UMLS:C0019204 - FACTA Search

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

Reproducible induction of the enzyme tyrosine aminotransferase by dibutyryl cAMP (Bt2cAMP) in a line of HTC hepatoma cells in suspension culture requires that the cells be preinduced with dexamethasone, a synthetic glucocorticoid which itself induces tyrosine aminotransferase. Concentrations of dexamethasone that do not induce tyrosine aminotransferase fail to support Bt2cAMP induction, removal of the steroid from the medium leads to a loss of the Bt2cAMP effect, and an HTC cell line whose aminotransferase is not steroid-inducible does not respond to the cyclic nucleotide. We show that the further induction of tyrosine aminotransferase by Bt2cAMP in dexamethasone-treated cells is due to an increased rate of enzyme synthesis. The cyclic nucleotide has no effect on aminotransferase synthesis in cells grown in the absence of steroid. Several lines of evidence suggest that dexamethasone acts at a step beyond the activation of protein kinase by cAMP: (a) basal levels of cAMP are not altered by growth of HTC cells in dexamethasone; (b) accumulation of cAMP from the medium is not enhanced; (c) the glucocorticoid does not induce cAMP-dependent protein kinase in HTC cells; and (d) there is no augmentation of cAMP binding to the regulatory protein, nor is there any change in cAMP activation of protein kinase caused by growth in dexamethasone. These results help define a system that should be useful in studying the interaction of cyclic nucleotides and steroid hormones.
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PMID:Interaction of glucocorticoid hormones and cyclic nucleotides in induction of tyrosine aminotransferase in cultured hepatoma cells. 1 22

We previously observed that Ser378 in the heparin-binding domain of vitronectin becomes phosphorylated by a protein kinase in plasma upon addition of ATP and divalent cations. We now report that purified plasma vitronectin contains approximately 2.5 mol of phosphate per mol of protein and that vitronectin becomes phosphorylated during biosynthesis in human hepatoma (HepG2) cells. In vitro, rabbit muscle cAMP-dependent protein kinase specifically phosphorylates Ser378 in single-chain (75 kDa) vitronectin but does not phosphorylate the two-chain (65/10 kDa) form cleaved at Arg379. Heparin affects neither the time course nor the extent of phosphorylation of Ser378 at neutral pH. The extent of phosphorylation of Ser378 achieved with cAMP-dependent protein kinase (greater than or equal to 0.3 mol phosphate per mol vitronectin) is greater than that obtainable in plasma and should enable comparisons to be made of the activities of the native and phosphorylated forms.
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PMID:Cyclic AMP-dependent protein kinase phosphorylates serine378 in vitronectin. 171 1

We applied Southwestern and Western blotting and gel retardation techniques to investigate the changes that occur in the cyclic adenosine monophosphate (cAMP)-responsive element (CRE) binding (CREB) proteins in rapidly growing, chemically induced 5123tc and 5123D Morris hepatomas. Using the CRE sequences from the c-fos, E2A, and somatostatin gene promoters, we identified in the nuclear proteins from normal unstimulated or proliferating rat liver cells six different protein factors of Mr 34,000, 36,000, 40,000, 47,000, 56,000, and 72,000 capable of binding to the element. The Mr 47,000 protein had the highest specificity for the core CRE, suggesting its importance in cAMP-mediated gene expression. We could not find the Mr 47,000 CREB protein in the 5123tc and 5123D hepatomas. Our efforts to detect this protein in the tumors by (a) using the CRE sequence from different gene promoters, (b) altering the protocol for extracting nuclear proteins, or (c) attempting to restore its DNA-binding property by phosphorylation [with endogenous protein kinase(s), a catalytic subunit of cAMP-dependent protein kinase, and protein kinase C/dephosphorylation (with alkaline phosphatase)] were unsuccessful. The loss of tje Mr 47,000 CREB protein from solid tumors of the Morris hepatoma is likely to be related to the neoplastic properties of the tumor cell rather than to cell growth because the level of this protein remained unchanged during a 6-day period of liver regeneration. The nuclear extract from the Morris hepatoma that did not have the Mr 47,000 CRE-binding factor contained proteins immunologically related to the CREB, c-Jun, and c-Fos proteins. We conclude that the Mr 47,000 factor represents a distinct member of the CRE-binding protein family and that its absence from the hepatomas may lead to aberrant expression of cAMP-inducible genes.
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PMID:Changes in cyclic adenosine monophosphate-responsive element binding proteins in rat hepatomas. 182 83

