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

HTC rat hepatoma cells were transfected with human insulin receptor cDNA to a level of 40,000 receptors/cell. In these cells, as well as in nontransfected cells, insulin stimulated the uptake of alpha-aminoisobutyric acid. Two monoclonal antibodies directed against the human insulin receptor alpha subunit, like insulin, stimulated amino acid uptake in transfected HTC cells, but not in nontransfected HTC cells. The antibodies, in contrast to insulin, failed to stimulate insulin receptor tyrosine kinase activity, both in intact transfected cells and in cell free extracts prepared from them. These data suggest, therefore, that activation of insulin receptor tyrosine kinase may not be an obligatory step in all of the transmembrane signaling mechanisms of the insulin receptor.
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PMID:Insulin receptor monoclonal antibodies that mimic insulin action without activating tyrosine kinase. 253 10

In human hepatoma cell line Hep3B/T2, the human heat-shock-inducible gene hsp70 could be induced by insulin. The dose-dependent insulin effect correlates very well with the dissociation constant of the insulin receptor, indicating that the insulin effect is mediated by the insulin receptor. The expression of hsp70 gene was neither significantly induced by growth factors of epidermal and platelet-derived growth factors, nor by tumor promoter, calcium ionophore, cAMP, and glucocorticoids. These results indicate that the induction of expression of hsp70 gene by insulin is very specific and not cell cycle-related. Furthermore, the insulin-induced expression of hsp70 gene is transient, occurring specifically from 4 to 8 h after insulin addition.
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PMID:Insulin-induced expression of human heat-shock protein gene hsp70. 253 47

Anti-insulin receptor monoclonal antibody MA-10 inhibits insulin receptor autophosphorylation of purified rat liver insulin receptors without affecting insulin binding (Cordera, R., Andraghetti, G., Gherzi, R., Adezati, L., Montemurro, A., Lauro, R., Goldfine, I. D., and De Pirro, R. (1987) Endocrinology 121, 2007-2010). The effect of MA-10 on insulin receptor autophosphorylation and on two insulin actions (thymidine incorporation into DNA and receptor down-regulation) was investigated in rat hepatoma Fao cells. MA-10 inhibits insulin-stimulated receptor autophosphorylation, thymidine incorporation into DNA, and insulin-induced receptor down-regulation without affecting insulin receptor binding. We show that MA-10 binds to a site of rat insulin receptors different from the insulin binding site in intact Fao cells. Insulin does not inhibit MA-10 binding, and MA-10 does not inhibit insulin binding to rat Fao cells. Moreover, MA-10 binding to down-regulated cells is reduced to the same extent as insulin binding. In rat insulin receptors the MA-10 binding site has been tentatively localized in the extracellular part of the insulin receptor beta-subunit based on the following evidence: (i) MA-10 binds to insulin receptor in intact rat cells; (ii) MA-10 immunoprecipitates isolated insulin receptor beta-subunits labeled with both [35S]methionine and 32P; (iii) MA-10 reacts with rat insulin receptor beta-subunits by the method of immunoblotting, similar to an antipeptide antibody directed against the carboxyl terminus of the insulin receptor beta-subunit. Moreover, MA-10 inhibits autophosphorylation and protein-tyrosine kinase activity of reduced and purified insulin receptor beta-subunits. The finding that MA-10 inhibits insulin-stimulated receptor autophosphorylation and reduces insulin-stimulated thymidine incorporation into DNA and receptor down-regulation suggests that the extracellular part of the insulin receptor beta-subunit plays a role in the regulation of insulin receptor protein-tyrosine kinase activity.
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PMID:An extracellular domain of the insulin receptor beta-subunit with regulatory function on protein-tyrosine kinase. 254 82

Glucose is known to affect mRNA levels of several genes. In order to investigate possible effects of glucose on insulin receptor mRNA levels, we cultured human hepatoma cells (HepG2) in two different culture media: DMEM containing 100 mg/dl glucose and DMEM containing 450 mg/dl glucose. Insulin receptor mRNA levels and insulin binding activity were reduced in HepG2 cultured at lower glucose concentrations. These data suggest that glucose affects insulin receptor gene expression.
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PMID:Effect of two different glucose concentrations on insulin receptor mRNA levels in human hepatoma HepG2 cells. 254 99

