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)

Retinoic acid (RA) stimulated the production of erythropoietin (Epo) in a human hepatoma cell line, HepG2 cells. The stimulation was due to the accumulation of Epo mRNA. The Epo production in HepG2 cells was also dependent on O2 tension for cell culture but the enhancement of Epo production by RA was independent of O2 tension, indicating that RA exerts its effect through a pathway different from O2. Oral administration of RA to the vitamin A-depleted rats elevated the concentration of Epo in serum. These results suggest that RA up-regulates EPO production in vivo as well as in vitro.
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PMID:Retinoic acid up-regulates erythropoietin production in hepatoma cells and in vitamin A-depleted rats. 805 May 71

Transcription of the phosphoenolpyruvate carboxykinase gene is stimulated by glucocorticoids, retinoic acid, and cAMP and is dominantly inhibited by insulin and phorbol esters. The glucocorticoid response is mediated by a complex regulatory unit that consists of two glucocorticoid receptor (GR) binding sites (GR1 and GR2) and two adjacent accessory factor elements (AF1 and AF2). Deletion of either the AF1 or the AF2 element results in a 50-75% reduction of the glucocorticoid response. In addition to their accessory role in glucocorticoid action, the AF1 and AF2 elements mediate retinoic acid and insulin/phorbol ester effects, respectively. Site-directed mutagenesis was performed on AF1 and AF2 to precisely locate the sequences responsible for accessory activity in each element. The glucocorticoid accessory activity of the AF1 element maps to the same 12-base pair sequence (TGACCTTTGGCC) involved in the response of the PEPCK gene to retinoic acid. The glucocorticoid accessory activity of the AF2 region maps to the same 10-base pair sequence (TGGTGTTTTG) responsible for mediating the insulin and phorbol ester responses through this element. The AF1 and AF2 elements bind different sets of nuclear proteins, and this binding is not qualitatively or quantitatively affected by treatment of the rat H4IIE hepatoma cells with retinoic acid (AF1) or insulin (AF2). AF2 functions in a heterologous context (a consensus glucocorticoid response element and the thymidine kinase promoter), whereas AF1 functions in this context only if the retinoic acid receptor is overexpressed in the cells. These results show that the AF1 and AF2 elements affect the glucocorticoid response through different protein DNA interactions, and that a small sequence in each serves multiple functions. Together with GR1 and GR2, they form a complex hormone response unit which provides an integrated response of the phosphoenolpyruvate carboxykinase gene to a variety of positive and negative signals.
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PMID:Integration of multiple signals through a complex hormone response unit in the phosphoenolpyruvate carboxykinase gene promoter. 805 68

The expression of the gene coding for retinol-binding protein has been studied in a system of cultured human hepatoma cells exposed to retinoids. We report that the gene is positively modulated by retinol and retinoic acid in a time- and dose-dependent fashion. The stimulation at the mRNA level is paralleled by an increase of the corresponding protein that is secreted in the presence of the physiological ligand. An RBP-CAT chimeric gene, introduced by transfection, is also responsive to the treatment, showing the gene dose-dependency as the endogenous gene. These results demonstrate that retinoids up-regulate the RBP gene and that the control takes place at transcriptional level.
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PMID:Retinoids regulate expression of the retinol-binding protein gene in hepatoma cells in culture. 807 97

The expression of gene 33 in rat liver and hepatoma cells is regulated by multiple hormones and other bioactive agents. Previous studies have demonstrated a 15-fold increase in gene 33 mRNA after 1 h of insulin treatment. We demonstrate in this report that retinoic acid (RA) also controls the expression of this gene. Gene 33 mRNA levels are rapidly elevated by RA, with maximal accumulation (19-fold over control) attained after just 1 h of RA treatment. The transcription rate of gene 33 was increased by RA to a maximum level 6-fold greater than control values. Studies with inhibitors of RNA synthesis demonstrated no increase in the stability of gene 33 mRNA in response to RA or insulin. In addition, a synergistic induction of both gene 33 mRNA levels and the transcription rate of gene 33 was observed when both RA and insulin were added together. In the presence of both hormones, the transcription rate was induced almost 20-fold in 30 min, followed by a 49-fold increase in mRNA levels after 1 h. Thus, gene 33 represents the first example of a gene whose transcription rate is elevated directly by both insulin and RA, and synergistically elevated by treatment with both hormones together.
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PMID:Synergistic induction of gene 33 expression by retinoic acid and insulin. 815 27