Tissue-specific extinguisher 1 (TSE1) is a trans-acting locus on human chromosome 17 that down-regulates expression of seven liver genes in hepatoma x fibroblast hybrids. To study the mechanism by which TSE1 functions, we used subtractive cDNA hybridization to clone transcripts encoded within a 2-4 Mb segment of chromosome 17 that includes TSE1. High resolution mapping within this region indicated that 8 of 9 different human cDNAs so obtained were distinct from TSE1. The remaining cDNA clone mapped concordantly with TSE1 in a panel of fragment-containing hybrids. DNA sequencing indicated that this cDNA encoded regulatory subunit RI alpha of cAMP-dependent protein kinase, and RI alpha mRNA levels correlated with TSE1 activity in various hybrid lines. Stable transfection of wild-type or cAMP-binding mutant RI alpha alleles into hepatoma recipients produced an extinction phenotype indistinguishable from that encoded by human TSE1. We conclude that TSE1 encodes a regulatory subunit of protein kinase A whose activity differs in different cell types.
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PMID:Subtractive hybridization cloning of a tissue-specific extinguisher: TSE1 encodes a regulatory subunit of protein kinase A. 188 88

A complementary DNA (cDNA) clone (B4) encoding the catalytic subunit of a cAMP-dependent protein kinase (PKAc) was isolated from a lambda gt10 rat brain cDNA library, using a synthetic oligonucleotide probe whose sequence was based on the known amino acid sequence of a bovine cardiac PKAc. Sequence analysis of this clone revealed a region of 1002 nucleotides which encodes a protein that is 92% homologous to amino acids 17-350 of the bovine cardiac PKAc protein. This clone lacks coding sequences for amino acids 1-16 of the latter protein. Nevertheless, it provided a useful probe to analyze expression of the related gene in a variety of systems. Northern blot analyses using a 32P-labeled probe prepared from a 0.6-kilobase PstI fragment of clone B4 revealed an abundant 4.6-kilobase band in rat brain RNA and lesser amounts of this 4.6-kilobase RNA in rat heart and liver. A 4.6-kilobase RNA was also detected in RNA samples obtained from mouse fibroblasts. This probe also detected homologous RNA in a variety of nonrodent species. In subsequent experiments, this cDNA was used as a probe to elucidate the role of PKAc in post-surgical hepatic regeneration and diethylnitrosamine-induced hepatomas in the rat. These experiments revealed that, following partial hepatectomy, PKAc mRNA is decreased 3-fold by 12 h, returning to normal by 72 h; hepatomas showed no consistent pattern of change in PKAc mRNA levels as compared to controls. Our results indicate that this cDNA encodes an isoform of PKAc which is distinct from PKAc-alpha isolated by Uhler et al. (Proc. Natl. Acad. Sci. USA, 83: 1300-1304, 1986) but highly homologous to PKAc-beta isolated by Showers and Maurer (J. Biol. Chem., 261: 16288-16291, 1986), that depression of cAMP-dependent protein phosphorylation may be an important mechanism in the regeneration of mature rat liver but is not a consistent alteration in chemically induced hepatoma, and that this cDNA is useful as a probe for the study of the role of PKAc gene expression in growth control, particularly in rodent species.
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PMID:Isolation of a complementary DNA encoding the catalytic subunit of protein kinase A and studies on the expression of this sequence in rat hepatomas and regenerating liver. 230 20

