefore studied the postreceptor actions of vanadate, focusing our attention on the steady-state levels of mRNA of enzymes involved in carbohydrate metabolism. When compared with their lean (ob/+) controls, the livers of ob/ob mice exhibited an approximately 90% reduction in the levels of phosphoenolpyruvate carboxykinase (PEPCK) mRNA and twofold to fivefold higher levels of the mRNAs for glyceraldehyde-3-phosphate dehydrogenase (GAPDH), the "liver beta-cell" glucose transporter (GLUT2), and the proto-oncogene c-myc. Administration of sodium vanadate (0.25 mg/mL) in the drinking water of ob/ob mice over a 45-day period resulted in a near normalization of blood glucose and increased PEPCK mRNA levels more than ninefold. Starvation of the ob/ob mice for 24 to 48 hours also increased PEPCK mRNA levels by fourfold to 15-fold. Vanadate treatment did not alter mRNA levels of any other proteins studied and had no effect on PEPCK mRNA in ob/+ mice. However, 1 to 100 mumol/L vanadate produced a concentration-dependent increase in PEPCK mRNA levels in an H35 hepatoma cell line, an effect opposite to the suppression of PEPCK mRNA produced by insulin. In summary, hyperglycemia in the ob/ob mouse is characterized by decreased expression of PEPCK and increased expression of GAPDH mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Vanadate normalizes hyperglycemia and phosphoenolpyruvate carboxykinase mRNA levels in ob/ob mice. 796 88

The gene responsible for transcribing glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is commonly used as a reporter gene to estimate the amount of RNA present in Northern analyses. However, recent data suggest that GAPDH gene expression may vary with the extent of cell proliferation and differentiation. 28S-ribosomal RNA (28S-rRNA) has also been employed to normalize Northern blots prepared with total RNA. In the present study, we compared the expression of GAPDH messenger RNA (mRNA) with 28S-rRNA by Northern blot analyses in human hepatocellular carcinoma tissues (HCC) and adjacent non-HCC tissues from eight patients with chronic viral hepatitis-induced cirrhosis and normal liver tissue from eight healthy control subjects. The results of the study revealed that GAPDH mRNA levels in HCC were significantly higher (14X-16x) than those in adjacent non-HCC and normal liver tissues. Conversely, 28S-rRNA levels did not vary among HCC, adjacent non-HCC, and normal liver tissues. We also demonstrated that the 28S-RNA signal was proportional to the amount of RNA loaded. These findings indicate that 28S-rRNA, rather than GAPDH mRNA, should be used as RNA loading controls for Northern blot analyses involving HCC and nontumor tissues. The findings also raise the possibility that GAPDH mRNA gene expression might serve as a diagnostic indicator for human HCC.
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PMID:Comparison of glyceraldehyde-3-phosphate dehydrogenase and 28s-ribosomal RNA gene expression in human hepatocellular carcinoma. 930 19

Beta-actin, cyclophilin and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) are all constantly expressed proteins that regulate cellular structures and endogenous cytoarchitectural functions. In this study, we used an in vivo N1S1 rat hepatoma model to examine changes in the expression levels of these housekeeping genes in normal and tumor liver samples. The beta-actin, cyclophilin and GAPDH genes were all up-regulated in tumor groups as compared to the controls. Our results suggest that up-regulation of beta-actin, cyclophilin and GAPDH genes may be essential for oncogenesis in hepatoma.
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PMID:Up-regulation of beta-actin, cyclophilin and GAPDH in N1S1 rat hepatoma. 946 81

Reference two-dimensional (2-D) gels are presented for human breast ductal carcinoma and histologically normal tissue. Whole biopsy fragments were analyzed, including epithelial and nonepithelial components. Thirty-five spots have been assigned by gel matching to the human liver SWISS-2DPAGE reference map and/or to the human primary keratinocyte IPG map from the Danish Center for Human Genome. N-terminal microsequencing was applied to confirm randomly chosen matching assignments and to identify six new spots. Protein expression profiles in ductal carcinoma and in normal breast tissue appeared to be similar, except for a pattern consisting of 32 spots, which were highly expressed in all carcinoma specimens, and less intense and occasionally undetectable in normal tissue. This difference was statistically significant. Assignment has been obtained for several spots, namely GRP94, GRP78, GRP75, mitochondrial HSP60, calreticulin, protein disulfide isomerase, peptidyl-prolyl cis-trans isomerase, collagen-binding protein 2, fructose bisphosphate aldolase, glyceraldehyde-3-phosphate dehydrogenase, thioredoxin, cytochrome c oxidase VA subunit, tubulin beta isoform and macrophage migration inhibitory factor (MIF). The cancer- and tissue-specificity of the described pattern was assessed by matching to the Swiss-2DPAGE human liver, hepatoma, lymphoma, erythroleukemia reference maps. The pattern of 32 spots was found to be indicative of epithelial neoplasia.
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PMID:Protein expression profiles in human breast ductal carcinoma and histologically normal tissue. 950 17

