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)

The role of protein synthesis in the control of phosphoenolpyruvate carboxykinase (PEPCK; 4.1.1.32) mRNA turnover was studied in FTO-2B rat hepatoma cells. A previous study demonstrated that incubation of these cells with cAMP prolongs the half-life of the otherwise short-lived PEPCK mRNA. The decay rate of PEPCK mRNA was also slowed in cells incubated with cycloheximide, but not in cells incubated with other translation inhibitors, such as puromycin or pactamycin, even though protein synthesis was inhibited 85-95% by these agents. No correlation was noted between the rate of L-[3H]valine incorporation into cellular proteins and PEPCK mRNA half-life, suggesting that protein synthesis per se is not required for breakdown of the mRNA. Exposure of cells to the translation initiation inhibitor pactamycin together with cycloheximide abolished the "slowing" effect of cycloheximide, and PEPCK mRNA decayed at the same rate as in cells incubated in the presence of pactamycin alone. In contrast, pactamycin did not reverse the effect of cAMP, and the mRNA decayed at the same slow rate in cells incubated in the presence of either (Bu)2cAMP alone or (Bu)2cAMP together with pactamycin. Since pactamycin promotes polysomes dissociation, these results suggest that cAMP enhances the stability of a polysome-free PEPCK mRNA. Furthermore, these results strongly indicate that neither the rapid decay of PEPCK mRNA nor the cAMP-mediated stabilization of the mRNA requires on-going protein synthesis.
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PMID:The role of protein synthesis in the decay of phosphoenolpyruvate carboxykinase messenger RNA. 133 75

Incubation of isolated hepatocytes from fasted rats with 20 mM LiCl for 1 h decreased glucose production from lactate, pyruvate, and alanine. In addition, phosphoenolpyruvate carboxykinase (PEPCK) gene expression in FTO-2B rat hepatoma cells was inhibited by treatment with LiCl. Lithium was also able to counteract the increased PEPCK mRNA levels caused by both Bt2cAMP and dexamethasone, in a concentration-dependent manner. A chimeric gene containing the PEPCK promoter (-550 to +73) linked to the amino-3-glycosyl phosphotransferase (neo) structural gene was transduced into FTO-2B cells using a Moloney murine leukemia virus-based retrovirus. In these infected cells, 20 mM LiCl decreased both the concentration of neo mRNA transcribed from the PEPCK-neo chimeric gene and mRNA from the endogenous PEPCK gene. Lithium also inhibited the stimulatory effect of Bt2cAMP and dexamethasone on both genes. The stability of neo mRNA was not altered by lithium, since in cells infected with retrovirus containing only the neo gene transcribed via the retroviral 5'-LTR and treated with 20 mM LiCl, no change in neo mRNA levels was observed. The intraperitoneal administration of LiCl to rats caused a decrease in hepatic PEPCK mRNA, indicating that lithium could also modify gene expression in vivo. The effects of lithium were not due to an increase in the concentration of insulin in the blood but were correlated with an increase in hepatic glycogen and fructose 2,6-bisphosphate levels. These results indicate that lithium ions, at concentrations normally used therapeutically for depression in humans, can inhibit glucose synthesis in the liver by a mechanism which can selectively modify the expression of hepatic phosphoenolpyruvate carboxykinase.
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PMID:Lithium inhibits hepatic gluconeogenesis and phosphoenolpyruvate carboxykinase gene expression. 137 Nov 8

We investigated the 5'-flanking region of the rat angiotensinogen gene to define the DNA elements conferring inducibility by glucocorticoids and estrogens. Two putative glucocorticoid-responsive elements (GREs) based on sequence comparison were identified. Here we report the functional importance of these sequences. We constructed several deletion mutants of the 5'-region in front of the bacterial reporter gene for chloramphenicol acetyltransferase (CAT). The angiotensinogen-CAT-reporter plasmids (pRagCAT) were transiently transfected into the rat hepatoma cells FTO 2B and Fe 33. All pRagCAT constructs in which the 5'-region contained at least one of the two GRE consensus sequences were stimulated by dexamethasone. On the other hand, deletion mutants containing no GRE sequences were not inducible with dexamethasone. In additional experiments, the transcriptional functions of the two putative GREs were assessed by cloning synthetic oligonucleotides encompassing the GRE sequences directly in front of the heterologous herpes simplex virus thymidine-kinase promoter. Our results showed that each synthetic GRE was capable of stimulating the heterologous TK promoter after administration of dexamethasone and that both GREs together act synergistically. We also investigated the transcriptional control of angiotensinogen by estrogen. Although no estrogen-responsive element consensus sequences were detectable by sequence comparison, we did identify sequences between -60 to -92 which conferred estrogen inducibility to the rat angiotensinogen gene. In this region, a so-called half-palindromic estrogen-responsive element is localized at nucleotides -87 to -91.
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PMID:Glucocorticoid- and estrogen-responsive elements in the 5'-flanking region of the rat angiotensinogen gene. 166 57

