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)

The paraneoplastic syndrome of erythrocytosis is associated with a variety of neoplasms including renal adenocarcinoma, cerebellar hemangioma, and hepatoma. We now report the characterization of the biological and molecular features of an erythropoietin-secreting human renal adenocarcinoma, designated RCCEp+. Serial transplantation of the tumor in athymic mice resulted in a dramatic increase in hematocrit and serum erythropoietin concentration. Growth in vitro was accompanied by a constant rate of erythropoietin secretion. Karyotype analysis demonstrated several unusual features, including the absence of 3p deletions and near tetraploidy. Erythropoietin mRNA was demonstrated by Northern blot both in freshly excised tumor and in tumor cells growing in vitro. Erythropoietin secretion was constitutive and was not induced either by cobalt or hypoxia. Southern blot analysis revealed no rearrangement of the erythropoietin gene in the tumor. Interestingly, in situ hybridization demonstrated erythropoietin mRNA in only a small population of the tumor cells. Further studies of RCCEp+ should prove useful in elucidating the molecular basis for this paraneoplastic syndrome.
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PMID:Constitutive secretion of erythropoietin by human renal adenocarcinoma cells in vivo and in vitro. 798 67

Erythropoietin (Epo), the hormone that stimulates red blood cell production, is induced by hypoxia. We have utilized the human hepatoma cell line, Hep3B, to investigate the regulation of the Epo gene. We present evidence that the oxygen sensor in Hep3B cells is a heme protein. Hypoxic and cobalt induction of Epo protein is paralleled by a 50- to 100-fold increase in Epo mRNA which we have accurately quantified by means of an assay based on competitive polymerase chain reaction. This increase in Epo mRNA is due primarily to increased transcription. Transfection experiments utilizing the sensitive luciferase reporter gene show that the minimal portions of the Epo gene required for hypoxic induction include a 53 bp promoter element and a 43 bp enhancer located downstream from the polyadenylation site. Gel shift experiments show that these two regions cross-compete for specific DNA binding proteins. The enhancer contains a hexanucleotide direct repeat with a two bp insert which footprints with nuclear extracts from Hep3B cells and, when mutated, results in loss of hypoxic induction. This sequence is likely to bind to a member of the steroid/thyroid hormone receptor family of DNA binding proteins. These enhancer and promoter elements appear to cooperate in enabling the Epo gene to respond to hypoxia in a physiologically appropriate manner.
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PMID:Regulation of the erythropoietin gene. 831 14

Serum erythropoietin (Epo) levels are depressed in anemic AIDS patients relative to controls. The basis for abnormal regulation of Epo has not been defined. The hepatoma cell line Hep3B produces Epo in response to hypoxia and serves as a model for the study of Epo regulation. Hep3B cells are infectible with human immunodeficiency virus-1 (HIV-1) and were used as a model for evaluating potential direct effects of HIV on Epo expression. HIV-1 infected or transfected Hep3B cells produced Epo at significantly lower levels than uninfected Hep3B cells under low O2 conditions or following exposure to cobalt chloride. Epo production induced by hypoxia of HIV-1 infected Hep3B cells was depressed compared with non-HIV containing Hep3B cells when normalized for cell number, total cellular protein or albumin, but not depressed when normalized for alpha-fetoprotein production. The cellular levels of Epo mRNA were not diminished in the HIV-1+ Hep3B cells, indicating a probable posttranscriptional effect of HIV-1 on Epo production. Cellular protein production or secretion rates as measured by precipitable 3H-leucine were not affected by the presence of HIV-1. HIV-1 appeared to depress the production of Epo and some, but not all, other cellular proteins. These results suggest that impaired production of Epo may be a direct effect of HIV-1 infection possibly contributing to anemia in AIDS.
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PMID:HIV-1 suppresses erythropoietin production in vitro. 839 Mar 70

The two steps of DNA digestion seen in apoptotic cells were recreated in nuclei isolated from 5123tc rat hepatoma cells. The initial DNA cleavage, into high molecular weight fragments (300-50 kb), was stimulated by magnesium ions alone, whereas the second step required both calcium and magnesium ions and produced the ladder of oligonucleosomes. Endonucleolytic activities involved in both steps of DNA cleavage could be separated under appropriate conditions since the magnesium-modulated activity was tightly bound to the chromatin whereas the calcium/magnesium-dependent internucleosomal cleaving activity was easily extractable with a low ionic strength buffer. This calcium/ magnesium-dependent activity was attributed to a novel 97 kDa endonuclease which was also activated by manganese and cobalt and inhibited by millimolar concentrations of zinc, consistent with the properties ascribed to the apoptotic endonuclease. Furthermore, this activity became resistant to extraction with a low salt buffer in nuclei of apoptotic cells. Isoelectrofocusing revealed that the p97 protein existed in multiple forms of different isoelectric points (pI range 4.6-5.0), indicative of its postranslational modification. The p97 enzyme was present constitutively in a variety of cultured cells and rat tissues. It was active over a broad range of pH (6-9), but it was inactivated by reducing agents. In vitro, it displayed both endo- and exonucleolytic activities, and it was capable of both single- and double-stranded DNA cleavage. Rabbit polyclonal anti-p97 antibodies were generated and used to further distinguish this protein from other known cellular nucleases, namely, DNases I and II.
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PMID:Identification of a novel 97 kDa endonuclease capable of internucleosomal DNA cleavage. 902 Jul 68

