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)

We have studied the phosphorylation state of the insulin receptor during receptor-mediated endocytosis in the well-differentiated rat hepatoma cell line Fao. Insulin induced the rapid internalization of surface-iodinated insulin receptors into a trypsin-resistant compartment, with a 3-fold increase in the internalization rate over that seen in the absence of insulin. Within 20 min of insulin stimulation, 30-35% of surface receptors were located inside the cell. This redistribution was half-maximal by 10.5 min. Similar results were obtained when the loss of surface receptors was measured by 125I-insulin binding. Tyrosyl phosphorylation of internalized insulin receptors was measured by immunoprecipitation with antiphosphotyrosine antibody. Immediately after insulin stimulation, 70-80% of internalized receptors were tyrosine phosphorylated. Internalized receptors persisted in a phosphorylated state after the dissociation of insulin but were dephosphorylated prior to their return to the plasma membrane. After 45-60 min of insulin stimulation, the tyrosine phosphorylation of the internal receptor pool decreased by 45%, whereas the phosphorylation of surface receptors was unchanged. These data suggest that insulin induces the internalization of phosphorylated insulin receptors into the cell and that the phosphorylation state of the internal receptor pool may be regulated by insulin.
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PMID:Tyrosine phosphorylation of the insulin receptor during insulin-stimulated internalization in rat hepatoma cells. 246 86

The immunoglobulin G (IgG) fraction obtained from the serum of a patient (B-10) with type B insulin resistance and acanthosis nigricans stimulated both glucose oxidation in rat adipocytes and autophosphorylation of tyrosine residues in the beta-subunit of insulin receptors in H-35 hepatoma cells. Partially purified insulin receptor from H-35 cells, when incubated with B-10 IgG, had increased tyrosine kinase activity for a synthetic peptide sequentially similar to the site of tyrosine phosphorylation in pp60v-arc (the gene product responsible for cellular transformation by the Rous sarcoma virus). In H-35 cells, both B-10 IgG and insulin stimulated tyrosine phosphorylation in an endogenous 185,000 mol wt protein. This phosphoprotein may be similar to the cellular substrate for insulin in hepatoma and other cultured cell lines demonstrated by others. These results suggest that antiinsulin receptor antibodies (B-10) may initiate their insulin-like effects via tyrosine phosphorylation of the insulin receptor, activation of its tyrosine kinase activity, and phosphorylation of a cellular protein substrate of 185,000 mol wt.
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PMID:Autoantibodies to the insulin receptor (B-10) can stimulate tyrosine phosphorylation of the beta-subunit of the insulin receptor and a 185,000 molecular weight protein in rat hepatoma cells. 246 44

Insulin treatment of rat H-35 hepatoma cells causes rapid tyrosine phosphorylation of a high molecular weight protein termed pp185 besides autophosphorylation of the beta-subunit of the insulin receptor (IR) in an intact cell system. To elucidate the molecular basis for tyrosine phosphorylation of pp185, cell-free phosphorylation of pp185 was performed using phosphotyrosine-containing proteins (PYPs) purified from detergent-solubilized cell lysates by immunoprecipitation with anti-phosphotyrosine antibody. After insulin treatment of cells, marked increases of tyrosine phosphorylation of pp185 and IR were observed compared to noninsulin-treated cells. Site-specific antibodies that specifically inactivate IR kinase inhibited tyrosine phosphorylation of pp185 as well as the beta-subunit of IR. PYPs purified from detergent-free cell extracts contained pp185 but little IR; tyrosine phosphorylation of pp185 did not occur. Addition of IR kinase purified from human placenta to these PYPs restored insulin-dependent tyrosine phosphorylation of pp185. These results suggest that tyrosine phosphorylation of pp185 is catalyzed directly by IR kinase in this cell-free system.
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PMID:Tyrosine phosphorylation of pp185 by insulin receptor kinase in a cell-free system. 246 62

Insulin produced increases in cell number, DNA synthesis and alpha-fetoprotein secretion of a human hepatoma cell line PLC/PRF/5. The insulin-treated cells showed a decrease in binding of 125I-insulin. The decreased binding was due to the decreased numbers as well as the low affinity constant of insulin receptor. These data suggest that insulin is a growth factor for the human hepatoma cells and that insulin receptor plays a role in the growth-promoting effect of insulin.
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PMID:Effect of insulin on the growth of a human hepatoma cell line PLC/PRF/5: a possible role of insulin receptor. 246 33

Receptors for Insulin, Epidermal Growth Factor, Platelet-Derived Growth Factor and Insulin-like Growth Factor type 1 are tyrosine-specific protein kinases. This enzymatic activity may play a role in mediating the biological actions of these peptides. It has recently been identified a Mr 120 KDa glycoprotein in rat liver plasma membranes which can be phosphorylated by the insulin receptor and by the EGF receptor in a cell-free system and by the insulin receptor in intact cultured H-35 hepatoma cells. In the present report it is shown that the solubilized Insulin-like Growth Factor type 1 receptor can phosphorylate tyrosine residues in the same 120 KDa glycoprotein from the AS-30D rat hepatoma cells.
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PMID:rp-120: a common endogenous substrate for insulin and IGF-1 receptor-associated tyrosine kinase activity in the highly malignant AS-30D rat hepatoma cells. 246 17