The NPLC-KC human hepatoma cell line expresses corticotropin-releasing factor (CRF) and it has been demonstrated that CRF secretion and synthesis in this cell line increases in response to activators of the protein kinase A (PKA) and C (PKC) pathways as well as interleukin-1 (IL1). CRF expression with all three agents can be inhibited with the synthetic steroid-dexamethasone (DEX). In this report, we have examined the effect of IL1 (beta form) in the presence and absence of DEX on CRF mRNA (mRNA) expression as well as the expression of human glucocorticoid receptor (GR) mRNA and the mRNA of the proto-oncogenes (c-jun and c-fos) that have been implicated in CRF regulation. NPLC-KC cells were incubated with picomolar concentrations of IL1. Following this total RNA was extracted from the cells and Northern Blots were probed with 32P-labelled human DNA probes for the CRF, GR, c-jun and c-fos genes. Levels of mRNA expression were measured using a PhosphoImager and were normalized to mRNA levels of control probe glyceraldehyde-3-phosphate dehydrogenase (GAPD). CRF mRNA was significantly increased with IL1 treatment in a time and concentration dependent manner. CRF mRNA expression increased with increasing concentrations of IL1 over the range of 1-100 pM; expression of CRF mRNA also peaked after 24 h of 100 pM IL1 treatment and reached a level of expression approximately seven times higher than control. This pattern of expression was significantly inhibited in the presence of 100 nM DEX. Levels of the GR, c-fos and c-jun mRNAs were also significantly increased in the presence of IL1 and inhibited when DEX was co-incubated with IL1. The results reveal that IL1 stimulation of CRF mRNA expression by IL1 in the NPLC-KC cell line is accompanied by activation of GR mRNA as well as the mRNA of the immediate early genes--c-fos and c-jun. The results also demonstrate that this cell line may serve as a model system for the molecular mechanisms by which IL1 regulates CRF in central nervous system (CNS) neurons.
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PMID:Interleukin-1 regulation of corticotropin-releasing factor (CRF), glucocorticoid receptor, c-fos and c-jun messenger RNA in the NPLC-KC cell line. 960 26

In order to characterize the hepatitis B virus (HBV) hepatocellular receptor, several proteins have previously been identified in HepG2 hepatoma cells and in primary cultured normal human hepatocytes (PCHs) that reacted with an anti-idiotypic antibody against a preS1(21-47)-specific MAb (F35.25). Here, we report the identification of one of these preS1-binding proteins, a 35 kDa protein (preS1-BP35), as glyceraldehyde-3-phosphate dehydrogenase (GAPD). GAPD is well-known as a key enzyme involved in glycolysis and gluconeogenesis. Nevertheless, GAPD has also been shown to have many other functions such as protein kinase activity (GAPD-PK). HBV core particles derived from infected hepatocytes possess an associated kinase activity that phosphorylates HBcAg, and the nucleocapsid may acquire sequential functions through selective phosphorylation. Therefore, we have investigated the potential role of GAPD-PK in HBV replication. In this study, we found that the endogenous PK associated with human liver-derived HBV core particles (hL-HBcAg) and GAPD-PK were sensitive to the same types of inhibitors. Interestingly, capsid protein phosphorylation decreased in a concentration-dependent manner (at concentrations of 5-30 mM) in the presence of specific inhibitors for GAPD-PK (NADH and GAP). Furthermore, we demonstrated in vitro that GAPD-PK could phosphorylate the major core protein P22 in hL-HBcAg particles. The data suggest that GAPD is an additional cellular kinase which might interfere in the life-cycle of HBV.
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PMID:Phosphorylation of the hepatitis B virus core protein by glyceraldehyde-3-phosphate dehydrogenase protein kinase activity. 968 Jan 29


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