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)

Although L-triiodothyronine (L-T3) lowers cholesterol, this hormone is not used to treat hypercholesterolemia because of its cardiotoxic effects. Thyromimetics, such as the novel compound CGS 23425, that mimic the beneficial but lack the detrimental effects of T3, may be useful in the treatment of hypercholesterolemia. To show that CGS 23425 has no cardiotoxicity, atrial contractility and force were both measured and found to be unchanged in rats treated with up to 10 mg/kg drug. The lipid lowering actions of this drug resulted in a 44% decrease in low-density lipoprotein (LDL) cholesterol in hypercholesterolemic rats treated with 10 microg/kg of the compound. Normal rats required a higher dose of 1000 microg/kg to elicit a similar 50% reduction in LDL cholesterol. Both CGS 23425 or T3 (10 nM) increased the specific binding of 125I-labeled LDL to Hep G2 cells and increased LDL receptor number by 44 and 49%, respectively. These data indicate that CGS 23425 enhances hepatic clearance of serum LDL cholesterol. Normal and fat-fed animals treated with the drug showed a dose-dependent increase in apolipoprotein AI, a protein that promotes the efflux of cholesterol from peripheral tissues. Transient transfection of a rat apolipoprotein AI promoter-chloramphenicol acetyltransferase construct, in human hepatoma cells, showed a dose-dependent increase in chloramphenicol acetyltransferase activity with EC50 values of 2 x 10(-12) M and 10(-10) M for thyroid hormone receptors beta1 and alpha1, respectively, with maximal responses at 10(-7) M. These data indicate that CGS 23425 is a thyromimetic that increases apolipoprotein AI expression via thyroid hormone receptor. In summary, CGS 23425 ameliorates hypercholesterolemia by increasing apolipoprotein A1 and the clearance of LDL cholesterol. Therefore, a compound like CGS 23425 may be useful for the prevention and reversal of atherosclerosis.
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PMID:Beneficial effects of a novel thyromimetic on lipoprotein metabolism. 928 17

To understand whether the transcriptional activity of thyroid hormone nuclear receptors (TRs) is modulated by cell-type specific factors, full length TR subtype alpha1 (TRalpha1) and beta1 (TRbeta1) cDNAs were cloned from human hepatoma cell lines: HA22T, SK-Hep-1 and HepG2. The cloned receptor bound to the thyroid hormone 3,3',5-triiodo-L-thyronine (T3) and the thyroid hormone response elements (TREs) similarly to those cloned from other tissues. They exhibited T3- and TRE-dependent transactivation activities, indicating these TRs were transcriptionally active. The lipogenic malic enzyme (ME), a T3-target gene in liver, was stimulated approximately 3- and 1.5-fold by T3 in HA22T and SK-Hep-1, respectively. The T3-stimulated ME gene expression was inhibited in HA22T, but stimulated in SK-Hep-1 cells by insulin. These results suggest that the gene regulating activity of TRs was modulated by cell-type specific factors. Furthermore, these cell-type specific factors could modulate the cross talk between TR- and insulin receptor-mediated pathways.
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PMID:The gene regulating activity of thyroid hormone nuclear receptors is modulated by cell-type specific factors. 929 94

The thyroid hormone (T3) was shown to down regulate the level of alpha-foetoprotein (AFP) mRNA in hepatoma cells HepG2. Recombinant plasmids containing segments from the mouse AFP gene promoter were transfected in HepG2 cells and transient expression assays showed that the T3 inhibitory effect depends on the sequence limited by positions -80 and -38, upstream from the TATA box. This sequence is able to confer T3 sensitivity to a heterologous promoter and contains a putative T3-responsive element, as well as likely CEBP- and HNF1-responsive elements. These observations suggest that T3 is a good candidate for hormonal control of the AFP gene expression and especially for the neonatal shut off of the gene.
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PMID:The thyroid hormone down-regulates the mouse alpha-foetoprotein promoter. 948 9

Evidence suggests that thyroid hormone plays a role in the regulation of hepatic IGF/IGFBP expression both in human and rats. In this study we compared the effect of T3 on IGFBP-1 and -4 expression in rat hepatocyte primary cultures and in the human hepatoma cell line HepG2. Northern blot analysis revealed that IGFBP-1 mRNA levels were not affected by T3 in cultured rat hepatocytes, whereas a net increase of IGFBP-1 transcript abundance was induced by the hormone in HepG2 cells. On the contrary, IGFBP-4 mRNA levels were increased in rat hepatocytes cultured in the presence of T3, but unaffected in T3-treated HepG2 cells. Therefore, thyroid hormone seems to regulate hepatic IGFBP expression in a direct and gene-specific way. Moreover, the effects of thyroid hormone depend strictly on the source of target hepatocyte.
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PMID:Regulation of IGFBP-1 and -4 expression by triiodothyronine (T3) in cultured hepatocytes is cell- and gene-specific. 954 Feb 32