The hormonal control of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene expression was studied in the rat hepatoma cells, FTO-2B. In contrast to another hepatoma cell line (HTC), the enzyme in FTO-2B cells displays both kinase and bisphosphatase activities. As in rat liver, the mRNA in FTO-2B cells is 2.2-kilobases in length. However, the 5' region of the mRNA differs from the mRNA in the liver in that it contains sequences unique to 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase mRNA from skeletal muscle. These results suggest that the mRNA in FTO-2B cells may represent an additional alternative splicing product of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene. Exposure of FTO-2B cells to media containing either insulin (10(-7) M) or dexamethasone (10(-6) M) induced about a 10-fold increase in the level of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase mRNA within 6-10 h of hormone treatment. The concentrations of insulin or dexamethasone giving half-maximal stimulation were 10(-9) M and 2 x 10(-8) M, respectively, and dibutyryl cyclic AMP (5 x 10(-7) M) completely prevented the increase in enzyme mRNA induced by these hormones. Exposure of cells to glucose-free medium abolished the insulin-mediated enhancement in 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase mRNA, but not that induced by dexamethasone. No alteration in the degradation rate of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase mRNA was noted when cells were treated with insulin. Run-on transcription assays with isolated nuclei showed an increase in the relative transcription rate of the gene in cells treated with either insulin or dexamethasone. The time course of transcription activation preceded the increase in the level of the mRNA, indicating that the main mechanism for the induction of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase expression by insulin and dexamethasone is mediated by stimulation of gene transcription.
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PMID:Hormonal control of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene expression in rat hepatoma cells. 184 60

The inducibility of the mammalian O6-methylguanine-DNA methyltransferase (MGMT) gene encoding the MGMT protein (EC 2.1.1.63) responsible for removal of the procarcinogenic and promutagenic lesion O6-alkylguanine from DNA was examined by an analysis of transcription of the MGMT gene following exposure of repair-competent (Mex+) and repair-deficient (Mex-) cells to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). While human and rodent Mex- cells (CHO-9, V79, HeLa MR) showed no detectable MGMT mRNA despite the presence of the gene in their genome, the amount of it in several Mex+ lines (NIH 3T3, HeLa S3, HepG2) paralleled their MGMT activity. However, none of these cell lines showed an increase in the MGMT mRNA level after treatment with various concentrations of MNNG. In contrast, MNNG-treated rat hepatoma cells, H4IIE and FTO-2B, both Mex+, had three- to fivefold more MGMT mRNA than the corresponding untreated controls as measured 12 to 72 h after alkylation. N-Methyl-N-nitrosourea, methyl methanesulfonate, N-hydroxyethyl-N-chloroethylnitrosourea, UV light, and X rays caused a similar accumulation of MGMT mRNA in rat hepatoma cells. Studies with inhibitors of RNA and protein synthesis indicate that the induced increase in the amount of MGMT mRNA was due to enhanced transcription of the gene. Furthermore, they revealed the turnover of the MGMT mRNA to be relatively low (half-life, greater than 7 h). Mutagen-induced increase of transcription of MGMT mRNA in H4IIE cells was accompanied by elevation of MGMT repair activity and resulted in reduction of mutation frequency after a challenge dose of MNNG. Although induction of MGMT mRNA transcription has been observed in two rodent hepatoma cell lines so far, this appears to be the first demonstration of inducibility of a mammalian gene encoding a clearly define DNA repair function. The transcription activation of the MGMT gene protects cells from the mutagenic effects of methylating agents.
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PMID:Inducibility of the DNA repair gene encoding O6-methylguanine-DNA methyltransferase in mammalian cells by DNA-damaging treatments. 187 45

