Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Acute (10-30 min) treatment of intact rat hepatoma (Fao) cells with H2O2, inhibits in vivo protein tyrosine phosphatase activity. Vanadate markedly potentiates this effect although it has only trivial effects of its own. Here we show that H2O2 inhibits a protein tyrosine phosphatase activity, but not a p-nitro phenyl phosphate hydrolysing activity, in cytosolic extracts of these cells. This effect is completely reversed by 10 mM dithiothreitol. Other oxidants have similar inhibitory effects. Vanadate inhibits the protein tyrosine phosphatase activity in vitro, and its effects are additive with those of H2O2. These findings suggest that H2O2 and vanadate interact with the protein tyrosine phosphatases at two independent sites. They also suggest that in intact cells H2O2 has a direct inhibitory effect on protein tyrosine phosphatase activity and an indirect effect of facilitating the entry of vanadate.
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PMID:Selective inhibition of protein tyrosine phosphatase activities by H2O2 and vanadate in vitro. 144 22

mRNA levels for ten protein tyrosine phosphatases (PTPs), PTP-S, PTPH1, PTP-1, GLEPP1, LRP, PTP1D, PTPG1, PTP gamma, PTP delta, and LAR, were determined during regeneration of rat liver, and mRNA levels for 5 PTPs, PTP-S, PTP-1, PTP gamma, PTP delta, and LRP, were determined in three lines of rat ascites hepatoma cells. In regenerating rat liver, the expression patterns of PTP genes after partial hepatectomy could be classified into four groups. In group 1 (PTP-S and PTPH1), the mRNA levels increased rapidly, reached a maximum 7 h after partial hepatectomy, remained at a plateau for 1-2 days and then decreased gradually. In group 2 (PTP-1, GLEPP1, and LRP), the mRNA levels showed two peaks on days 1 and 5, and then decreased gradually. In group 3 (PTP1D and PTPG1), the mRNA levels increased rapidly, reached a maximum at 7 h, remained high for several days, and then did not decrease but rather increased after day 7. In group 4 (PTP gamma, PTP delta, and LAR), the mRNA levels remained constant for the first 5 days and increased over the control levels after day 7. In rat ascites hepatomas, gene expression of non-receptor-like PTPs (PTP-S and PTP-1) showed various neoplastic alterations, whereas mRNAs of receptor-like PTPs (PTP gamma, PTP delta, and LRP) were lost or drastically decreased.
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PMID:Gene expressions of protein tyrosine phosphatases in regenerating rat liver and rat ascites hepatoma cells. 759 57

We investigated the mRNA expression of cytosolic protein tyrosine phosphatase (PTPH1), which has a homologous domain to cytoskeletal-associated proteins, in human hepatocellular carcinomas (HCCs) by using reverse transcriptase-polymerase chain reaction (RT-PCR). PTPH1 mRNA was detected in all HCC cell lines (n = 6), and HCC and adjacent noncancerous tissues (n = 8) examined, indicating that PTPH1 was expressed in HCCs and hepatocytes. There was no remarkable difference in the level expression of PTPH1 mRNA between HCC and adjacent noncancerous tissues. We also performed RT-PCR single-strand conformation polymorphism (SSCP) analysis in HCC cell lines and tissues in the C-terminal region of the catalytic domain of PTPH1. In the cHc4 cell line and a HCC tissue specimen, a shifted band was detected, although it was not found in the non-cancerous tissue of the HCC specimen. Nucleotide sequence analysis showed a common mutation from T to C at the third letter of codon 919 which did not lead to amino acid substitution. These results suggest that another mutation leading to the development of HCC could occur in some region of PTPH1 other than that investigated in this study.
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PMID:Expression of cytoskeletal-associated protein tyrosine phosphatase PTPH1 mRNA in human hepatocellular carcinoma. 787 67