Expression of the apolipoprotein AI (apoAI) gene in the liver is controlled by a liver-specific enhancer. The function of this enhancer depends on synergistic interactions between transcription factors bound to at least three sites (designated A, B, and C) located within this enhancer. We have previously shown that an apoAI gene reporter construct containing the entire enhancer is expressed efficiently in a hepatoma cell line and that its activity is repressed by the orphan receptor ARP-1. Moreover, repression by ARP-1 is overcome by the retinoid X receptor RXR alpha in the presence of retinoic acid. In this study, we show that ARP-1 represses the apoAI promoter by binding to site A of the apoAI liver-specific enhancer, the repression being a promoter context-specific event. Mapping analysis of ARP-1 indicated that its DNA binding domain is essential but not sufficient for repression. Two separate repression domains located at the amino- and carboxyl-terminal halves of ARP-1 were found to individually complement the DNA binding domain for efficient repression. We also demonstrate the reversibility of ARP-1 repression by transcription factors C/EBP and Egr-1, which might also be involved in apoAI gene expression. Significantly, repression by ARP-1 was found to be a prerequisite for C/EBP-mediated transactivation. We interpret our results in terms of a model in which ARP-1 repression via its interaction with site A is an obligatory intermediate step in switching from one activated state of the apoAI gene to another.
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PMID:Transcriptional repression of apolipoprotein AI gene expression by orphan receptor ARP-1. 817 47

We used human hepatoma Hep3B/C16 cells as a model to examine the effect of all-trans retinoic acid on the gene expression of hepatitis B surface antigen (HBsAg). Hep3B/C16 is a clonal derivative of human hepatoma Hep3B cell which was stably transfected with HBsAg DNA sequences and can produce hepatitis B virus surface antigen. We analyzed the HBsAg product and mRNA in Hep3B/C16 cells which were exposed to retinoic acid for different periods of time. The level of HBsAg started to increase after 24 h and reached maximum at 48 h of retinoic acid treatment. However, the level of HBsAg expression was severely suppressed compared to the control cells after long term (120 h) retinoic acid treatment. Such biphasic regulation of HBsAg production by retinoic acid was paralleled by the changes of HBsAg mRNA. Nuclear run-on assays also demonstrated that the retinoic acid-mediated regulation was determined at least in part at the transcriptional level. Furthermore, an exposure of the cells to retinoic acid for only 8 h was sufficient to show that up- and down-regulation of HBsAg gene occurred 2 and 5 days later. Using a transient expression system, we demonstrated that the retinoic acid response element is located within the 5'-flanking region of the HBsAg gene.
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PMID:Retinoic acid biphasically regulates the gene expression of hepatitis B virus surface antigen in human hepatoma Hep3B cells. 822 26

Apolipoprotein (apo) A-I is the major protein component of high-density lipoproteins (HDLs), which are responsible for reverse cholesterol transport from peripheral tissues to the liver. A low level of plasma HDL is correlated with susceptibility to atherosclerosis and coronary heart disease. Mammalian apo A-I synthesis has been attributed mainly to liver and intestine. Recently, apo A-I expression has been shown in porcine brain capillaries, suggesting an independent lipid metabolism within the brain. In this study, protein synthesis and secretion were investigated in primary cultures of porcine brain microvascular endothelial cells and compared with those in large vessel endothelium. Active protein synthesis in vitro was demonstrated by metabolic labeling. Cerebral endothelial cells were shown to secrete apo A-I into the culture supernatant, whereas aortic endothelial cells were negative for apo A-I expression. Further studies of transcriptional regulation showed that cerebral endothelium was responsive to apo A-I-inducing agents, such as cholesterol, insulin, and retinoic acid, as previously shown in human hepatoma HepG2 cells. Thus, cultures of porcine cerebral endothelial cells may represent a suitable model for physiological studies of apo A-I-regulation with regard to brain lipid metabolism and blood-brain barrier function. To investigate the interspecies conservation of regulatory elements, 178 bp of the 5' flanking region of the porcine apo A-I gene was cloned using PCR techniques. Alignments of the cDNA, of the deduced apo A-I protein sequence, and of the 5' promoter region with the corresponding genomic sequences of different species show a high degree of similarity between the porcine and the primate apo A-I genes, thus indicating a similar function and possibly common regulatory mechanisms in those species. In contrast, the rodent and avian apolipoprotein A-I promoter sequences differed significantly.
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PMID:Expression of apolipoprotein A-I in porcine brain endothelium in vitro. 829 40

