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)

An antiserum to the Rous sarcoma virus-transforming protein pp60v-src, raised in rabbits immunized with the bacterially produced protein alpha p60 serum (M. D. Resh and R. L. Erikson, J. Cell Biol. 100:409-417, 1985) previously reported to detect very specifically a novel population of pp60v-src and pp60c-src molecules associated with juxtareticular nuclear membranes in normal and Rous sarcoma virus-infected cells of avian and mammalian origin, was used here to investigate by immunofluorescence microscopy localization patterns of Src molecules in human cell lines, either normal or derived from spontaneous tumors. We found that the alpha p60 serum reveals nuclear and nucleolar concentrations of antigens in all the human cell lines tested and in two rat and mouse hepatoma cell lines derived from adult tumorous tissues but not in any established rat and mouse cell lines either untransformed or transformed by the src and ras oncogenes. Both the nuclear and nucleolar stainings can be totally extinguished by preincubation of the serum with highly purified chicken c-Src. We show also that the partitioning of the alpha p60-reactive proteins among the whole nucleus and the nucleolus depends mostly on two different parameters: the position in the cell cycle and the degree of cell confluency. Our observations raise the attractive possibility that, in differentiated cells, pp60c-src and related proteins might be involved not only in mediating the transduction of mitogenic signals at the plasma membrane level but also in controlling progression through the cell cycle and entry in mitosis by interacting with cell division cycle regulatory components at the nuclear level.
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PMID:Highly specific antibody to Rous sarcoma virus src gene product recognizes nuclear and nucleolar antigens in human cells. 785 7

Point mutations in ras protooncogenes and in the p53 tumor suppressor gene are common in many forms of human cancer. The identification of carcinogens which are responsible for their induction in humans is of great interest because it may suggest measures for disease prevention. Furthermore, the load of somatic mutations in cancer-related genes in premalignant tissues may become a useful parameter for risk assessment. For the measurement of such mutations, highly sensitive genotypic mutation systems are required which avoid the selection and clonal expansion of cells on the basis of a mutated phenotype. We have developed the restriction fragment length polymorphism/polymerase chain reaction method for genotypic mutation analysis and applied it to the study of the mutability of hot-spot codons in c-H-ras1 and p53 genes with human carcinogens. In particular, we studied the mutability of codons 247-250 of p53 with the mycotoxin aflatoxin B1 (AFB1) in human hepatocytes. AFB1 preferentially induced the transversion of guanosine to thymidine in the third position of codon 249, generating the same mutation which is found in a large fraction of hepatocellular carcinomas from regions of the world with AFB1-contaminated food. Our results are in support of AFB1 as an etiological factor for hepatocellular carcinoma in AFB1-contaminated areas. In an ongoing study we are comparing the load of mutations in hot-spot codon 12 of c-H-ras1 in urinary bladder carcinoma and in normal tissue, by restriction fragment length polymorphism/polymerase chain reaction. We observed moderately elevated abundances of guanosine to thymidine transversions in the middle position of codon 12 in tumor DNA. These results may reflect a mutator phenotype of the tumor tissue or they could be the consequence of the heterogeneity of the biopsies which were analyzed.
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PMID:Mutagenesis of the H-ras protooncogene and the p53 tumor suppressor gene. 790 48