Basic fibroblast growth factor (FGF) is synthesized as a phosphoprotein by both bovine capillary endothelial and human hepatoma cells in culture. Because basic FGF is characterized by its high affinity for heparin and its association in vivo with the extracellular matrix, we examined the possibility that the phosphorylation of this growth factor by purified protein kinase C (PK-C) and the catalytic subunit of cAMP-dependent protein kinase-A (PK-A) can be modulated by components of the extracellular matrix. Heparin and other glycosaminoglycans (GAGs) inhibit the ability of PK-C to phosphorylate basic FGF. In contrast, heparin can directly increase the phosphorylation of basic FGF by PK-A. While fibronectin, laminin, and collagen IV have no effect on the ability of PK-C to phosphorylate basic FGF, they all can inhibit the effects of PK-A. Thus, there is a differential effect of extracellular matrix-derived proteins and GAGs on the phosphorylation of basic FGF. The enhanced phosphorylation of basic FGF that is mediated by heparin is associated with a change in the kinetics of the reaction and the identity of the amino acid targeted by this enzyme. The amino acids that are targeted by PK-C and PK-A have been identified by phosphopeptide analyses as Ser64 and Thr112, respectively. In the presence of heparin, basic FGF is no longer phosphorylated by PK-A at the usual PK-A consensus site (Thr112), but instead is phosphorylated at the canonical PK-C site (Ser64). Accordingly, heparin inhibits the phosphorylation of basic FGF by PK-C presumably by masking the PK-C dependent consensus sequence surrounding Ser64. Thus, when basic FGF is no longer phosphorylated by PK-A in the receptor binding domain (Thr112), it loses the increased receptor binding ability that characterizes PK-A phosphorylated basic FGF. The results presented here demonstrate three novel features of basic FGF. First, they identify a functional effect of the binding of heparin to basic FGF. Second, they establish that the binding of heparin to basic FGF can induce structural changes that alter the substrate specificity of protein kinases. Third, and perhaps most important, the results demonstrate the existence of a novel interaction between basic FGF, fibronectin, and laminin. Although the physiological significance of this phosphorylation is not known, these results clearly suggest that the biological activities of basic FGF are regulated by a complex array of biochemical interactions with the proteins, proteoglycans, and glycosaminoglycans present in the extracellular milieu and the cytoplasm.
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PMID:Differential effects of heparin, fibronectin, and laminin on the phosphorylation of basic fibroblast growth factor by protein kinase C and the catalytic subunit of protein kinase A. 259 18

beta-Glucuronidases purified from human hepatoma and from normal liver could serve as a substrate for a cAMP-dependent protein kinase. The rate of phosphorylation reaction of the hepatoma beta-glucuronidase was rapid, whereas that of the normal liver beta-glucuronidase was slow and much lower. Stoichiometry of phosphorylation was 4.3 and 0.46 mol of phosphate/mol of the beta-glucuronidase from the hepatoma and normal liver, respectively. Tryptic peptide mapping of 32P-labeled beta-glucuronidase from hepatoma identified two distinct phosphopeptides (X and Y). The peptide from hepatoma hydrolase was phosphorylated predominantly at the X, while the peptide Y was the major phosphopeptide in the hydrolase of normal liver. Analysis of phosphoamino acids revealed two sites, phosphoserine and phosphothreonine. beta-Glucuronidase from hepatoma consisted of a major subunit with molecular mass of 64,000 (64 kDa) and a minor subunit with 76 kDa, whereas the hydrolase from normal liver had almost exclusively 64 kDa subunit. 32P-labeled beta-glucuronidase indicated that the 64 kDa subunit was phosphorylated both in hepatoma and normal liver beta-glucuronidases.
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PMID:Phosphorylation of beta-glucuronidases from human normal liver and hepatoma by cAMP-dependent protein kinase. 283 20

beta-Glucuronidase purified from human hepatocellular carcinoma consisted of a major subunit with molecular weight of 64,000 (64K-Da) and a minor 76K-Da subunit, whereas the hydrolase from normal liver had almost exclusively 64K-Da subunit. beta-Glucuronidase from the hepatoma and normal liver could serve as a substrate for a cAMP-dependent protein kinase. The rate of phosphorylation reaction of the hepatoma beta-glucuronidase was rapid, whereas that of the normal liver beta-glucuronidase was slow and much lower. Stoichiometry of beta-glucuronidase was 4.3 mol and 0.46 mol of phosphate per mol of the beta-glucuronidase from the hepatoma and normal liver, respectively. Sodium dodecyl sulfate polyacrylamide gel electrophoresis of 32P-labeled beta-glucuronidase indicated that the 64K-dalton subunit was phosphorylated both in hepatoma and normal liver beta-glucuronidase. Tryptic peptide mapping of 32P-labeled beta-glucuronidase from hepatoma identified two distinct phosphopeptides (X and Y). The peptide from hepatoma hydrolase was phosphorylated predominantly at the X, while the peptide Y was the major phosphopeptide in the hydrolase of normal liver. Two-dimensional analysis of phosphoamino acids revealed two sites, phosphoserine and phosphothreonine.
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PMID:[Cancer-associated alterations of human hepatocellular carcinoma beta-glucuronidase--study on phosphorylation by 3', 5'-cyclic AMP dependent-protein kinase]. 283 6

