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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A full-length cDNA clone for rat asparagine synthetase (AS) was isolated from a cDNA library enriched for amino acid-regulated sequences. The AS cDNA was used to investigate the amino acid-dependent repression of AS mRNA content in rat Fao hepatoma cells. In response to complete amino acid starvation, there was an approximately 10-fold increase in the level of AS mRNA. Three species of mRNA, of approx. sizes 2.0, 2.5 and 4.0 kb, were detected and each was simultaneously regulated to the same degree. The expression of AS mRNA increased by 6 h after removal of amino acids, reached a plateau after 9 h, and was blocked by either actinomycin D or cycloheximide. Partial repression of the AS mRNA content was maintained by the presence of a single amino acid in the culture medium, but the degree of effectiveness for each one varied widely. Glutamine showed the greatest ability to repress the AS mRNA content, even at an extracellular concentration 10 times below its plasma level. Other effective repressors included the amino acids asparagine, histidine and leucine, as well as ammonia. Depletion of selected single amino acids from an otherwise complete culture medium also caused up-regulation. In particular, removal of histidine, threonine or tryptophan from the medium, or the addition of histidinol to inhibit histidinyl-tRNA synthetase, resulted in a significant increase in AS mRNA content. The data indicate that nutrient regulation of AS mRNA occurs by a general control mechanism that is responsive to a spectrum of amino acids.
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PMID:Cloning of rat asparagine synthetase and specificity of the amino acid-dependent control of its mRNA content. 781 76

We showed previously that the abundance of serum albumin mRNA is decreased in H4-II-E rat hepatoma cells limited for a single essential amino acid (phenylalanine, methionine, leucine, or tryptophan). To define the specificity of this phenomenon, we examined the effect of amino acid limitation on the abundance of mRNAs for 19 genes in the H4-II-E cells. These genes included six genes whose expression is either completely liver-specific or highly enriched in the liver compared with other tissues [albumin, transthyretin (TTR), transferrin, carbamyl phosphate synthetase-I, urate oxidase, class I alcohol dehydrogenase], as well as a number of ubiquitously expressed "housekeeping" genes. The results indicated that the 19 genes could be divided into three classes based on their response to amino acid limitation. Class I genes (the six liver-specific genes and alpha-tubulin) exhibit decreased expression in response to amino acid limitation. The expression of class II genes [beta 2-microglobulin, hypoxanthine-guanine phosphoribosyl transferase (HPRT), H-ferritin, ubiquitin (UbB), insulin-like growth factor binding protein-4, HNF-1 alpha] is not significantly affected by amino acid limitation. Class III genes [gadd153, beta-actin, ubiquitin (UbC), phosphoglycerate kinase-1, C/EBP alpha, C/EBP beta] exhibit increased expression in response to amino acid limitation. Thus, specific inductive as well as repressive effects on gene expression are quite common in amino acid-limited cells. The observation that all six genes whose expression is liver-specific exhibited decreased expression in amino acid-limited cells suggests a common mode of regulation of these genes by amino acid availability. The strong induction by amino acid limitation of the C/EBP inhibitor gadd153 is of interest in this regard, as increased levels of gadd153 could interfere with C/EBP, which is required for high expression of most liver-specific genes. To investigate further the molecular mechanism for the decrease in albumin mRNA abundance, albumin nuclear transcript levels were quantified in control and tryptophan-limited cells. Tryptophan limitation caused a decrease in albumin nuclear transcript abundance, and this decrease preceded the decrease in albumin mRNA, suggesting that the decrease in albumin mRNA was caused at least partly by a decrease in albumin gene transcription. Additional experiments with actinomycin D indicated that albumin mRNA was also destabilized in the tryptophan-limited cells. Thus, the overall results indicate that the decrease in albumin mRNA in the tryptophan-limited cells is caused by a specific decrease in albumin nuclear transcript abundance and destabilization of albumin mRNA.
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PMID:Effect of amino acid limitation on the expression of 19 genes in rat hepatoma cells. 818 73

Familial amyloidotic polyneuropathy (FAP) is a genetic disease characterized by systemic amyloid deposition particularly in the peripheral nervous system. These deposits are composed mainly of a mutant form of the serum protein transthyretin (TTR) having a methionine for valine substitution at position 30-TTR Met 30. The factors involved in the formation of these deposits are unknown. The existence of animal models for FAP should allow elucidation of these factors. As one approach to the development of animal models for amyloidogenesis in FAP, we have constructed recombinant retrovirus vectors, carrying the full length human cDNA for either TTR or TTR Met 30 under the control of the Moloney murine leukemia virus (MoMLV) LTR element. After transfection of the packaging cell line, psi 2, viral stocks were used to infect a rat hepatoma cell line, H56, mouse fibroblast cell line, NIH3T3, and mouse primary fibroblasts. H56 cells efficiently secreted both TTR and TTR Met 30 as assessed by immunoprecipitation and ELISA, whereas NIH3T3 fibroblasts appeared not to release these proteins under the conditions tested. Primary fibroblasts secreted the mutant protein as assessed by ELISA. These genetically modified cells can be grafted into animals for in vivo study of amyloidogenesis, as well as be used in culture to investigate factors that might regulate the rate of amyloid deposition.
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PMID:Retrovirus-mediated gene transfer of transthyretin and transthyretin-methionine 30: a potential tool for the study of amyloidogenesis. 826 24