To develop a model for studies of liver growth control, we characterized cell cycle synchronization of liver-derived cells with sodium butyrate. Exposure of cultured HTC (rat hepatoma) cells to 5 mM butyrate arrested cell growth in a reversible manner. Flow cytometric analysis revealed that butyrate-treated HTC cells were restricted in G0/G1, as well as S/G2M phases. After release from butyrate arrest, HTC cells underwent synchronous cycles of DNA synthesis and transited through S phase. Inhibition of cell growth by butyrate was associated with a complex pattern of cell cycle regulated gene expression, including a decoupling of c-fos and c-jun gene expression. Transcription of c-fos, as well as c-jun increased with butyrate arrest, whereas steady rate mRNA levels of c-jun only were increased, suggesting additional regulation of c-fos. In addition, butyrate-arrested cells exhibited a transcriptionally determined accumulation of H3 histone, C-Ha-ras and ornithine decarboxylase mRNAs, suggesting that cell cycle-related check points following the onset of S phase were modulated. An increase in c-myc mRNA levels in butyrate-arrested cells was post-transcriptionally regulated. After release from butyrate-arrest, the abundance of immediate early, as well as S phase regulated, gene expression changed coordinately with S phase cell transitions. Thus, exposure of HTC cells to butyrate modulates cell cycle regulated gene expression, inhibits cycling, and results in accumulation of cells in specific compartments. Synchronization of liver cells with butyrate should, therefore, provide a useful model for defining cell cycle-related events in response to various mitogenic stimuli.
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PMID:Butyrate synchronization of hepatocytes: modulation of cycling and cell cycle regulated gene expression. 794 6

Calcipotriol (MC903) is a side chain analog of the vitamin D hormone calcitriol, containing a 22-23 double bond, a 24(S)-hydroxyl function, and carbons 25, 26, and 27 incorporated into a cyclopropane ring which has been developed for treating psoriasis. The in vitro metabolism of calcipotriol was studied in two keratinocyte cell models, HPK1A and HPK1A-ras. Calcipotriol was initially converted into the 24-ketone (MC1046) and its 22,23-hydrogenated derivative (MC1080), metabolites observed in osteosarcoma, kidney, and hepatoma cell lines. We also observed the formation of further metabolites, identified as the two 23-hydroxylated derivatives of MC1080 (MC1439 and MC1441), the two 23,24-dihydroxylated compounds (MC1575 and 1577), and the side chain-cleaved compounds, tetranor-1,23-(OH)2D3 and calcitroic acid, the end products of catabolism of calcitriol. These findings suggest that calcitriol and calcipotriol may share catabolic enzymes. The biological activity of each of the principal metabolites of calcipotriol, assessed using a growth hormone reporter gene transcriptional activation system and a vitamin D receptor assay, was found to be lower than that of calcipotriol. If the extensive in vitro metabolism of calcipotriol is also found in normal and psoriatic keratinocytes in vivo, then this may explain the lack of systemic calcemic activity of topically applied drug.
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PMID:In vitro metabolism of the anti-psoriatic vitamin D analog, calcipotriol, in two cultured human keratinocyte models. 810 49

Chronic infection with hepatitis B virus (HBV) is accompanied by an increasing risk of developing hepatocellular carcinoma. There are indications that the HBx protein of HBV is involved in the process of tumour formation. HBx also transactivates several transcription factor binding sites. Recently, we reported that HBx can use a tumour promotor pathway for transactivation. In particular, we found that transactivation of the binding motif for transcription factor AP-1 (JUN/FOS) by HBx is dependent on functional protein kinase C (PKC), as indicated by abolition of the transcriptional stimulation following downregulation or inhibition of the enzyme. Moreover, HBx activates PKC, probably via increasing the endogenous PKC activator sn-1,2-diacylglycerol (DAG). Here we extend these data and report on the time course of PKC activation. We found that activation of PKC by HBx is transient and differs from activation of PKC by the ras oncogene product or phorbol ester in that it does not lead to rapid downregulation of the enzyme subsequent to the activation. Moreover, we provide evidence that an increase in cellular DAG is observable not only as an early event in response to HBx but also in cell lines transformed after transfection with HBV DNA and stably expressing HBx. Besides its important role in the regulation of cellular genes, PKC is also the intracellular receptor for tumour-promoting agents and an activator of proto-oncogenes, suggesting that our observations might provide an explanation for the oncogenic properties of HBx.
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PMID:The hepatitis B virus transactivator HBx causes elevation of diacylglycerol and activation of protein kinase C. 821 Jul 15