The effects of retinoic acid on the expression of the Ha-ras gene were studied in transformed rat hepatoma cells (H4IIE) and in rat aortic smooth muscle cells (ASMC) treated with benzo(a)pyrene (30 microM) in vitro. In H4IIE cells, a dose-dependent increase in steady state Ha-ras mRNA levels was observed upon exposure to retinoic acid for 24 hr. Exposure of ASMC to 10 microM retinoic acid under similar experimental conditions was also associated with increased Ha-ras expression. In contrast, retinoic acid (1 and 10 microM) inhibited benzo(a)pyrene-induced expression of Ha-ras in ASMC. These results suggest that retinoic acid modulates spontaneous and carcinogen-induced expression of Ha-ras in a differential manner.
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PMID:Modulation by retinoic acid of spontaneous and benzo(a)pyrene-induced c-Ha-ras expression. 830 37

The retinoic acid (RA) receptor-beta (RAR beta) gene is dramatically up-regulated by RA in F9 teratocarcinoma cells due to the presence of an RA-responsive element (RARE) in its promoter. Remarkably, however, RAR beta mRNA was essentially unaffected by RA in rat pituitary GH3 cells, even though the GH gene was induced by RA, and these cells express mRNAs specific for multiple RAR subtypes and for the potential RAR coactivators, retinoid X-receptors. The absence of RA induction of RAR beta was also observed in GH1 cells as well as in murine AtT-20 pituitary cells and rat H35 hepatocarcinoma cells. The RA unresponsiveness of the RAR beta gene in GH3 and AtT-20 cells was not due to a mutation in the RARE, which was identical to that in RA-responsive F9 cells. Furthermore, while AtT-20 and F9 cells both expressed multiple RAR beta isoforms, including RAR beta 2, which was profoundly induced by RA in F9 cells, none of these was highly regulated by RA in AtT-20 cells. The failure of RA to induce RAR beta mRNA in certain murine and rat pituitary and nonpituitary cell lines indicates that target gene responsiveness to RA is cell type specific in some cases.
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PMID:Induction of retinoic acid receptor-beta by retinoic acid is cell specific. 838 88

In cultured hepatoma HepG2 cells, serum retinol-binding protein (RBP) is secreted more rapidly in the presence of retinol than in its absence (Tosetti, F., Ferrari, N., Pfeffer, U., Brigati, C., and Vidali, G. (1992) Exp. Cell Res. 200, 467-472). In the presence of millimolar concentration of DTT, HepG2 cells synthesize fully reduced RBP within the endoplasmic reticulum (ER) which, upon removal of DTT, forms disulfide bonds post-translationally. Secretion of this post-translationally folded RBP is also dependent on the presence of retinol. Using nonreducing gel electrophoresis, we resolved disulfide-bonded RBP folding intermediates. In addition, two other intracellular folding intermediates, compact I and II, which co-migrate with mature RBP were resolved by their different sensitivity to DTT-induced unfolding. Retinol, as well as retinoic acid, stabilized both compact I and II RBP intermediates to DTT-induced unfolding, suggesting that RBP assumes different conformations in the ER in the presence and absence of a ligand. However, only RBP synthesized in the presence of retinol is rapidly secreted, indicating that the ER export quality control system recognizes RBP containing retinol, but not retinoic acid, as fully folded and competent for export. Folding of RBP so that it is stabilized to DTT reduction is not a sufficient condition for ER exit.
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PMID:Unfolding of newly made retinol-binding protein by dithiothreitol. Sensitivity to retinoids. 840 80


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