The purpose of these studies was to determine whether the catalytic subunit of cAMP-dependent protein kinase is involved in the regulation of P-enolpyruvate carboxykinase (PEPCK) gene transcription. Cyclic AMP analog pairs that preferentially stimulate either type I or type II protein kinase in a synergistic manner were used to compare regulation of mRNAPEPCK synthesis in H4IIE rat hepatoma cells with protein kinase activation in vitro. Type II protein kinase is predominant in H4IIE cells and analog pairs directed toward this isozyme resulted in a synergistic increase of mRNAPEPCK that was due to a corresponding enhancement of PEPCK gene transcription. When compared to a single analog the addition of a type II-directed analog pair reduced the total analog concentration required for maximal induction of transcription by about 30-fold. H4IIE cells have a small amount of type I kinase; pairs specific for this form of the enzyme were also effective, but to a lesser extent than those for the type II kinase. (Rp)-cAMPS, a cyclic nucleotide-dependent protein kinase antagonist, inhibited the agonist-induced increase of mRNAPEPCK in a concentration-dependent manner. The results indicate that the activation of PEPCK gene transcription by cAMP in H4IIE cells is mediated by cAMP-dependent protein kinase. Although the type II isozyme is primarily responsible, type I is also effective. These isozymes have identical catalytic subunits, hence this component presumably mediates the cAMP effect.
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PMID:Regulation of phosphoenolpyruvate carboxykinase gene transcription in H4IIE hepatoma cells: evidence for a primary role of the catalytic subunit of 3',5'-cyclic adenosine monophosphate-dependent protein kinase. 285 13

Insulin caused a rapid, dose-dependent increase in the binding of 125I-insulin-like growth factor-II (IGF-II) to the surface of cultured H-35 hepatoma cells. The [32P]phosphate content of the IGF-II receptors, immunoprecipitated from extracts of H-35 cell monolayers previously incubated with [32P]phosphate for 24 h, was decreased after brief exposure of the cells to insulin. Analysis of tryptic digests of labeled IGF-II receptors by bidimensional peptide mapping revealed that the decrease in the content of [32P]phosphate occurred to varying degrees on three tryptic phosphopeptides. Thin layer electrophoresis of an acid hydrolysate of isolated IGF-II receptors revealed the presence of [32P] phosphoserine and [32P]phosphothreonine. Insulin treatment of cells caused a decrease in the labeled phosphoserine and phosphothreonine content of IGF-II receptors. The ability of a number of highly purified protein kinases (cAMP-dependent protein kinase, protein kinase C, phosphorylase kinase, and casein kinase II) to catalyze the phosphorylation of purified IGF-II receptors was examined. Casein kinase II was the only kinase capable of catalyzing the phosphorylation of the IGF-II receptor on serine and threonine residues under the conditions of our assay. Bidimensional peptide mapping revealed that the kinase catalyzed phosphorylation of the IGF-II receptor on a tryptic phosphopeptide which comigrated with the main tryptic phosphopeptide found in receptors obtained from cells labeled in vivo with [32P]phosphate. IGF-II receptors isolated by immunoadsorption from insulin-treated H-35 cells were phosphorylated in vitro by casein kinase II to a greater extent than the receptors isolated from control cells. Similarly, IGF-II receptors from plasma membranes obtained from insulin-treated adipocytes were phosphorylated by casein kinase II to a greater extent than the receptors from control adipocyte plasma membranes. Thus, the insulin-regulated phosphorylation sites on the IGF-II receptor appear to serve as substrates in vivo for casein kinase II or an enzyme with similar substrate specificity.
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PMID:Insulin action inhibits insulin-like growth factor-II (IGF-II) receptor phosphorylation in H-35 hepatoma cells. IGF-II receptors isolated from insulin-treated cells exhibit enhanced in vitro phosphorylation by casein kinase II. 296 23

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