Dehydroepiandrosterone sulfotransferase (Std) catalyzes sulfonation of androgenic steroids and certain aromatic procarcinogens. In rats, this enzyme is selectively expressed in the liver, and its expression is strongly repressed by androgens. DNase I footprinting and electrophoretic mobility shift analyses revealed two hepatocyte nuclear factor-1 (HNF1), three CCAAT/enhancer-binding protein (C/EBP), and one consensus palindromic thyroid hormone response elements within the first 215 base pairs (bp) of the promoter sequence of rat Std. This promoter is normally inactive in fibroblast-derived NIH 3T3 cells. However, overexpression of HNF1 and C/EBP resulted in synergistic activation of the Std promoter in this cell type, indicating essential roles of these two trans-regulators in liver-selective expression of the rat Std gene. On the other hand, point mutations at any one of five cis elements proximal to the -215 bp region markedly reduced reporter gene expression, suggesting that all of these sites are important for overall promoter function. Androgenic repression of the Std gene in rat liver can be recapitulated in androgen receptor (AR)-negative HepG2 hepatoma cells after cotransfection with an AR expression plasmid. Functional assay of a nested set of 5'-deleted promoters mapped the negative androgen response region between positions -235 and -310. Antibody supershift and oligonucleotide competition identified three OCT-1 and two C/EBP elements between bp -231 and -292. An additional OCT-1 site was found to overlap with a C/EBP element at the -262/-252 position. Mutational inactivation of any one of five cis elements within the -231/-292 region abolished negative androgen response. However, none of these cis elements showed DNase I protection by recombinant AR in footprinting assay, suggesting the absence of a direct AR-DNA interaction. Thus, these studies on rat Std promoter function indicate that (i) HNF1 and C/EBP are responsible for liver specificity of the rat Std gene; (ii) androgenic repression of the gene requires the presence of all of the OCT-1 and C/EBP elements between positions -231 and -292; and (iii) AR may exert its negative regulatory effect indirectly through transcriptional interference of OCT-1 and C/EBP rather than through a direct DNA-AR interaction.
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PMID:Tissue-specific and androgen-repressible regulation of the rat dehydroepiandrosterone sulfotransferase gene promoter. 970 24

Rats bearing the Zajdela hepatoma tumor and T3-treated hypothyroid rats were used to study the role of protein degradation in the process of mitochondrial biogenesis. It was shown that the activity, protein and mRNA levels of the ATP-dependent Lon protease increased in rapidly growing Zajdela hepatoma cells. The increase in the rate of mitochondrial biogenesis by thyroid hormone was similarly accompanied by enhanced expression of the Lon protease. The results imply that mitochondrial biogenesis in mammalian cells is, at least partially, regulated by the matrix Lon protease.
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PMID:Enhanced mitochondrial biogenesis is associated with increased expression of the mitochondrial ATP-dependent Lon protease. 1005 Jul 56

Hexachlorobenzene (HCB) is a dioxin-type chemical that acts mainly through the aryl hydrocarbon receptor. Chronic exposure of rats to HCB increases the activity of malic enzyme (ME). In this report, we show that this increase is correlated with an induction of ME messenger RNA (mRNA) levels, with the maximal HCB effect achieved after 9 days of intoxication. This effect is specific for ME, as other liver enzymes, such as glyceraldehyde-3-phosphate dehydrogenase, phosphoenol pyruvate carboxykinase, and mitochondrial alpha-glycerol-3-phosphate dehydrogenase, are not affected by HCB. The induction of ME mRNA levels is accompanied by an increase in ME promoter activity, as demonstrated by transient transfection experiments performed in rat hepatoma H35 cells. In an attempt to identify the cis-regulatory elements responsible for the HCB effect, different promoter deletions and mutations were used. The results obtained localize the responsive region between positions -315 and -177. This region does not contain either consensus xenobiotic response or activating protein-1 elements, the two main mediators of dioxin compounds described to date. In contrast, a thyroid hormone response element (TRE) is located between -281 to -261. Deletions and mutations of the TRE element do not respond to HCB, demonstrating that this element mediates the response of this dioxin-type compound. As ME gene expression is regulated mainly by thyroid hormones, we next investigated the role of T3 receptor (T3R) in the ME gene transcriptional induction mediated by HCB. Using Scatchard analysis, we show that neither T3R binding features for its ligand nor alpha1 or beta1T3R mRNA levels are changed with the toxic. In gel shift assays, however, we observed that protein/DNA complexes formed on TRE from the ME promoter were induced by HCB. Using an oligonucleotide with a mutation that eliminates the TRE function, we demonstrate a loss of the induced protein/DNA complexes. Together, these data suggest that the dioxin-type compound HCB increases ME gene transcription by modulating the levels of still unidentified nuclear proteins that bind to the TRE element of the ME promoter.
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PMID:Hexachlorobenzene, a dioxin-type compound, increases malic enzyme gene transcription through a mechanism involving the thyroid hormone response element. 1046 87