We have recently proposed a H2O2-generating b-type cytochrome as part of the cellular oxygen sensor that controls O2-dependent erythropoietin (Epo) production in the human hepatocellular carcinoma cell line HepG2. H2O2 could act as an intracellular signaling molecule because its production in HepG2 cells is strictly dependent on the pericellular PO2. High cellular levels of H2O2 inhibit hypoxia-induced Epo production while low levels-as under hypoxic conditions-allow full expression of the Epo gene. Since cobalt chloride (CoCl2) and the iron chelator desferrioxamine (DSF) both mimic the hypoxic induction of Epo production we studied the influence of CoCl2 and DSF on the formation and on the action of reactive O2-species with respect to Epo production. Both chemicals reduced the H2O2-dependent 123-dihydrorhodamine fluorescence in HepG2 cells. The inhibition of Epo production by exogenous H2O2 was completely antagonized by DSF. This might indicate that H2O2 exerts its inhibition through a Fenton type reaction. On the other hand, NADPH and pyrogallol which stimulate the production of O2- inhibited Epo production. CoCl2 antagonized their effects. From our results we propose different sites of interaction with the putative signaling chain for DSF and CoCl2. While DSF appears to reduce the action of the H2O2 molecule, CoCl2 might act further upstream through the induction of H2O2-scavenger systems or by interfering with its production.
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PMID:Cobalt chloride and desferrioxamine antagonize the inhibition of erythropoietin production by reactive oxygen species. 902 28

Although hypoxia (lack of oxygen in body tissues) is perhaps the most physiological inducer of the wild-type p53 gene, the mechanism of this induction is unknown. Cells may detect low oxygen levels through a haem-containing sensor protein. The hypoxic state can be mimicked by using cobalt chloride and the iron chelator desferrioxamine: like hypoxia, cobalt chloride and desferrioxamine activate hypoxia-inducible factor 1alpha (HIF-1alpha), which stimulates the transcription of several genes that are associated with hypoxia. Here we show that these treatments induce accumulation of wild-type p53 through HIF-1alpha-dependent stabilization of p53 protein. Induction of p53 does not occur in either a mutant hepatoma cell line that is unable to induce HIF-1alpha or embryonic stem cells derived from mice lacking HIF-1beta. HIF-1alpha is found in p53 immunoprecipitates from MCF7 cells that express wild-type p53 and are either hypoxic or have been exposed to desferrioxamine. Similarly, anti-haemagglutinin immunoprecipitates from lysates of normoxic PC3M cells that had been co-transfected with haemagglutinin-tagged HIF-1alpha and wild-type p53 also contain p53. Transfection of normoxic MCF7 cells with HIF-1alpha stimulates a co-transfected p53-dependent reporter plasmid and increases the amount of endogenous p53. Our results suggest that hypoxic induction of transcriptionally active wild-type p53 is achieved as a result of the stabilization of p53 by its association with HIF-1alpha.
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PMID:Stabilization of wild-type p53 by hypoxia-inducible factor 1alpha. 953 26

Nitric oxide (NO) is known to have various biologic and pathophysiologic effects on organisms. The molecular mechanisms by which NO exerts harmful effects are unknown, although various O2 radicals and ions that result from reactivity of NO are presumed to be involved. Here we report that adaptive cellular response controlled by the transcription factor hypoxia-inducible factor 1 (HIF-1) in hypoxia is suppressed by NO. Induction of erythropoietin and glycolytic aldolase A mRNAs in hypoxically cultured Hep3B cells, a human hepatoma cell line, was completely and partially inhibited, respectively, by the addition of sodium nitroprusside (SNP), which spontaneously releases NO. A reporter plasmid carrying four hypoxia-response element sequences connected to the luciferase structural gene was constructed and transfected into Hep3B cells. Inducibly expressed luciferase activity in hypoxia was inhibited by the addition of SNP and two other structurally different NO donors, S-nitroso-L-glutathione and 3-morpholinosydnonimine, giving IC50 values of 7.8, 211, and 490 microM, respectively. Inhibition by SNP was also observed in Neuro 2A and HeLa cells, indicating that the inhibition was not cell-type-specific. The vascular endothelial growth factor promoter activity that is controlled by HIF-1 was also inhibited by SNP (IC50 = 6.6 microM). Induction generated by the addition of cobalt ion (this treatment mimics hypoxia) was also inhibited by SNP (IC50 = 2.5 microM). Increased luciferase activity expressed by cotransfection of effector plasmids for HIF-1alpha or HIF-1alpha-like factor in hypoxia was also inhibited by the NO donor. We also showed that the inhibition was performed by blocking an activation step of HIF-1alpha to a DNA-binding form.
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PMID:Inhibition of hypoxia-inducible factor 1 activity by nitric oxide donors in hypoxia. 963 55