The relation between insulin-stimulated autophosphorylation of the insulin receptor and internalization of the receptor was studied in Fao rat hepatoma cells. Treatment of Fao cells with 2,4-dinitrophenol for 45 min depleted cellular ATP by 80% and equally inhibited insulin-stimulated receptor autophosphorylation, as determined by immunoprecipitation of surface-iodinated or [32P]phosphate-labeled cells with anti-phosphotyrosine antibody. In contrast, internalization of the insulin receptor and internalization and degradation of 125I-labeled insulin by 2,4-dinitrophenol-treated cells were normal. These data show that autophosphorylation of the insulin receptor is not required for the receptor-mediated internalization of insulin in Fao cells and suggest that insulin receptor recycling is independent of autophosphorylation.
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PMID:Tyrosine phosphorylation of the insulin receptor is not required for receptor internalization: studies in 2,4-dinitrophenol-treated cells. 247 95

The human hepatoma Hep3B cells contain integrated hepatitis B viral genome and continually secret hepatitis B surface antigen (HBsAg). The production of HBsAg (but not alpha-fetoprotein) was suppressed by addition of low concentrations (0.1-1 nM) of insulin into serum-free medium. In addition, the suppression of HBsAg production by insulin was paralleled with the decrease in HBsAg mRNA abundance. Insulin also cause a rapid rate of disappearance of HBsAg mRNA (t 1/2, 2 h) in Hep3B cells. The Hep3B cells carry specific receptor with high affinity for insulin (Kd = 1.8 nM). The receptor showed an insulin-dependent protein tyrosine kinase activity. The half-maximal insulin concentration for the activation of the receptor kinase was about 5 nM. Only very high concentrations of insulin-like growth factor I and human proinsulin can compete for the insulin receptor binding and suppress HBsAg production, this suggests that insulin may act through its receptor binding to suppress HBsAg expression in human hepatoma Hep3B cells.
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PMID:Insulin suppresses hepatitis B surface antigen expression in human hepatoma cells. 247 98

Insulin elicits the autophosphorylation of the beta-subunit of its receptor on tyrosine residues: this effect appears to be the earliest post-binding event involved in insulin action. In the present study we have raised highly specific antibodies to phosphotyrosine residues, and we have taken advantage of these antibodies to further evaluate the role of the insulin receptor tyrosine kinase in the generation of insulin's biological responses. Using a cell-free phosphorylation assay, we show here that these antibodies increase the tyrosine kinase activity of the receptor, and its phosphorylation on tyrosine residues. In contrast, the antibodies do not interfere with dephosphorylation of the insulin receptor. Introduction of the same antibodies in living Fao hepatoma cells enhances the effect of insulin on both glucose transport and aminoacid uptake. As a whole our data indicate that the insulin receptor kinase is involved in the generation of an early (glucose transport) and late (aminoacid uptake) response to insulin. Further, conformational changes in phosphotyrosine containing domains of the insulin receptor appear to modulate insulin's biological effects. Finally, the injection of antibodies in intact cells provides us with a novel and promising tool to search for cellular substrates for the insulin receptor tyrosine kinase.
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PMID:Antiphosphotyrosine antibodies modulate insulin receptor kinase activity and insulin action. 248 34

The expression of insulin receptor mRNA was studied in human and rodent tissues by Northern analysis. Human EBV-transformed lymphocytes contained four receptor mRNA species of sufficient length to encode the entire proreceptor: 9.5, 7.9, 7.1, and 5.7 kb. In human fibroblasts, the same four species were observed; however, the 7.9 and 5.7 kb mRNAs were markedly decreased. In mouse liver, rat hepatoma cells, and normal rat brain, kidney, liver, and muscle only two mRNA species (7.4 and 9.6 kb) were detected. Each of these human and rodent mRNAs hybridized equally well with cDNA sequences encoding the binding and kinase domains of the insulin receptor. Several smaller polyadenylated mRNAs (approximately 1.8 to 3.3 kb) were also identified in human cell lines that appeared to separately encode either alpha- or beta-subunit sequences of the receptor. In rats, liver had the highest content of insulin receptor mRNA, followed by kidney, brain, and muscle. The relative amount of the two mRNA species also varied among the rat tissues. The ratio of the 9.6-7.4 kb species was 2.7 in brain but only 1.0 to 1.6 in the other tissues (P less than 0.025). Dexamethasone treatment increased the content of the two insulin receptor mRNAs in rat liver by 2-fold. The half-life of both mRNA species was 70 min in rat hepatoma cells. These findings indicate that insulin receptor gene expression is complex and regulated with differential expression of insulin receptor mRNA and/or alterations in mRNA processing among various tissues.
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PMID:Variation in insulin receptor messenger ribonucleic acid expression in human and rodent tissues. 248 15

In two-dimensional tryptic phosphopeptide mapping, the beta-subunit of the insulin receptor phosphorylated by 12-O-tetradecanoylphorbol-13-acetate in rat hepatoma cells (H-35) was separated into one phosphothreonine-containing peptide and several phosphoserine-containing peptides. The synthetic peptide coding residues 1327-1343 in the C-terminal region of the rat insulin receptor was phosphorylated at the threonine residue by protein kinase C in a phosphatidylserine and oleoylacetylglycerol dependent manner. Tryptic digest of this phosphopeptide migrated to the same position as the phosphothreonine containing peptide obtained from the beta-subunit in two-dimensional phosphopeptide mapping. These data suggested that Thr 1336 of the insulin receptor is the site of phosphorylation by protein kinase C in intact cells.
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PMID:Identification of a phosphorylation site of the rat insulin receptor catalyzed by protein kinase C in an intact cell. 250 75


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