To understand the expression and role of thyroid hormone nuclear receptors (TRs) in hepatocarcinogenesis, we characterized the TRs in 16 human hepatocellular carcinoma (HCC) specimens. The full-length cDNAs for the two TR subtypes, alpha1 and beta1, were cloned from several tumors by reverse transcription-polymerase chain reaction. Southern blot analysis indicated that, in addition to the full-length cDNA, truncated TRalpha1 and TRbeta1 cDNAs were present in nine tumors (53%). In addition, point mutations detected by the mismatch RNase cleavage assay in TRalpha1 and TRbeta1 were found in 65% and 76% of the tumors, respectively. The mutations were confirmed by DNA sequencing. Interestingly, most of the TRalpha1 mutations were in amino acid codons 209-228 and 245-256, two hot-spots in HCC patients. However, no hot-spot was detected in TRbeta1. The expression of TRalpha1 and TRbeta1 proteins was determined in the tissue extracts by western blotting. TRbeta1 protein was expressed or elevated in 10 tumors but not in normal livers, whereas the expression of TRalpha1 was variable among tumors. The mutant TR proteins were translated in vitro, and their hormone- and DNA-binding activities were evaluated. Abnormal binding to the thyroid hormone response elements was observed. The proteins' DNA binding activity was either partially impaired or completely lost. The high prevalence of TR mutations found in the tumors of patients with hepatocellular carcinoma suggests that mutant TRs could play an important role in liver carcinogenesis.
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PMID:Expression of mutant thyroid hormone nuclear receptors in human hepatocellular carcinoma cells. 1048 22

Glucocorticoids are primarily recognized for their profound anti-inflammatory actions and their ability to induce lymphocyte apoptosis. We report here that, in contrast to their effect on cells of the immune system, glucocorticoids suppress serum deprivation induced apoptosis of rat hepatoma (HTC) cells. Suppression of apoptosis in these cells occurs at physiological concentrations of glucocorticoid and is abrogated by the glucocorticoid antagonist RU486. Although HTC cells also express receptors for progesterone, estrogen, and thyroid hormone, ligands for these receptors fail to rescue these cells from programmed cell death. Because the sensitivity of cells to apoptotic stimuli is often regulated by the ratio of antiapoptotic to proapoptotic Bcl-2 family members, we analyzed the influence of glucocorticoids and induction of apoptosis by serum starvation on the expression of these proteins. Bcl-2, Bcl-xL, Bad, Bak, and Bax levels were not altered by either treatment. Mitochondrial function has recently been implicated as a critical early regulator of apoptosis in many cells including hepatocytes. Dexamethasone treatment blocked a decrease in this potential (delta psi(m)) during serum deprivation induced apoptosis in HTC cells, indicating an action of this hormone upstream of mitochondria. We also show that the induction of apoptosis in HTC cells is associated with a decrease in nuclear factor (NF)-kappaB. Treatment with dexamethasone effectively blocked the loss of nuclear NF-kappaB, suggesting that this hormone acts to suppress apoptosis of HTC cells via regulation of this nuclear transcription factor. This hypothesis was confirmed by transfection experiments that show that expression of a superrepressor of NF-kappaB inhibits the ability of dexamethasone to rescue HTC cells from apoptosis induced by serum deprivation.
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PMID:Delineation of an antiapoptotic action of glucocorticoids in hepatoma cells: the role of nuclear factor-kappaB. 1080 96

The thyromimetic compound SK&F L-94901 shows more potent thyromimetic activity in the liver than in the pituitary gland or heart when administered to rats. The mechanisms of liver-selectivity of SK&F L-94901 were examined using cultured rat hepatoma cells (dRLH-84) and rat pituitary tumor cells (GH3), both of which showed saturable cellular uptake of tri-iodothyronine (T(3)). When isolated nuclei with partial disruption of the outer nuclear membrane were used, SK&F L-94901 competed for [(125)I]T(3) binding to nuclear receptors almost equally in dRLH-84 and GH3 cells. SK&F L-94901 also did not discriminate thyroid hormone receptors (TR) alpha1 and beta1 in terms of binding affinity and activation of the thyroid hormone responsive element. In intact cells, however, SK&F L-94901 was a more potent inhibitor of nuclear [(125)I]T(3) binding in dRLH-84 cells than in GH3 cells at an early phase of the nuclear uptake process and after binding equilibrium. These data suggest that SK&F L-94901 is more effectively transported to nuclear TRs in hepatic cells than in pituitary cells and therefore shows liver-selective thyromimetic activity. In conclusion, SK&F L-94901 discriminates hepatic cells and pituitary cells at the nuclear transport process. The cellular transporters responsible for this discrimination were not evident.
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PMID:Mechanism of liver-selective thyromimetic activity of SK&F L-94901: evidence for the presence of a cell-type-specific nuclear iodothyronine transport process. 1081 Mar 3


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