Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expression of retinoic acid receptor alpha, beta, and gamma mRNA was examined in developing rat livers and rat hepatoma-derived cell lines H-4-II-E, McA-RH 7777, and 8994 that represent different hepatocyte phenotypes. Northern blot hybridization demonstrated that all three receptor mRNAs were expressed in the fetal livers of different gestational ages, and the levels of expression increased significantly 3 to 4 weeks after birth. In the hepatoma cell lines, the expression pattern of retinoic acid receptor alpha and gamma mRNA did not correlate with the phenotype. In contrast, retinoic acid receptor beta mRNA was only detected in the adult phenotypic H-4-II-E cells but not in McA-RH 7777 and 8994 cells, which represent embryonic and fetal hepatocyte phenotypes, respectively. The levels of retinoic acid receptor beta mRNA in hepatoma cell lines were lower than adult rat liver. These data suggest that the increased expression of retinoic acid receptor beta gene is associated with differentiation or maturation of rat hepatocytes. The effect of retinoic acid on retinoic acid receptor gene expression was also studied in hepatoma cells. Retinoic acid did not regulate retinoic acid receptor gene expression in McA-RH 7777 and 8994 cells, and the retinoic acid receptor beta gene remained inactivated in these cells. However, Southern blot hybridization indicated that the gross structure of retinoic acid receptor beta gene was not altered during malignant transformation. In H-4-II-E cells, retinoic acid increased the expression of retinoic acid receptor beta and gamma gene. Because of the similarity between H-4-II-E cells and normal adult hepatocytes, this type of autoregulation may be a mechanism by which retinoic acid regulates its own effect in vivo.
 ...
PMID:Expression of retinoic acid receptor genes in developing rat livers and hepatoma cells. 131 6

Retinoic acid regulation of one member of the human class I alcohol dehydrogenase (ADH) gene family was demonstrated, suggesting that the retinol dehydrogenase function of ADH may play a regulatory role in the biosynthetic pathway for retinoic acid. Promoter activity of human ADH3, but not ADH1 or ADH2, was shown to be activated by retinoic acid in transient transfection assays of Hep3B human hepatoma cells. Deletion mapping experiments identified a region in the ADH3 promoter located between -328 and -272 bp which confers retinoic acid activation. This region was also demonstrated to confer retinoic acid responsiveness on the ADH1 and ADH2 genes in heterologous promoter fusions. Within a 34-bp stretch, the ADH3 retinoic acid response element (RARE) contains two TGACC motifs and one TGAAC motif, both of which exist in RAREs controlling other genes. A block mutation of the TGACC sequence located at -289 to -285 bp eliminated the retinoic acid response. As assayed by gel shift DNA binding studies, the RARE region (-328 to -272 bp) of ADH3 bound the human retinoic acid receptor beta (RAR beta) and was competed for by DNA containing a RARE present in the gene encoding RAR beta. Since ADH catalyzes the conversion of retinol to retinal, which can be further converted to retinoic acid by aldehyde dehydrogenase, these results suggest that retinoic acid activation of ADH3 constitutes a positive feedback loop regulating retinoic acid synthesis.
 ...
PMID:Retinoic acid response element in the human alcohol dehydrogenase gene ADH3: implications for regulation of retinoic acid synthesis. 199 13

Retinoic acid (RA) is a vitamin A derivative that exhibits major effects on biological processes such as cell differentiation and embryo pattern formation. Two human retinoic acid receptors (RAR alpha and beta) have been recently characterized. These receptors are encoded by two genes and their affinities for RA differ, suggesting that these two nuclear receptors may have distinct roles in mediating the varied biological effects of RA. Here we show that RAR alpha and beta differ in the regulation of expression of their mRNAs. Different levels of RAR alpha and beta transcripts were found in the various human tissues analysed. In addition, treatment of human hepatoma cells with RA leads to a rapid 10- to 50-fold increase in RAR beta mRNA levels, whereas RAR alpha mRNA expression is not affected. The induction of RAR beta transcription does not require de novo protein synthesis but is completely abolished by inhibitors of RNA synthesis. Nuclear transcript elongation assays indicate that the mechanism of RAR beta mRNA induction lies at the transcriptional level. These data demonstrate that the RAR beta gene is a primary target for RA. The differences in regulation of RAR gene expression might be a fundamental aspect of retinoid physiology and may prove especially important in the analysis of the morphogenic properties of RA.
 ...
PMID:Differential expression and ligand regulation of the retinoic acid receptor alpha and beta genes. 254 14

