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)

Male inbred Fischer rats were fed a diet containing 5 p.p.m. aflatoxin for 1, 3, 4 1/2 and 6 weeks at which times groups were killed for histological and histochemical study. Aflatoxin produced a scattered individual cell necrosis of parenchymal cells by 1 week. At 3 weeks small basophilic proliferative foci were seen which increased in size and abundance to 6 weeks. These foci showed starvation-resistant glycogen, variable depletion of glucose-6-phosphatase, succinic dehydrogenase, aniline hydrogenase, membrane ATPase and acid phosphatase. At 6 weeks the foci showed the presence of gamma glutamyl transpeptidase and glucose-6-phosphate dehydrogenase. The basophilic foci were not preceded by other focal histological and histochemical change. The basophilic proliferative lesions are observed when an irreversible change has been induced in the liver. The role of such lesions in the histogenesis of hepatocellular carcinoma is discussed.
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PMID:Histochemical studies on the early proliferative lesion induced in the rat liver by aflatoxin. 724 Dec 69

Rat hepatoma cells accumulate considerably less 2-aminoisobutyrate after cultivating in the absence of serum--the change in rate of aminoisobutyrate uptake takes place within 1 h of serum starvation. Starvation of amino acids by contrast raises aminoisobutyrate uptake in the presence or absence of serum, but the cells are much less responsive to amino acid supply than to availability of serum. Phosphate (10 mM) reduced aminoisobutyrate uptake by cells grown in serum to that exhibited by serum-starved cells. Aminoisobutyrate uptake by cells grown in serum was reduced by glycine, proline, alanine, serine, glutamine, methylaminoisobutyrate and 2-aminonorbornane-2-carboxylate, the effects of methylaminoisobutyrate and 2-aminonorbornane-2-carboxylate being additive. However, similar inhibition phenomena were not seen for cells deprived of serum where aminoisobutyrate uptake tended to a relatively constant level insensitive to inhibitory influences, yet substantially greater than that arising by simple diffusion. The comparative insensitivity of our hepatoma line when starved of serum to competition and repression phenomena is in contrast to findings of others. Our results also suggest a lack of clear delineation of specificities for the A and L transport systems as usually defined.
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PMID:Influence of serum and amino acids on the accumulation of aminoisobutyrate by rat hepatoma cells. A dedifferentiation of transport routes? 730 45

1. A systematic study is reported on the control of 1-phosphatidylinositol 4-kinase (PI kinase) and PI 4-phosphate 5-kinase (PIP kinase), enzymes of the phosphatidylinositol phosphorylation pathway which leads to the production of second messengers. IP3 and DAG. In liver of normal male, adult, fed Wistar rats the steady state activity of PI kinase was 0.5 +/- 0.01 and that of PIP kinase was 0.046 +/- 0.003 nmol/hr/mg protein. The concentration of IP3 was 1.8 +/- 0.1 pmol/mg protein. 2. That the two kinases have short half-lives was observed in starvation. where in the rat liver or bone marrow activities rapidly decreased and on refeeding were restored in a day. Injection to rats of the protein synthetic inhibitor, cycloheximide, yielded t1/2 = 80 min for the two enzymes in bone marrow and t1/2 = 80 min in liver. 3. Linkage of the signal transduction enzymes with proliferation was shown by the high activities as compared to liver of these enzymes in rat organs of high cell renewal capacity, e.g., thymus, bone marrow, spleen and testes. 4. Linkage with malignant proliferation was indicated by the observation that in rat hepatomas the enzyme activities increased 5- to 9-fold and were highest in rapidly growing hepatoma 3924A (29- and 45-fold). 5. In human primary ovarian carcinoma PI and PIP kinase activities were elevated 4.4 and 2.9-fold, respectively, and in OVCAR-5 cells, 32- and 11-fold, respectively. Similar increases were observed in MDA-MB-435 human breast carcinoma cells in comparison with normal breast parenchymal cells. 6. The linkage of signal transduction enzyme activities with malignant proliferation was also observed in experiments when human breast carcinoma cells were plated in flasks and expressed their proliferative capacity in the log phase. PI and PIP kinase activities steadily and coordinately increased to a peak 11-fold rise in mid-log phase. In late log and plateau phases the kinase activities gradually declined to the starting level. Similar observations were made for the two enzymes in human ovarian carcinoma OVCAR-5 cells and in rat hepatoma 3924A cells in tissue culture. 7. In animals injected with cycloheximide the bone marrow PI and PIP kinase activities exhibited t1/2 = 0.12 hr, the shortest decay rate in comparison with 8 enzymes of purine and pyrimidine biosynthesis with t1/2 = 0.6 to 4.3 hr. 8. Injection of tiazofurin decreased PI and PIP kinase activities in the bone marrow with t1/2 = 82 and 78 min, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation of signal transduction. 757 37