FTO-2B rat hepatoma cells acquired mouse VL30 retrotransposon(s) when infected with Moloney murine leukemia virus (MoMLV) recombinant retroviruses produced from psi 2 cells. The VL30 provirus was integrated into the rat genome, expressed at high levels, and its transcription induced 40-fold by dexamethasone, VL30 RNA was detected in hepatoma cells even without selection for the expression of the amino-3'-glycosyl phosphotransferase (neo) gene, which was co-transferred with a MoMLV retrovirus. However, the extent of transfer of the VL30 RNA was inversely related to the titer of the MoMLV recombinant retrovirus. The restriction map analysis of the transferred VL30 provirus was identical to the mouse VL30s of the NVL subfamily which is known to be a significant fraction of the transcriptionally active VL30 subset. Additionally, the regenerating liver from an adult rat, which was infected with a defective MoMLV-derived retrovirus, expressed VL30 RNA. These results indicate that great care should be given to the transfer of unwanted passengers, like VL30, present in retroviral packaging cell lines like the psi 2 cells, which are currently being used for gene therapy.
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PMID:Efficient packaging of a specific VL30 retroelement by psi 2 cells which produce MoMLV recombinant retroviruses. 196 95

The interaction of promoters contained in a Moloney murine leukemia virus (MoMLV)-based retroviral vector was studied after infection of FTO-2B rat hepatoma and NIH 3T3 mouse fibroblast cells. Segments of the phosphoenolpyruvate carboxykinase (PEPCK) promoter-regulatory region, which are known from previous studies to confer responsiveness to hormones, were linked to the structural genes for bovine growth hormone, amino-3'-glycosyl phosphotransferase (neo), and herpes-virus thymidine kinase and inserted into a MoMLV-based retroviral vector. In vectors in which PEPCK was the only internal promoter, it was the major site of gene transcription. This dominant effect was independent of the orientation of the PEPCK promoter relative to the 5' long terminal repeat of the provirus and was noted with as little as -174 base pairs of the 5'-flanking sequence. NIH 3T3 cells, which do not express the endogenous PEPCK gene, transcribed the transduced PEPCK-chimeric genes at the same high levels as was observed in hepatoma cells. When two promoters were present in the provirus, the expression of chimeric structural genes depended on the relative position and orientation of these genes as well as the type of cell infected by the retrovirus. Differential responses of proviral promoters in infected cells were also observed in the presence of hormones. Dibutyryl cyclic AMP increased the expression of genes linked to the PEPCK promoter in FTO-2B and NIH 3T3 cells, whereas glucocorticoids stimulated transcription from both the PEPCK promoter and the long terminal repeat in FTO-2B cells. The effect of these hormones on transcription of proviral promoters depended on their position relative to the 5' long terminal repeat. In contrast, insulin uniformly inhibited transcription from the PEPCK promoter in a position-independent manner but only in hepatoma cells and not in fibroblasts. In clonally isolated FTO-2B cells infected with a retrovirus, the site of proviral integration was also a major factor determining the expression and hormonal regulation from the internal promoters. The data suggest that the hormonal regulation of the expression of genes contained in retroviral vectors depends on the type and position of the regulatory elements present in the provirus and the lineage of the infected cell.
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PMID:Hormonal control of interacting promoters introduced into cells by retroviruses. 202 56

