Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activated c-raf(-1) gene was found in three transformants obtained by transfecting DNAs from rat hepatocellular carcinoma, metastasis of human colon cancer in mesocolon and normal mucosa from a different colon cancer patient. Rat and human activated c-raf(-1) genes were cloned into cosmid vectors; restriction enzyme mapping revealed both activated c-raf(-1) genes to have rearrangement in the center of the normal form of the gene, and the upstream sequences were replaced by unrelated sequences. Using genomic DNA fragments located immediately downstream of the recombination points, the activations of all these c-raf(-1) were shown to have occurred during the transfection process. The recombination points in both the rat and human clones isolated were located in the intron between exons 7 and 8, and nucleotide sequencing around these recombination points showed there to be an inverted repeat which could be involved in inducing in vitro recombination. Nucleotide sequencing of rat and human c-raf(-1) cDNAs revealed the upstream sequences, recombined to the 3' half of c-raf(-1), to be expressed as fusion mRNAs; the production of fused proteins was predicted from a long open reading frame, which is in-frame with the kinase domain encoded from the 3' half of the c-raf(-1) gene. There is a cysteine clustering region in an N-terminal region of the c-raf(-1) product deduced from the nucleotide sequence, and this cysteine clustering region was found to be highly homologous to that present in an N-terminal region of protein kinase C, although, in the latter cysteine clusters are present in duplicate. From analogy with the activation mechanism of protein kinase C, the N-terminal region of serine/threonine kinase coded by the c-raf(-1) gene is suggested to be a regulatory part of the enzyme activity, and it proposed that the replacement or truncation of this regulatory part could be the mechanism whereby c-raf(-1) is activated.
 ...
PMID:Activation of rat and human c-raf(-1) by rearrangement. 333 22

Human hepatoma cell lines (Hep 3B-TS, PLC/PRF/5, and Hep G2), sensitive to growth inhibition by transforming growth factor beta 1 (TGF-beta 1), express TGF-beta receptors type I, type II, and type III. We report that TGF-beta 1 protein selectively increased steady-state levels of the mRNA for the serine/threonine kinase receptor 1 (SKR1), a member of the TGF-beta superfamily receptor genes in these cells, whereas TGF-beta 1 had little effect on expression of the TGF-beta receptor type II gene. This increase of SKR1 mRNA in Hep 3B-TS cells could be detected by Northern blot analysis within 3 h of addition of TGF-beta 1 to the cells, and enhanced message levels peaked at 12 h as long as TGF-beta 1 was present in the culture medium. Hep 3B-TR cells which were resistant to TGF-beta 1 due to lack of both TGF-beta receptors type I and type II, expressed SKR1 mRNA, but it was not induced by TGF-beta 1 protein. The increased expression of SKR1 mRNA in the cells was actinomycin D-sensitive and was not dependent on new protein synthesis. The results indicate that TGF-beta 1 selectively induces SKR1 message at a transcriptional level by a positive regulator.
 ...
PMID:Transforming growth factor beta 1 selectively increases gene expression of the serine/threonine kinase receptor 1 (SKR1) in human hepatoma cell lines. 785 Aug 92

We have studied insulin-stimulated threonine phosphorylation of cellular proteins by immunoblotting and immunoprecipitation using antiphosphothreonine antibody (anti-P-Thr). A 50-kilodalton protein (p50) was found to be greatly phosphorylated on threonine residues upon insulin stimulation in intact rat hepatoma cells (Fao) and Chinese hamster ovary cells overexpressing human insulin receptor (CHO-HIR). Insulin induced threonine phosphorylation of this protein in a dose-dependent manner, with an ED50 of 3-6 x 10(-9) M. The 50-kilodalton phosphoprotein (pp50) was detectable 20 min after exposure of the cells to insulin, and phosphorylation reached a maximum after 90 min. Immunoprecipitation of pp50 with anti-P-Thr required extraction of the cellular proteins with sodium dodecyl sulfate and dithiothreitol, and subcellular fractionation of the cells revealed that pp50 is present in the membrane fraction, implying that pp50 is a protein integrated into the membrane component in the cells. Tryptic phosphopeptide mapping of the pp50 was distinct from that of the insulin receptor beta-subunit. Phosphoamino acid analysis of the pp50 demonstrated that insulin increased phosphorylation, mainly of threonine and moderately of serine, whereas pp50 did not contain phosphotyrosine. Cycloheximide, a protein synthesis inhibitor, did not affect the insulin-induced appearance of pp50 in the cells. pp50 was not detectable in A431 cells and KB cells stimulated by epidermal growth factor. These data suggest that p50 is a novel endogenous substrate for insulin-sensitive serine/threonine kinase in intact cells.
 ...
PMID:A novel substrate for insulin-sensitive serine/threonine kinase in intact cells. 792 13