PRL-1 is a particularly interesting immediate-early gene because it is induced in mitogen-stimulated cells and regenerating liver but is constitutively expressed in insulin-treated rat H35 hepatoma cells, which otherwise show normal regulation of immediate-early genes. PRL-1 is expressed throughout the course of hepatic regeneration, and its expression is elevated in a number of tumor cell lines. Sequence analysis reveals that PRL-1 encodes a 20-kDa protein with an eight-amino-acid consensus protein tyrosine phosphatase (PTPase) active site. PRL-1 is able to dephosphorylate phosphotyrosine substrates, and mutation of the active-site cysteine residue abolishes this activity. As PRL-1 has no homology to other PTPases outside the active site, it is a new type of PTPase. PRL-1 is located primarily in the cell nucleus. Stably transfected cells which overexpress PRL-1 demonstrate altered cellular growth and morphology and a transformed phenotype. It appears that PRL-1 is important in normal cellular growth control and could contribute to the tumorigenicity of some cancer cells.
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PMID:PRL-1, a unique nuclear protein tyrosine phosphatase, affects cell growth. 819 18

Using rats with hepatocellular carcinoma induced by 3'-methyl-4-dimethylamino-azobenzene (3'-MeDAB), we evaluated the expression of a protein tyrosine phosphatase (PTPase) in the tumor region, non-tumorous region and control rat liver. The expression of SHPTP2 increased 4.1 fold (p < 0.05) in mRNA, 2.1 fold (p < 0.01) in cytosol fraction, and 5.1 fold (p < 0.05) in membrane fraction, respectively, at a protein level in the tumor region compared with control liver. The expression of other phosphatases, LAR, LRP, and PTPase1B, did not change significantly. SHPTP2 phosphatase activity in the tumor region from rats also increased compared with control, suggesting that an increase of this activity may parallel the expression of SHPTP2. This increase of expression of SHPTP2 may contribute to the progression of hepatocellular carcinoma in this rat model.
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PMID:Changes of expressions of phosphotyrosine phosphatases in rat hepatocellular carcinoma induced by 3'-methyl-4-dimethylamino-azobenzene. 887 28

The protein tyrosine phosphatase (PTP) inhibitors vanadate and pervanadate (pV) exert insulin-like biologic effects. In cultured differentiated rat L6 skeletal muscle cells, vanadate and pV stimulated 2-deoxy-D-[3H]glucose uptake in a dose- and time-dependent manner. There was no increase in maximum stimulation by additional insulin. In contrast, whereas insulin stimulated [14C]methylaminoisobutyric acid (MeAIB) uptake, basal uptake was inhibited by vanadate and pV. Insulin-stimulated MeAIB uptake was also inhibited in a dose-dependent manner and completely abolished by 5 mM vanadate or 0.1 mM pV. The inhibitory effect on basal MeAIB uptake was associated with a decrease in transporter affinity and a small decrease in maximum transport capacity, whereas the insulin-stimulated increase in maximum transport capacity was completely inhibited. Inhibition of MeAIB uptake by vanadate and pV was not blocked by cycloheximide, and oubain did not inhibit uptake. Vanadate also inhibited amino acid deprivation-stimulated MeAIB uptake. Insulin-stimulated MeAIB uptake was also inhibited in rat hepatoma cells. Thus vanadate and pV mimic insulin to stimulate glucose uptake but inhibit system A amino acid uptake. The relative inhibitory concentrations of vanadate and pV suggest that the mechanism may involve PTP inhibition.
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PMID:Insulin-mimetic agents vanadate and pervanadate stimulate glucose but inhibit amino acid uptake. 903 21