A rapid, simple, and nonradioactive method for diagnosing point mutations of c-K-ras oncogenes in gastroenterologic cancers is described. This method involved the selective amplification of DNA fragments from cancer tissues of surgical specimens with specific oligonucleotide primers, followed by digestion with restriction enzymes that recognized artificially created or naturally occurring restriction sites. To detect codon 12 mutations, an artificial Msp I site was created by introducing a single nucleotide mismatch into the 5' mutagenesis primer. Using a similar approach, an Hae III site was created to detect codon 13 mutations. Bal I and MBo II sites were used to detect codon 61 mutations. A total of 61 gastroenterologic cancer cases were studied. Of 35 cases of colorectal cancer, 7 showed mutations: 6 at codon 12 and 1 at codon 13. In 1 of 2 cases of cholangiocellular carcinoma, point mutation at codon 12 was found. One case of duodenal cancer showed point mutation at codon 12. No mutations were found in the cases of hepatocellular carcinoma (4), gastric cancer (12), esophageal cancer (3), or pancreatic cancer (2).
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PMID:Mutation analysis of K-ras oncogenes in gastroenterologic cancers by the amplified created restriction sites method. 824 18

Insertional mutagenesis of growth related genes by hepatitis B virus (HBV) DNA is presumed to play a role in hepatocarcinogenesis. Here, we report on insertional activation of the mevalonate kinase (MK) gene in the human hepatoma cell line PLC/PRF/5. Integration of HBV DNA dissociated the promoter and upstream regulatory elements of the gene from its coding sequences. This led to the over-expression of hybrid transcripts arising from an HBV promoter and the consequent over-production of functionally active mevalonate kinase. MK phosphorylates mevalonate, a major intermediate in the branched cholesterol/isoprenoid biosynthetic pathway. Isoprenylation is crucial to the functions of cellular proteins related to growth control, including the proto-oncogene ras. As the enzymes of these biosynthetic pathways are regulated at multiple points by negative feedback, both transcriptionally and at the protein level, the results discussed here support the idea that aberrant growth could result from deregulated overexpression of MK and, perhaps, other enzymes in the cholesterol pathway. These results invoke novel mechanisms by which cell transformation might occur.
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PMID:Insertional activation of mevalonate kinase by hepatitis B virus DNA in a human hepatoma cell line. 830 6

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

Biosynthesis of several rat liver proteins is enhanced by amino acid deprivation of cultured hepatocytes or hepatoma cells. One of these proteins, MP-73, was synthesized at a rate 2- to 3-fold greater when cells were incubated for 3-9 h under conditions of amino acid deprivation versus amino acid supplementation. Immunoblotting with polyclonal antibodies prepared against MP-73 localized it to the inner mitochondrial membrane. MP-73 appears to be a hydrophobic, integral membrane protein. MP-73 antibody was used to identify a partial cDNA (NS3.2) of approximately 2 kb. A probe prepared from pNS3.2 identified a transcript in rat Fao hepatoma cells of approximately 4.4 kb that was increased in abundance by more than 20-fold following amino acid starvation of the cells.
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PMID:Enhanced mRNA content in response to amino acid starvation for a 73 kDa protein of the inner mitochondrial membrane. 832 32

From an hepatocarcinoma cell line (LFCL.2A), unable to grow in a culture medium in which methionine was replaced by L-homocysteine, we had previously isolated revertant clones presenting a low growth rate, a loss of tumorigenicity and an inhibition of transcription of three oncogenes: c-Ki-ras, c-Ha-ras and c-myc. Here we showed that long-term deprivation of methionine led to a depletion of spermine, while putrescine and spermidine contents remained unchanged. When the revertant cells were shifted in a medium containing methionine, the oncogene transcription (except the p53 gene) started very rapidly in parallel with an increase in the putrescine content. By contrast, spermidine and spermine contents decreased during the first hours but were not significantly different from control values after numerous subcultures in methionine-containing medium.
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PMID:Polyamine content and oncogene expression in hepatoma cells in culture during methionine deprivation and refeeding. 839 Aug 3


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