To investigate the regulation of expression of the human mdr1 gene, the response of the mdr1 promoter to signals involved in cell proliferation was examined. The activity of the mdr1 promoter was measured in transiently transfected NIH 3T3 cells, which were stimulated to enter the cell cycle by addition of serum, platelet-derived growth factor, or transforming growth factor alpha. Addition of serum to quiescent NIH 3T3 cells resulted in a 6-8-fold activation of mdr1 promoter activity, which peaked at 10 h, just prior to S-phase. Treatment of serum-starved cells with the serum mitogens platelet-derived growth factor and transforming growth factor alpha also activated the mdr1 promoter. To define components of the signal cascade resulting in mdr1 promoter activation, the role of c-Raf kinase, a serine/threonine kinase important in mitogen-activated signal transduction, was examined. We measured the effects of a constitutively activated Raf kinase, v-raf, and a dominant negative Raf mutant, c-Raf-C4, on mdr1 promoter activity in NIH 3T3 and HepG2 cells. In serum-starved NIH 3T3 cells, v-raf increased mdr1 promoter activity approximately 10-fold compared to a v-raf frame-shift control. Raf responsiveness of the mdr1 promoter was localized to sequences between -69 and -41, relative to the initiation site. Serum stimulation of the mdr1 promoter was blocked by co-transfection of NIH 3T3 cells with the dominant negative Raf mutant c-Raf-C4. In the human hepatoma cell line HepG2, which has high endogenous Raf kinase activity (Bruder, J. T., Heidecker, G., and Rapp, U. R. (1992) Genes & Dev. 6, 545-556), co-transfection with c-Raf-C4 decreased mdr1 promoter activity 20-fold. Taken together, these data suggest that the mdr1 gene is transcriptionally regulated by normal cellular signaling events involving activation of c-Raf kinase.
 ...
PMID:A signal transduction pathway for activation of the mdr1 promoter involves the proto-oncogene c-raf kinase. 810 39

Hepatic metabolism and gene expression are among other regulatory mechanisms controlled by the cellular hydration state, which changes rapidly in response to anisotonicity, concentrative substrate uptake, oxidative stress, and under the influence of hormones such as insulin and glucagon. Differential screening for cell volume sensitive transcripts in a human hepatoma cell line revealed a gene for a putative serine/threonine kinase, h-sgk, which has 98% sequence identity to a serum- and glucocorticoid regulated kinase, sgk, cloned from a rat mammary tumor cell line. h-sgk transcript levels were strongly altered during anisotonic and isotonic cell volume changes. Within 30 min h-sgk RNA was, independent of de novo protein synthesis, induced upon cell shrinkage and, due to a complete stop in h-sgk transcription, reduced upon cell swelling. Comparable changes of sgk transcript levels were observed in a renal epithelial cell line. h-sgk mRNA was detected in all human tissues tested, with the highest levels in pancreas, liver, and heart. The putative serine/threonine protein kinase h-sgk may provide a functional link between the cellular hydration state and metabolic control.
 ...
PMID:Cloning and characterization of a putative human serine/threonine protein kinase transcriptionally modified during anisotonic and isotonic alterations of cell volume. 911 8