Peroxovanadiums (pVs) are potent protein tyrosine phosphatase (PTP) inhibitors with insulin-mimetic properties in vivo and in vitro. We have established the existence of an insulin receptor kinase (IRK)-associated PTP whose inhibition by pVs correlates closely with IRK tyrosine phosphorylation, activation, and downstream signaling. pVs have also been shown to activate various tyrosine kinases (TKs) that could participate in activation of the insulin-signaling pathway. In the present study we have sought to determine whether pV-induced IRK tyrosine phosphorylation requires the intrinsic kinase activity of the IRK, and whether IRK activation is necessary to realize the early steps in the insulin-signaling cascade. To address this we evaluated the effect of a pure pV compound, bis peroxovanadium 1,10-phenanthroline [bpV(phen)], in HTC rat hepatoma cells overexpressing normal (HTC-IR) or kinase-deficient (HTC-M1030) mutant IRKs. We showed that at a dose of 0.1 mM, but not 1 mM, bpV(phen) induced IRK-dependent events. Thus, 0.1 mM bpV(phen) increased tyrosine phosphorylation and IRK activity in HTC-IR but not HTC-M1030 cells. Tyrosine phosphorylation of insulin signal-transducing molecules was promoted in HTC-IR but not HTC-M1030 cells by bpV(phen). The association of p185 and p60 with the src homology-2 (SH2) domains of Syp and the p85-regulatory subunit of phosphatidylinositol 3'-kinase was induced by bpV(phen) in HTC-IR, but not in HTC-M1030 cells, as was insulin receptor substrate-1-associated phosphatidylinositol 3'-kinase activity. Thus autophosphorylation and activation of the IRK by bpV(phen) is effected by the IRK itself, and the early events in the insulin- signaling cascade follow from this activation event. This establishes a critical role for PTP(s) in the regulation of IRK activity. bpV(phen) could be distinguished from insulin only in its ability to activate ERK1 in HTC-M1030 cells, thus indicating that this event is IRK independent, consistent with our previous hypothesis that bpV(phen) inhibits a PTP involved in the negative regulation of mitogen-activated protein kinases.
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PMID:Early signaling events triggered by peroxovanadium [bpV(phen)] are insulin receptor kinase (IRK)-dependent: specificity of inhibition of IRK-associated protein tyrosine phosphatase(s) by bpV(phen). 941 95

Signals propagated via the gp130 subunit of the interleukin-6 (IL-6)-type cytokine receptors mediate, among various cellular responses, proliferation of hematopoietic cells and induction of acute-phase plasma protein (APP) genes in hepatic cells. Hematopoietic growth control by gp130 is critically dependent on activation of both STAT3 and protein tyrosine phosphatase 2 (SHP-2). To investigate whether induction of APP genes has a similar requirement for SHP-2, we constructed two chimeric receptors, G-gp130 and G-gp130(Y2F), consisting of the transmembrane and cytoplasmic domains of gp130 harboring either a wild-type or a mutated SHP-2 binding site, respectively, fused to the extracellular domain of the granulocyte colony-stimulating factor (G-CSF) receptor. Rat hepatoma H-35 cells stably expressing the chimeric receptors were generated by retroviral transduction. Both chimeric receptors transmitted a G-CSF-induced signal characteristic of that triggered by IL-6 through the endogenous gp130 receptor; i.e., both activated the appropriate JAK, induced DNA binding activity by STAT1 and STAT3, and up-regulated expression of the target APP genes, those for alpha-fibrinogen and haptoglobin. Notwithstanding these similarities in the patterns of signaling responses elicited, mutation of the SHP-2 interaction site in G-gp130(Y2F) abrogated ligand-activated receptor recruitment of SHP-2 as expected. Moreover, the tyrosine phosphorylation state of the chimeric receptor, the associated JAK activity, and the induced DNA binding activity of STAT1 and STAT3 were maintained at elevated levels and for an extended period of time in G-gp130(Y2F)-expressing cells following G-CSF treatment compared to that in cells displaying the G-gp130 receptor. H-35 cells ectopically expressing G-gp130(Y2F) were also found to display an enhanced sensitivity to G-CSF and a higher level of induction of APP genes. Overexpression of the enzymatically inactive SHP-2 enhanced the signaling by the wild-type but not by the Y2F mutant G-gp130 receptor. These results indicate that gp130 signaling for APP gene induction in hepatic cells differs qualitatively from that controlling the proliferative response in hematopoietic cells in not being strictly dependent on SHP-2. The data further suggest that SHP-2 functions normally to attenuate gp130-mediated signaling in hepatic (and, perhaps, other) cells by moderating JAK action.
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PMID:Protein tyrosine phosphatase 2 (SHP-2) moderates signaling by gp130 but is not required for the induction of acute-phase plasma protein genes in hepatic cells. 948 69