The Class 3 aldehyde dehydrogenase gene (ALDH3) is expressed differentially in a tissue-specific manner, occurring constitutively in some tissues and in others as a result of xenobiotic induction via the Ah receptor/ARNT pathway. ARNT is also involved in regulating gene expression in response to hypoxia. It dimerizes with hypoxia-inducible factor 1 alpha (HIF-1 alpha) and enhances expression of hypoxia-responsive genes. To determine if ARNT plays a role in regulating ALDH3 in response to low oxygen tension, we studied the effects of 1% oxygen and the hypoxia mimic cobalt chloride on constitutive and inducible ALDH3 expression in rat hepatoma cells and rat corneal epithelial cells. Hypoxia sharply down-regulates constitutive ALDH3 expression in corneal epithelial cells. Likewise, aromatic hydrocarbon-induced ALDH3 expression in H4-II-EC3 cells is significantly reduced by hypoxia. In contrast, hypoxia has no effect on constitutive or aromatic hydrocarbon-inducible ALDH3 expression in HTC cells. Our data indicate that hypoxia exerts cell type-specific effects on both constitutive and induced ALDH3 expression.
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PMID:Hypoxia exerts cell-type-specific effects on expression of the class 3 aldehyde dehydrogenase gene. 973 Dec 2

This study applies biophysical methods like light absorption spectrophotometry of cytochromes, determination of NAD(P)H-dependent superoxide anion (O2-) formation and localisation of hydroxyl radicals (*OH) by 3-dimensional (3D) confocal laser scanning microscopy to reveal in human cells putative members of the oxygen sensing signal pathway leading to enhanced gene expression under hypoxia. A cell membrane localised non-mitochondrial cytochrome b558 seems to be involved as an oxygen sensor in the hepatoma cell line HepG2 in cooperation with the mitochondrial cytochrome b563 probably probing additionally metabolic changes. *OH the putative second messenger of the oxygen sensing pathway generated by a Fenton reaction could be visualized in the perinuclear space of the three human cell lines used. Substances like cobalt or the iron chelator desferrioxamine, which have been applied in HepG2 cells to mimic hypoxia induced gene expression, interact on various sides of the oxygen sensing pathway confirming the importance of b-type cytochromes and the Fenton reaction.
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PMID:Cytochromes and oxygen radicals as putative members of the oxygen sensing pathway. 985 48

Hemopexin protects cells lacking hemopexin receptors by tightly binding heme abrogating its deleterious effects and preventing nonspecific heme uptake, whereas cells with hemopexin receptors undergo a series of cellular events upon encountering heme-hemopexin. The biochemical responses to heme-hemopexin depend on its extracellular concentration and range from stimulation of cell growth at low levels to cell survival at otherwise toxic levels of heme. High (2-10 microM) but not low (0.01-1 microM) concentrations of heme-hemopexin increase, albeit transiently, the protein carbonyl content of mouse hepatoma (Hepa) cells. This is due to events associated with heme transport since cobalt-protoporphyrin IX-hemopexin, which binds to the receptor and activates signaling pathways without tetrapyrrole transport, does not increase carbonyl content. The N-terminal c-Jun kinase (JNK) is rapidly activated by 2-10 microM heme-hemopexin, yet the increased intracellular heme levels are neither toxic nor apoptotic. After 24 h exposure to 10 microM heme-hemopexin, Hepa cells become refractory to the growth stimulation seen with 0.1-0.75 microM heme-hemopexin but HO-1 remains responsive to induction by heme-hemopexin. Since free heme does not induce JNK, the signaling events, like phosphorylation of c-Jun via activation of JNK as well as the nuclear translocation of NFkappaB, G2/M arrest, and increased expression of p53 and of the cell cycle inhibitor p21(WAF1/CIP1/SDI1) generated by heme-hemopexin appear to be of paramount importance in cellular protection by heme-hemopexin.
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PMID:Cellular protection mechanisms against extracellular heme. heme-hemopexin, but not free heme, activates the N-terminal c-jun kinase. 987 97


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