We screened for rat hepatocellular carcinoma (HCC)-related genes by a novel cDNA subtraction method and obtained one gene. This gene was transcribed as 2.0- and 2.5-kb mRNAs, and its transcription was specifically enhanced in HCC. These cDNAs had the same open reading frame, but the 2.5 kb transcript had an extra 495 bases of 5'-UTR at the 5'-terminus. The deduced aa sequence revealed a basic-leucine zipper (b-ZIP) and proline/glutamine-rich structures, both of which are characteristic motifs for transcription factors. We designated the translation product of this gene HTF (Hepatocarcinogenesis-related Transcription Factor). Electrophoretic mobility shift assay demonstrated the DNA-binding ability of the recombinant HTF. It is most interesting that HTF had a considerable homology with human XBP/TREB5, which has been reported to be a binding factor for the X-box of the MHC class II gene and for the 21-bp enhancer of the HTLV-1 LTR. Genomic Southern analysis suggested that the 2.0- and 2.5-kb mRNAs are transcribed by a dual promoter of a single gene. Our results may suggest that HTF is a b-ZIP-type transcription factor involved in rat hepatocellular carcinoma.
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PMID:HTF: A b-ZIP transcription factor that is closely related to the human XBP/TREB5 and is activated by hepatocellular carcinoma in rats. 868 68

Mouse hepatoma Hepa-lclc7 (Hepa-1) cells were cultivated in the presence of UV-irradiated amino acids. The results demonstrated that all of the amino acids tested, UV-oxidized tryptophan caused the highest induction of 7-ethoxyresorufin O-deethylase (EROD) activity compared with the controls (P < 0.01). The induction of EROD activity by oxidized tryptophan was dose dependent, and maximal induction was obtained at 12 hr after administration. Studies with various Hepa-1 mutants, which are defective in either the aryl hydrocarbon (Ah) receptor or Ah receptor nuclear translocator protein, indicated that the induction of EROD activity by oxidized tryptophan occurs through the Ah receptor. Gel mobility shift assays using nuclear extracts of Hepa-1 cells revealed that oxidized products of tryptophan can induce both Ah receptor transformation and binding of the liganded Ah receptor complex to its specific DNA recognition site. CYP1A1 mRNA, quantified by reverse transcription-polymerase chain reaction, and CYP1A1 protein were induced markedly in the oxidized tryptophan group compared with the controls. Injection of isolated oxidized tryptophan products into adult male rats caused significant induction of EROD activity in the pulmonary and hepatic microsomes compared with the controls (P < 0.01). These results demonstrated that oxidized tryptophan induces Ah receptor activation and binding of the liganded Ah receptor complex to its specific DNA recognition site, thereby initiating transcription and translation of the CYP1A1 gene with concomitant increase of EROD activity in Hepa-1 cells. Induction of EROD activity in the liver and lungs after injection of isolated oxidized tryptophan products into rats suggests that a similar mechanism may be operative in vivo.
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PMID:Induction of cytochrome P4501A1 by photooxidized tryptophan in Hepa lclc7 cells. 895 47

The influence of an antisense phosphorothioate oligonucleotide has been investigated on 7-ethoxyresorufin O-deethylase (EROD) activity and CYP1A1 protein in wild type mouse hepatoma Hepa lclc7 (Hepa-1) cells. The results show that administration of a 15-mer antisense phosphorothioate oligonucleotide in ribonucleoside-free minimum essential medium effectively inhibited UV-oxidized tryptophan-inducible EROD activity and CYP1A1 protein. The inhibition of EROD activity was dose- and time-dependent. The inhibition of oxidized tryptophan-inducible EROD activity after administration of 5 microM antisense oligonucleotide for 18 hours was 74% over the control oligonucleotide-administered cells. There was no effect of the control or antisense oligonucleotide on the cell growth. This is the first demonstration that inducible CYP1A1 can be effectively inhibited by antisense phosphorothioate oligonucleotide in Hepa-1 cells. Utility of this approach should be useful in elucidating the role(s) of CYP1A1 in chemical carcinogenesis.
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PMID:Inhibition of cytochrome P450 1A1 by antisense phosphorothioate oligonucleotide in Hepa lclc7 cells. 895 56