The influence of p53 on cytokine-triggered Janus kinase-STAT signaling was investigated in human hepatoma Hep3B cell lines engineered to constitutively express the temperature-sensitive Val135 mutant of p53. In comparison to the parental p53-free Hep3B cells, these p53-Val135-containing Hep3B cell lines displayed a reduced response to IL-6 at the wild-type-like p53 temperature (32.5 degrees C). In these cells, IL-6 induced a marked reduction in the immunologic accessibility of cytoplasmic and nuclear STAT3 and STAT5 within 20 to 30 min that lasted 2 to 4 h (STAT-masking) provided that the cells had been previously cultured at 32.5 degrees C for at least 18 to 20 h. The onset of IL-6-induced STAT-masking required protein tyrosine kinase, protein tyrosine phosphatase, proteasomal, phospholipase C, and mitogen-activated protein kinase kinase 1 activities. The maintenance of IL-6-induced STAT-masking was dependent on continued signaling through the phosphatidylinositol-dependent phospholipase C pathway. Despite a reduction in IL-6-induced STAT3 DNA binding activity in the nuclear compartment during STAT-masking, there was increased and prolonged accumulation of tyrosine-phosphorylated STAT3 in both the cytoplasmic and nuclear compartments, indicating that the capacity of tyrosine-phosphorylated STAT3 to bind DNA was reduced during STAT-masking. Thus, IL-6-induced STAT-masking, as dramatically evident on immunomicroscopy, is a visible consequence of a novel cellular process by which a p53-Val135-induced gene product(s) regulates the association of masking protein(s) with and the DNA-binding capacity of STAT3.
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PMID:Regulation of IL-6 signaling by p53: STAT3- and STAT5-masking in p53-Val135-containing human hepatoma Hep3B cell lines. 964 40

Interleukin (IL)-6 is a major regulator of hepatic acute-phase plasma protein (APP) genes. The membrane-proximal 133-amino acid cytoplasmic domain of glycoprotein (gp) 130, containing one copy of the Box3 motif, is sufficient to transmit a productive signal to endogenous APP genes in rat hepatoma H-35 cells. In contrast, a mutant gp130 domain lacking the Box3 motif activates Janus kinases to a normal level but fails to activate signal transducer and activator of transcription 3 and to up-regulate a number of APP genes, including thiostatin, fibrinogen, hemopexin, and haptoglobin. However, in the absence of Box3, gp130 still stimulates the expression of alpha2-macroglobulin and synergizes with IL-1 to up-regulate alpha1-acid glycoprotein. The Box3 motif is not required for activation of the SH2-containing protein tyrosine phosphatase 2 or the mitogen-activated protein kinase (MAPK), nor is the immediate induction of egr-1 and junB significantly altered. Surprisingly, gp130 without any functional Box3 stimulates prolonged activation of MAPK, leading to an extended period of up-regulation of egr-1 and to an extracellularly regulated kinase-mediated reduction in the IL-6-stimulated production of thiostatin. IL-6 reduces proliferation of H-35 cells through signaling by the Box3. In addition, cells expressing Box3-deficient gp130 showed distinct morphologic changes upon receptor activation. Taken together, these results indicate that Box3-derived and Box3-independent signals cooperate in the control of hepatic APP genes and that Box3 may be involved in the modulation of MAPK activity in gp130 signaling.
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PMID:The STAT3-independent signaling pathway by glycoprotein 130 in hepatic cells. 1007 71


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