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

Starvation of mouse hepatoma cells for essential amino acids or glucose results in the ADP-ribosylation of the molecular chaperone BiP/GRP78. Addition of the missing nutrient to the medium reverses the reaction. The signal mediating the response to environmental nutrients involves the translational efficiency. An inhibitor of proteins synthesis, cycloheximide, or reduced temperature, both of which reduce translational efficiency, stimulate the ADP-ribosylation of BiP/GRP78. Inhibition of N-linked glycosylation of proteins results in the overproduction of BiP/GRP78. The over produced protein is not ADP-ribosylated suggesting that this is the functional form of BiP/GRP78. The over produced BiP/GRP78 can, however, be ADP-ribosylated if the cells are starved for an essential amino acid. BiP/GRP78 resides in the lumen of the endoplasmic reticulum where it participates in the assembly of secretory and integral membrane proteins. ADP-ribosylation of BiP/GRP78 during starvation is probably part of a nutritional stress response which conserves limited nutrients by slowing flow through the secretory pathway.
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PMID:ADP-ribosylation of the molecular chaperone GRP78/BiP. 789 57

Oral vanadate administration has been demonstrated to normalize blood glucose levels in ob/ob and db/db mice and streptozotocin (STZ) diabetic rats. The exact mechanism of this vanadate effect is uncertain, since there are no consistent effects on the insulin receptor tyrosine kinase activity or phosphotyrosine phosphatase activity. We have therefore studied the postreceptor actions of vanadate, focusing our attention on the steady-state levels of mRNA of enzymes involved in carbohydrate metabolism. When compared with their lean (ob/+) controls, the livers of ob/ob mice exhibited an approximately 90% reduction in the levels of phosphoenolpyruvate carboxykinase (PEPCK) mRNA and twofold to fivefold higher levels of the mRNAs for glyceraldehyde-3-phosphate dehydrogenase (GAPDH), the "liver beta-cell" glucose transporter (GLUT2), and the proto-oncogene c-myc. Administration of sodium vanadate (0.25 mg/mL) in the drinking water of ob/ob mice over a 45-day period resulted in a near normalization of blood glucose and increased PEPCK mRNA levels more than ninefold. Starvation of the ob/ob mice for 24 to 48 hours also increased PEPCK mRNA levels by fourfold to 15-fold. Vanadate treatment did not alter mRNA levels of any other proteins studied and had no effect on PEPCK mRNA in ob/+ mice. However, 1 to 100 mumol/L vanadate produced a concentration-dependent increase in PEPCK mRNA levels in an H35 hepatoma cell line, an effect opposite to the suppression of PEPCK mRNA produced by insulin. In summary, hyperglycemia in the ob/ob mouse is characterized by decreased expression of PEPCK and increased expression of GAPDH mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Vanadate normalizes hyperglycemia and phosphoenolpyruvate carboxykinase mRNA levels in ob/ob mice. 796 88

An amino acid starvation-induced mRNA, increased up to 4-fold in the absence of amino acids, was identified previously as rat 60 S subunit ribosomal protein L17. The data presented here demonstrate that among ribosomal proteins, L17, as well as the smaller subunit ribosomal protein S25, are uniquely regulated by amino acid deprivation of cells; the increase in L17 and S25 mRNA content in response to substrate starvation is not shared by the 11 other ribosomal proteins tested. When rat Fao hepatoma cells were incubated in the presence of actinomycin D, the L17 mRNA level decayed below the basal level, regardless of medium amino acid content, and nuclear run-off assays confirmed that nutrient starvation leads to enhanced transcription of the L17 ribosomal protein gene. Likewise, the induction of S25 mRNA also was prevented in the presence of actinomycin D. Furthermore, the induction of L17 and S25 mRNA content was blocked by cycloheximide, demonstrating the requirement for a newly synthesized protein in the signaling pathway. Northern analysis with RNA isolated from cytoplasmic, polysomal, and nuclear enriched fractions indicated that the starvation-dependent increase in the S25 and L17 mRNAs is retained within the nucleus and not is available for translation. Amino acid refeeding of the cells caused the translocation of the stored nuclear mRNAs to the polysomal fraction.
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PMID:Nuclear retention of the induced mRNA following amino acid-dependent transcriptional regulation of mammalian ribosomal proteins L17 and S25. 814 59