2,3,7,8-Tetrachlorodibenzo-p-dioxin and related environmental pollutants exert most of their adverse effects such as immunosuppression, induction of endocrine dysfunction, tumor promotion, and teratogenicity via the aryl hydrocarbon or dioxin receptor. While most potent agonists of the aryl hydrocarbon receptor are of synthetic origin, an increasing number of natural compounds are now recognized as receptor agonists. Our findings demonstrated that some tryptanthrin derivatives biosynthesized in incubations of Candida lipolytica with tryptophan and anthranilic acid or its derivatives were agonists of the aryl hydrocarbon receptor. The biosynthetic products 8-methyltryptanthrin, 8-chlorotryptanthrin, and 8-bromotryptanthrin induced cytochrome P4501A1 mRNA and protein in rat hepatocytes in primary culture, characteristic features of aryl hydrocarbon receptor agonists. Log-probit analysis of the catalytic activity of cytochrome P4501A1, 7-ethoxyresorufin O-deethylase (EROD), revealed EC50 induction values of 1.7, 0.25, and 0.17 microM for 8-methyltryptanthrin, 8-chlorotryptanthrin, and 8-bromotryptanthrin, respectively. Interestingly, the nonsubstituted tryptanthrin molecule, biosynthesized from the common physiological precursors tryptophan and anthranilic acid, was also active as an inducer. The specificity of the inducing effect of tryptanthrins was demonstrated in gel retardation experiments in Hepa-1 mouse hepatoma cells, showing the characteristic interaction of the activated aryl hydrocarbon receptor with an oligonucleotide containing a xenobiotic-responsive element. It is suggested that the receptor may be part of a defense system protecting higher organisms from secondary metabolites formed by the microflora of the host or its environment.
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PMID:Tryptanthrins: a novel class of agonists of the aryl hydrocarbon receptor. 929 63

99mTc-N-pyridoxyl-5-methyl-tryptophan (PMT) scintigraphy, which exhibits highly specific for the diagnosis of primary hepatocellular carcinoma (HCC), was performed for recurrent HCC following non-surgical treatment. Eighty-four patients (total 351 examinations) were selected for the study. The ability of PMT scintigraphy to diagnose recurrent HCC after treatment was compared with that of computed tomography, ultrasonography and angiography. The results showed that 1) sixty-three (75%) of 84 cases demonstrated positive findings during our follow-up period, 2) most of the tumors initially showing positive findings remained PMT positive when they recurred and 3) PMT studies shortly after treatment demonstrated wider tracer uptake rather than the actual tumor area. In conclusion. PMT scintigraphy for patients with HCC after non-surgical treatment exhibited high accuracy in identifying viable HCC only for tumors indicating positive findings.
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PMID:[Radionuclear estimation with 99mTc-N-pyridoxyl-5-methyl-tryptophan (PMT) scintigraphy of recurrent hepatocellular carcinoma after non-surgical treatment]. 939 70

The mutation in the Z deficiency variant of alpha1-antitrypsin perturbs the structure of the protein to allow a unique intermolecular linkage. These loop-sheet polymers are retained within the endoplasmic reticulum of hepatocytes to form inclusions that are associated with neonatal hepatitis, juvenile cirrhosis, and hepatocellular carcinoma. The process of polymer formation has been investigated here by intrinsic tryptophan fluorescence, fluorescence polarization, circular dichroic spectra and extrinsic fluorescence with 8-anilino-1-naphthalenesulfonic acid and tetramethylrhodamine-5-iodoacetamide. These biophysical techniques have demonstrated that alpha1-antitrypsin polymerization is a two-stage process and have allowed the calculation of rates for both of these steps. The initial fast phase is unimolecular and likely to represent temperature-induced protein unfolding, while the slow phase is bimolecular and associated with loop-sheet interaction and polymer formation. The naturally occurring Z, S, and I variants and recombinant site-directed reactive loop and shutter domain mutants of alpha1-antitrypsin were used to demonstrate the close association between protein stability and rate of alpha1-antitrypsin polymerization. Taken together, these data allow us to propose a kinetic mechanism for alpha1-antitrypsin polymer formation that involves the generation of an unstable intermediate, which can form polymers or generate latent protein.
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PMID:A kinetic mechanism for the polymerization of alpha1-antitrypsin. 1009 40

Recent studies from this laboratory have demonstrated that L-tryptophan, after oxidation either by UV-irradiation or ozone, induces aryl hydrocarbon receptor (AhR) activation and binding of the liganded AhR complex to its specific DNA recognition site, thereby initiating transcription of the cytochrome P-450 1a1 (Cyp1a1) gene with concomitant increase of CYP1A1 protein and 7-ethoxyresorufin O-deethylase activity in wild-type mouse hepatoma cells, Hepa lclc7 (Hepa-1), in culture. Temporary inhibition of protein synthesis by cycloheximide resulted in superinduction of oxidized tryptophan-inducible CYP1A1 mRNA, protein, and 7-ethoxyresorufin O-deethylase activity in Hepa-1 cells. In the present communication, the results obtained by immunoblot analyses with monoclonal CYP1A1/1A2 antibody (NIH 1-7-1) demonstrate that both UV- or ozone-oxidized tryptophan also induce CYP1A2 protein in Hepa-1 cells. CYP1A2 mRNA, detected by reverse transcription-polymerase chain reaction, was markedly induced in the UV- or ozone-oxidized tryptophan-treated cells. Temporary inhibition of protein synthesis by cycloheximide further induced oxidized tryptophan-inducible CYP1A2 mRNA as well as the protein in Hepa-1 cells. This is the first report demonstrating the induction of CYP1A2 mRNA and protein in Hepa-1 cells.
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PMID:Induction of cytochrome P-450 1A2 by oxidized tryptophan in Hepa lclc7 cells. 1068 17


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