In cultures of the differentiated clones Faza 967, Fao and HF, derived from Reuber hepatoma, physiological doses of glucocorticoid induce chenodeoxycholate 6 beta-hydroxylation, a microsomal cytochrome-P-450-mediated activity (enhanced in liver by phenobarbital and not by benzo[a]anthracene). Whereas 12-O-tetradecanoylphorbol 13-acetate (TPA) alone has no effect the tumor promoter, when added to dexamethasone, enhances this induction. This enhancement, half-maximum with 10 ng/ml TPA, is a function of the dose between 1 ng/ml and 50 ng/ml; 50 ng/ml (80 nM) increase 4-7-fold the induction rate (as measured in cultures by the amount of bile acid hydroxylated per 10(6) cells in 24 h, and in homogenates from treated cells) and 2.5-fold the maximum activity attained by the third day of induction. When added to cultures of the dedifferentiated clone H5, treated with benzo[a]anthracene, TPA does not influence benzo[a]pyrene hydroxylase induction, as shown by the total and relative amounts of the various hydrosoluble benzo[a]pyrene metabolites. TPA does not affect tyrosine aminotransferase induction in dexamethasone-treated Fao cultures. The enhancement is not suppressed by indomethacin, an inhibitor of prostaglandin synthesis. After dexamethasone removal from induced Faza 967 cultures, addition of TPA to the medium does not affect the decay rate of the chenodeoxycholate-hydroxylating activity. Retinoic acid similarly enhances the induction by dexamethasone of chenodeoxycholate hydroxylation, both in treated Faza 967 cultures and in homogenates from treated cultures. The effects of TPA and retinoic acid are additive. These results suggest a possible cooperation at the transcriptional level between transactive factors, involving TPA-mediated alterations, retinoic acid and glucocorticoid receptors. The system described might provide a convenient experimental approach in the study of its mechanism.
 ...
PMID:Enhancing effect of a phorbol ester and of retinoic acid on glucocorticoid induction of chenodeoxycholate hydroxylation in hepatoma cultures. 340 83

Rat hepatoma cells were cultured in a medium with suboptimal concentration of fetal calf serum. In this low serum culture, retinoic acid inhibited the cell proliferation and enhanced the number of receptors for epidermal growth factor (EGF). On the contrary, teleocidin, a possible naturally occurring tumor promoter from Streptomyces, was a weak mitogen and inhibited EGF binding. A concurrent treatment of AH66 cells with these two compounds showed that they acted antagonistically. Retinoic acid inhibited the mitogenic action of teleocidin, while teleocidin suppressed the retinoic-acid enhancement of the number of EGF receptors. Retinoic acid could not prevent the alterations of the cell surface properties induced by a prolonged treatment with teleocidin. Furthermore, these two compounds appeared to be involved in the regulation of glycoprotein synthesis and the stimulation of cellular glycoprotein synthesis by retinoic acid was abolished by teleocidin. The present data suggest that retinoic acid selectively antagonizes the mitogenic action of teleocidin, and also indicate that the hepatoma cell cultures appear to prove a useful system for exploring the mechanisms of action of both retinoic acid and teleocidin.
 ...
PMID:Antagonistic action of retinoic acid and teleocidin on the proliferation and epidermal growth factor binding of rat hepatoma cells. 679 26

Rat hepatoma cells H-35 cultured in serum-free medium were exposed to interleukin-6 (IL-6), interleukin-1 (IL-1), hepatocyte growth factor (HGF), retinoic acid (RA), or a mixture of these factors. Production of acute phase proteins, responding to IL-6 alone (type 2) or to the mixture of IL-6 and IL-1, was assessed by electroimmunoassay and the corresponding mRNAs were compared by Northern blot analysis. HGF enhanced IL-6-induced synthesis of alpha-2-macroglobulin but reduced synthesis of C3 complement and alpha-1-acid glycoprotein. Retinoic acid reduced the response to IL-6 of alpha-2-macroglobulin but enhanced that of alpha-1-acid glycoprotein and especially of C3 complement. In general, changes in protein secretion were correlated with the contents of their corresponding cellular mRNAs. These results indicate that hepatocyte growth factor can enhance basal or IL-6-induced gene expression of type 2 and reduce the expression of type 1 acute phase proteins, whereas the action of retinoic acid is opposite. The modulation of acute phase response by HGF and RA likely involves transcriptional factors and regulatory sequences in the genes coding for these two types of acute phase proteins.
 ...
PMID:Hepatocyte growth factor and retinoic acid exert opposite effects on synthesis of type 1 and type 2 acute phase proteins in rat hepatoma cells. 753 94