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

(1) Deoxycytidine kinase activity increased in a transformation- and progression-linked fashion in rat hepatomas of different proliferation rates. The activity also increased and was growth rate-linked in a series of tissue culture cell lines of human and animal tumors. (2) Deoxycytidine kinase activity was stringently linked with expression of the neoplastic proliferative program as it sharply increased in log phase in tissue culture cells of hepatoma 3924A and several human carcinoma strains. (3) Deoxycytidine kinase is subject to nutritional and hormonal regulation. On starvation the activity in liver decreased and on refeeding it returned to normal. Steroid hormone increased liver enzymic activity. Deoxycytidine kinase is substrate-inducible, since deoxycytidine injections in rat led to a 2- to 3-fold increase in hepatic enzyme activity. (4) Actinomycin or cycloheximide treatment blocked the increase in liver deoxycytidine kinase activity induced by steroid or deoxycytidine treatment. Therefore, it is assumed that the rise in deoxycytidine kinase activity requires new RNA and protein synthesis. (5) Cycloheximide treatment of rats carrying hepatomas yielded a t1/2 = 3.4 hr in the tumor for deoxycytidine kinase activity which was the shortest among the examined enzymes of purine and pyrimidine biosynthesis. (6) Actinomycin treatment of rats carrying hepatomas yielded a t1/2 of 5.8 hr for deoxycytidine kinase activity in the tumor which was one of the shortest in the examined enzymes of purine and pyrimidine biosynthesis. (7) Difluorodeoxycytidine (DFDC) is a competitive inhibitor (Ki = 7-28 microM) of deoxycytidine kinase from rat hepatoma and from human pancreatic carcinoma and ovarian carcinoma cells in culture.
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PMID:Regulation of deoxycytidine kinase activity and inhibition by DFDC. 835 16

1. We have established a murine hybridoma (F86) that secretes a monoclonal antibody (MoAb) specific for a 120 kDa nuclear protein (p120). p120 is expressed in all human cell lines investigated, whether of tumor or normal cell origin. 2. However, expression of p120 is significantly higher in neoplastic cells than in normal cells. The amount of p120 is relatively constant through the cell cycle and does not appear to be modulated by 72 hr serum starvation. 3. These results suggest that p120 plays some role in nuclear events associated with neoplastic phenotypes rather than in cell proliferation. 4. In situ immunofluorescence analyses indicate that p120 is located exclusively in nuclei of interphase cells. It is not present in nucleoli. 5. During mitosis, p120 is distributed in the cytoplasm and is not associated with condensed chromosomes which, together with RNAse experiments, suggests that it may be associated with hnRNA or hnRNP particles. 6. Western blot analyses indicate that p120 consists of two molecular weight forms which differ by 2-3 kDa in reduced SDS-PAGE, and several isoelectric variants in the acidic range. 7. Fractionation studies indicate that p120 has accessible free sulfhydryl group(s) and can bind ssDNA and heparin. 8. A partial cDNA clone, encoding the carboxyl terminus of p120, was isolated from a lambda gt11 library which had been prepared from human hepatoma cells (KYN-1). 9. Sequence analysis of the open reading frame revealed two possible nuclear localization sequences and several clusters of acidic amino acid residues, including a continuous run of 11 glutamic acid residues. 10. Northern blot analyses of human hepatoma RNA revealed hybridization to three transcripts which are about 4.1, 3.6, and 0.6 kb in size. 11. Dot blot analyses show that these transcripts are about 10-fold more abundant in KYN-1 hepatoma cells than in normal liver cells.
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PMID:A tumor-associated 120 kDa nuclear protein: characterization using a monoclonal antibody and a partial cDNA clone. 844 14


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