Phosphorylation of glucocorticoid receptors is increased by hormone binding and has been implicated in transcriptional regulation. We performed a phosphoamino acid analysis and identified the phosphorylated regions of the glucocorticoid receptor with respect to its functional domains before and after hormone activation. Receptor was isolated by immunoprecipitation from [32P]orthophosphate-labeled FTO 2B rat hepatoma cells grown in the absence or presence of glucocorticoids. The receptor contained mainly phosphoserine, with little phosphothreonine and no phosphotyrosine. Partial proteolysis of receptor from hormone-treated or control cells revealed a similar phosphopeptide pattern. Chemical cleavage with hydroxylamine and cyanogen bromide or digestion with trypsin and chymotrypsin localized the majority of receptor phosphorylation sites to a transactivation domain amino-terminal of the DNA-binding domain. Phosphorylation of this region, termed tau 1/enh2, was increased 2-3-fold by hormone treatment. The DNA-binding domain itself is weakly phosphorylated; no phosphorylation was found in the hormone-binding domain. Phosphorylated regions were also identified in receptor deletion mutants stably transfected into CV-1 monkey kidney cells. Hormone-independent phosphorylation was observed with a strong constitutively active mutant lacking the hormone-binding domain. No phosphorylation was detected in a mutant lacking the amino-terminal region, which showed only weak, hormone-dependent activity. These results support the idea that phosphorylation is important for the strength of the glucocorticoid receptor as a transcriptional regulator.
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PMID:Hormone-dependent phosphorylation of the glucocorticoid receptor occurs mainly in the amino-terminal transactivation domain. 210 36

Vanadate, at concentrations between 0.5 and 2 mM, rapidly decreased the basal level of P-enolpyruvate carboxykinase (GTP) (EC 4.1.1.32) mRNA and blocked the dibutyryl cyclic AMP (Bt2cAMP)-induced increase in enzyme mRNA in both FTO-2B and H4IIE rat hepatoma cells. The concentration of vanadate necessary to inhibit the expression of this gene was similar to that required for the vanadate-mediated activation of the insulin receptor tyrosine kinase. To determine whether vanadate could inhibit PEPCK gene transcription, a series of chimeric genes containing several deletions in the P-enolypyruvate carboxykinase promoter between -550 and -68 was linked to the structural genes for either amino-3-glycosyl phosphotransferase (neo) or chloramphenicol acetyltransferase and introduced into hepatoma cells using three methods: (a) infection with a Moloney murine leukemia virus-based retrovirus, (b) transfection and stable selection for neo expression, or (c) transient expression of chloroamphenicol acetyltransferase. In FTO-2B hepatoma cells infected with retrovirus, vanadate rapidly (within 1 h) inhibited transcription of the PEPCK-neo gene and blocked induction of gene expression caused by the addition of either Bt2cAMP or dexamethasone to the cells. Vanadate was not a general transcription inhibitor since, it like insulin, stimulated the expression of the c-fos gene. Also, the inhibitory effect of vanadate was rapidly reversible in FTO-2B cells since PEPCK gene expression could be stimulated by Bt2cAMP and dexamethasone after removal of vanadate. A series of 5' deletions in the P-enolpyruvate carboxykinase promoter (-550 to +73) was ligated to the structural gene for neo and stably transfected into hepatoma cells. Sequences responsive to vanadate were detected between -109 and -68. This result was confirmed using H4IIE hepatoma cells transiently expressing the PEPCK-CAT gene. The most likely target for vanadate in that region of the P-enolpyruvate carboxykinase promoter is cAMP regulatory element 1 which maps from -91 to -84. A comparison of the inhibitory effects of insulin and vanadate in this system indicated a major difference in the site of action of these two compounds on PEPCK gene transcription.
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PMID:Vanadate inhibits expression of the gene for phosphoenolpyruvate carboxykinase (GTP) in rat hepatoma cells. 216 40

Protein purification and molecular cloning have defined five classes of protein serine-threonine phosphatase catalytic subunits referred to as types 1, 2A, 2B (calcineurin), 2C, and X. Protein serine-threonine phosphatases 1, 2A, 2B, and X appear to have significant sequence homologies, whereas the 2C enzyme is more divergent. We have used the polymerase chain reaction to define the multiplicity of the closely related types 1, 2A, 2B, and X phosphatase catalytic subunits in two clonal cell lines, rat PC12 pheochromocytoma and rat FTO-2B hepatoma. RNAs for all four related phosphatase types were expressed in both cell lines. In addition to the phosphatase X enzyme, four phosphatase 1, two phosphatase 2A, and three phosphatase 2B isoforms were identified in PC12 and FTO-2B cells. The results indicate a large multiplicity of protein serine-threonine phosphatases within clonal cells of different tissue origin, suggesting that their role in cell regulation will be as divergent as that for the protein serine-threonine kinases.
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PMID:Multiplicity of protein serine-threonine phosphatases in PC12 pheochromocytoma and FTO-2B hepatoma cells. 217 76

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