Subconfluent monolayers of human hepatoma HepG2 cells were cultured for 2 days in serum-free DMEM containing 1 microM dexamethasone and human recombinant hepatocyte growth factor (HGF), retinoic acid (RA), IL-1, IL-6, LIF and mixtures of these factors. Incorporation of labelled thymidine was significantly decreased by IL-6, IL-1 and HGF but only slightly by LIF and RA. Synthesis of acute phase proteins secreted daily to the media was measured by electroimmunoassay with monospecific antisera. In addition, the synthesis and secretion of some proteinase inhibitors (alpha-1-proteinase inhibitor, alpha-1-antichymotrypsin, C1-inactivator, plasminogen activator inhibitor-1, inter-alpha-trypsin inhibitor and pre-alpha-inhibitor) was evaluated by incorporation of labelled methionine and fluorography. Among the cytokines tested IL-6 was the most potent regulator of acute phase protein synthesis. Hepatocyte growth factor stimulated basal synthesis of alpha-1-antichymotrypsin, and to a lesser extent affected some other proteins. Retinoic acid preferentially increased synthesis of alpha-1-antichymotrypsin, ceruloplasmin and plasminogen activator inhibitor-1. Both HGF and RA slightly modulated cytokine-induced synthesis of several acute phase proteins in HepG2 cells.
 ...
PMID:Regulation of synthesis of some proteinase inhibitors in human hepatoma cells HepG2 by cytokines, hepatocyte growth factor and retinoic acid. 768 88

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.
 ...
PMID:Retinoic acid up-regulates erythropoietin production in hepatoma cells and in vitamin A-depleted rats. 805 May 71

The effects of retinoids and the peroxisome proliferator clofibric acid on peroxisomal enzyme pathways were studied in hepatocytes from both rat and rabbit. Retinoic acid and retinol increased the activity of acyl-CoA oxidase in rabbit hepatocytes around 60% and around 30% in rat hepatocytes. Exposure to clofibric acid caused an increase in acyl-CoA oxidase activity of 115% in rat hepatocytes and of 40% in rabbit hepatocytes, indicating that rabbit is less sensitive to peroxisome proliferator than rat. Simultaneous exposure to clofibric acid and retinoids did not act additatively or synergistically. Both rabbit and rat hepatocytes expressed mRNA for the peroxisome proliferator activated receptor, (PPAR), although the transcript in rabbit was slightly smaller compared to that expressed in rat hepatocytes. The effect of retinoic acid in 7800 C1 Morris rat hepatoma cells, a cell line known to have an inducible peroxisomal beta-oxidation of fatty acids, was only slight with an increase of the acyl-CoA oxidase activity of 25% compared with control cells. As for clofibric acid, which gave a 2-fold induction of the acyl-CoA oxidase activity, the effect of retinoic acid was potentiated by dexamethasone. These cells also expressed mRNA for PPAR, with the same size as that found in rat hepatocytes. The oxidation of 3 alpha,7 alpha,12 alpha-trihydroxy-5 beta-cholestanoic acid (THCA), an intermediate in bile acid formation, in rat hepatocytes increased 110% by clofibric acid and around 80% by retinoic acid. In rabbit hepatocytes, clofibric acid increased the oxidation rate 75% and retinoic acid 100%. The results presented here show similarities in the effects of retinoids and clofibric acid on the acyl-CoA oxidase activity and the oxidation rate of THCA, since they increase these two peroxisomal activities in hepatocytes in vitro. A decrease in both these enzyme activities occurs during cultivation time in untreated primary hepatocyte cultures. The present data may therefore either be explained by an increased expression or an induced stability of the enzymes involved.
 ...
PMID:The effect of retinoids and clofibric acid on the peroxisomal oxidation of palmitic acid and of 3 alpha,7 alpha,12 alpha-trihydroxy-5 beta-cholestanoic acid in rat and rabbit hepatocytes. 850 35

Retinoic acid (RA) is known to have potent effects on development and differentiation. RA exerts its effects on transcription through two distinct classes of nuclear receptors, the retinoic acid receptor (RAR) and the retinoid X receptor (RXR), that bind to specific RA-responsive elements (RARE) in target genes. alpha-Fetoprotein (AFP), a hepatocyte differentiation, maturation, and carcinogenesis marker, is transcriptionally upregulated by RA in McA-RH8994 hepatoma cells. Using deletion mapping analysis, we have identified a RARE-like sequence that is located between -2406 and -2378 of the transcription initiation site of the rat AFP gene. Sequence analysis demonstrated that this cis-acting element consists of three direct repeats and one inverted repeat of a GGGTCA-like half-site. The putative RARE can specifically bind to both RXR homodimers and RAR/RXR heterodimers as determined by gel mobility shift assays. A DR1 direct repeat was more efficient than a DR5 direct repeat oligonucleotide in competition for binding of the putative RARE to RXR and RAR/RXR. A mutagenesis study indicated that to have a full-strength induction, all the repeats were required. To further analyze the function of this element in vivo, a reporter gene construct of the putative RARE combined with the thymidine kinase promoter was cotransfected with RAR and RXR expression plasmids in CV1 cells. CAT assays demonstrated that overexpression of RXRalpha conferred the best RA response, consistent with our previous observation that 9-cis-RA is more potent than all-trans-RA for inducing the expression of the AFP gene. In addition, the RXR selective ligand LG100153 alone can stimulate the expression of the AFP gene. Our data suggest that an RXR-mediated pathway exists for modulation of AFP gene expression through a specific element.
 ...
PMID:RXR-mediated regulation of the alpha-fetoprotein gene through an upstream element. 894 36


1 2 3 4 Next >>