The BCR gene is located on human chromosome 22. The normal cellular BCR gene encodes a 160,000-dalton phosphoprotein associated with a serine/threonine kinase activity. The BCR protein is involved in signal transduction. We investigated the expression of the BCR protein in hepatocellular carcinoma (HCC), surrounding noncancerous liver tissue, liver cirrhosis (LC), chronic hepatitis (CH), and normal liver with immunohistochemistry and a western blot analysis. BCR immunoreactivity was detected using a monoclonal antibody. In normal liver, and both CH and LC without association of HCC, the immunoreactivity of the BCR protein was minimal. In contrast, 73% (22 of 30) of noncancerous liver tissue adjacent to the HCC and 40% (12 of 30) of HCC expressed BCR protein; this difference was statistically significant (P < 0.01). The expression of the BCR protein expression correlated with the degree of histological differentiation of HCC (P < 0.05). In addition, the amplification of BCR protein in noncancerous cells was supported by the detection of specific protein using a western blot analysis. In two cases, the expression of BCR protein occurred only in overtly malignant HCC cells. As a result, the expression of the BCR protein may be associated with oncogenesis in human HCC.
 ...
PMID:Amplification of BCR protein associated with oncogenesis in human hepatocellular carcinoma. 914 44

The tumor-promoting phorbol ester, phorbol 12-myristate 13-acetate (PMA), acutely stimulates the tyrosine phosphorylation of proteins of approximately 190, 120, and 70 kDa in the well differentiated Fao rat hepatoma cell line. This phosphorylation is dependent on protein kinase C (PKC) and is abolished by down-regulation of PKC or pretreatment with a PKC inhibitor. Purification of the 190-kDa tyrosine-phosphorylated protein revealed that it consists of both ErbB2 and ErbB3. Following PMA-induced tyrosine phosphorylation, ErbB2 and ErbB3 were able to associate with the SH2 domains of several signaling proteins including the p85alpha subunit of phosphatidylinositol 3-kinase, Syp, and Grb2. The 120-kDa protein phosphorylated in response to PMA consists of at least two proteins: focal adhesion kinase that exhibits a minor increase in tyrosine phosphorylation following treatment with PMA, and a major 120-kDa tyrosine-phosphorylated species in PMA-stimulated Fao cells which as yet is unidentified. Similarly, the 70-kDa tyrosine-phosphorylated protein also appears to represent more than one protein, including paxillin and a second protein of similar mobility which appears to be the major tyrosine phosphorylation in response to PMA. Both ErbB2 and paxillin also exhibit reduced migration on SDS-polyacrylamide gel electrophoresis following PMA treatment, suggesting that they are also phosphorylated on serine/threonine residues. The mobility shift of both of these proteins is abolished by treatment with inhibitors of PKC or mitogen-activated protein kinase/extracellular signal-related kinase kinase. These results suggest a novel mechanism of cross-talk between the serine/threonine kinase PKC and tyrosine phosphorylation pathways. The activation of ErbB2 and ErbB3 that is initiated by PMA may contribute to the tumor promoting activity of these compounds.
 ...
PMID:Cross-talk between phorbol ester-mediated signaling and tyrosine kinase proto-oncogenes. I. Activation of protein kinase C stimulates tyrosine phosphorylation and activation of ErbB2 and ErbB3. 938 71

Insulin regulates the expression of multiple hepatic genes through a conserved insulin response sequence (IRS) (CAAAAC/TAA) by an as yet undetermined mechanism. Protein kinase B/Akt (PKB/Akt), a member of the PKA/PKC serine/threonine kinase family, functions downstream from phosphatidylinositol 3'-kinase (PI3K) in mediating effects of insulin on glucose transport and glycogen synthesis. We asked whether PKB/Akt mediates sequence-specific effects of insulin on hepatic gene expression using the model of the insulin-like growth factor binding protein-1 (IGFBP-1) promoter. Insulin lowers IGFBP-1 mRNA levels, inhibits IGFBP-1 promoter activity, and activates PKB/Akt in HepG2 hepatoma cells through a PI3K-dependent, rapamycin-insensitive mechanism. Constitutively active PI3K and PKB/Akt are each sufficient to mediate effects of insulin on the IGFBP-1 promoter in a nonadditive fashion. Dominant negative K179 PKB/Akt disrupts the ability of insulin and PI3K to activate PKB/Akt and to inhibit promoter activity. The IGFBP-1 promoter contains two IRSs each of which is sufficient to mediate sequence-specific effects of insulin, PI3K, and PKB/Akt on promoter activity. Highly related IRSs from the phosphoenolpyruvate carboxykinase and apolipoprotein CIII genes also are effective in this setting. These results indicate that PKB/Akt functions downstream from PI3K in mediating sequence-specific effects of insulin on the expression of IGFBP-1 and perhaps multiple hepatic genes through a conserved IRS.
 ...
PMID:Protein kinase B/Akt mediates effects of insulin on hepatic insulin-like growth factor-binding protein-1 gene expression through a conserved insulin response sequence. 949 82

We used mouse hepatoma (Hepa1c1c7) cells to study the role of the serine/threonine kinase Akt in the induction of GLUT1 gene expression. In order to selectively turn on the Akt kinase cascade, we expressed a hydroxytamoxifen-regulatable form of Akt (myristoylated Akt1 estrogen receptor chimera (MER-Akt1)) in the Hepa1c1c7 cells; we verified that hydroxytamoxifen stimulates MER-Akt1 activity to a similar extent as the activation of endogenous Akt by insulin. Our studies reveal that stimulation of MER-Akt1 by hydroxytamoxifen induces GLUT1 mRNA and protein accumulation to levels comparable to that induced by insulin; therefore, activation of the Akt cascade suffices to induce GLUT1 gene expression in this cell system. Furthermore, expression of a kinase-inactive Akt mutant partially inhibits the response of the GLUT1 gene to insulin. Additional studies reveal that the induction of GLUT1 mRNA by Akt and by insulin reflects increased mRNA synthesis and not decreased mRNA degradation. Our findings imply that the GLUT1 gene responds to insulin at the transcriptional level and that Akt mediates a step in the activation of GLUT1 gene expression in this system.
 ...
PMID:Regulation of GLUT1 gene transcription by the serine/threonine kinase Akt1. 1040 Jun 47

Transforming growth factor beta (TGF-beta) initiates signaling through heteromeric complexes of transmembrane type I and type II serine/threonine kinase receptors. Activated TGF-beta type I receptor phosphorylates receptor-regulated Smads (2 and 3). Antagonistic Smad 7 forms stable association with the activated TGF-beta type I receptor, blocking phosphorylation of receptor-regulated Smads. On the other hand, elevated serum concentration of TGF-beta along with resistance to its growth-inhibitory effect is commonly observed in human hepatocellular carcinoma (HCC) patients. In this study, we investigated the mechanisms of resistance to tumor-derived TGF-beta in human HCC and hepatoblastoma-derived cell lines, focusing on the roles of receptor-regulated Smads and antagonistic Smad 7. HuH-7 and HepG2 cells showed poor response to TGF-beta-mediated growth inhibition. Because neutralization of TGF-beta in the medium or blockage of signal transduction pathway by inductions of dominant negative Smad 2/3 resulted in a stimulation of cell growth, tumor-derived TGF-beta signal acts on cell growth negatively. However, Smad 7 induced by TGF-beta negatively regulated Smad 2 action and rendered most Smad 2 proteins in the cytoplasm. Taken together, these results indicate that endogenous TGF-beta-mediated induction of Smad 7 results in a higher "threshold" for the antiproliferative signals mediated by receptor-regulated Smads, and can be involved in reduced responsiveness to the cytokine in some human HCC cells.
 ...
PMID:Regulatory mechanisms for transforming growth factor beta as an autocrine inhibitor in human hepatocellular carcinoma: implications for roles of smads in its growth. 1091 27


1 2 3 4 5 6 7 8 9 10 Next >>