The insulin-like properties of anti-insulin receptor antibodies (P95 Ab) that have been characterized as being directed against the receptor beta-subunit, were studied as probes to assess the interrelationship between insulin action and receptor phosphorylation. When tested on intact cells, P95 Ab mimicked insulin effects. On isolated fat cells, they stimulated 2-deoxyglucose (2-DG) transport and lipogenesis and the P95 antibody maximal effects (173 and 232% of the control values, respectively) represented about 50% of the maximal effects elicited by insulin (317 and 475% of the control values). On cultured Zajdela hepatoma cells (ZHC cells), P95 Ab also mimicked insulin action on the incorporation of [U-14C]glucose into glycogen (158 and 207% of the control value for antibody- and insulin-treated cells, respectively). In all cases the antibody effects were dose-dependent, specific and, when maximal, were not additive with those elicited by insulin. When tested in a cell-free system, P95 Ab faithfully reproduced insulin action on the phosphorylation of the receptor beta-subunit. The maximal antibody and insulin effects (317 and 328% of the control value, respectively) were not additive. P95 Ab were also equally potent as insulin to stimulate the receptor-mediated phosphorylation of an exogenous substrate (365 and 379% of the control value in P95 antibody- and insulin-treated receptors, respectively). As well, P95 Ab proved as able as insulin in stimulating the tyrosine kinase activity of the receptor (89% of the hormone effect) when the activation was carried out in vivo. Taken together, these results are consistent with a role for the kinase activity of the insulin receptor in mediating the action of insulin.
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PMID:Insulin action is mimicked by polyclonal antireceptor antibodies that activate the insulin receptor tyrosine kinase. 255 Mar 43

Our previous studies indicated that amino acid residues 240-250 in the cysteine-rich region of the human insulin receptor alpha-subunit constitute a site in which insulin binds (Yip, C. C., Hsu, H., Patel, R. G., Hawley, D. M., Maddux, B. A., and Goldfine, I. D. (1988) Biochem. Biophys. Res. Commun. 157, 321-329). We have now constructed a human insulin receptor mutant in which 3 residues in this sequence were altered (Thr-Cys-Pro-Pro-Pro-Tyr-Tyr-His-Phe-Gln-Asp to Thr-Cys-Pro-Arg-Arg-Tyr-Tyr-Asp-Phe-Gln-Asp) and have expressed this mutant in rat hepatoma (HTC) cells. When compared with cells transfected with normal insulin receptors, cells transfected with mutant receptors had an increase in insulin-binding affinity and a decrease in the dissociation of bound 125I-insulin. Studies using solubilized receptors also demonstrated that mutant receptors had a higher binding affinity than normal receptors. In contrast, cells transfected with either mutant or normal receptors bound monoclonal antibodies against the receptor alpha-subunit with equal affinity. When receptor tyrosine kinase activity and alpha-aminoisobutyric acid uptake were measured, cells transfected with mutant insulin receptors were more sensitive to insulin than cells transfected with normal receptors. These findings lend further support therefore to the hypothesis that amino acid sequence 240-250 of the human insulin receptor alpha-subunit constitutes one site that interacts with insulin, and they indicate that mutations in this site can influence insulin receptor binding and transmembrane signaling.
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PMID:Mutation of the high cysteine region of the human insulin receptor alpha-subunit increases insulin receptor binding affinity and transmembrane signaling. 255 Apr 26

The effects of species-specific monoclonal antibodies to the human insulin receptor on ribosomal protein S6 phosphorylation were studied in rodent cell lines transfected with human insulin receptors. First, Swiss mouse 3T3 fibroblasts expressing normal human insulin receptors (3T3/HIR cells) were studied. Three monoclonal antibodies, MA-5, MA-20, and MA-51, activated S6 kinase in these cells but had no effects in untransfected 3T3 cells. Both insulin and MA-5, the most potent antibody, activated S6 kinase in a similar time- and dose-dependent manner. To measure S6 phosphorylation in vivo, 3T3/HIR cells were preincubated with [32P]Pi and treated with insulin and MA-5. Both agents increased S6 phosphorylation, and their tryptic phosphopeptide maps were similar. MA-5 and the other monoclonal antibodies, unlike insulin, failed to stimulate insulin receptor tyrosine kinase activity either in vitro or in vivo. Moreover, unlike insulin, they failed to increase the tyrosine phosphorylation of the endogenous cytoplasmic protein, pp 185. Next, HTC rat hepatoma cells, expressing a human insulin receptor mutant that had three key tyrosine autophosphorylation sites in the beta-subunit changed to phenylalanines (HTC-IR-F3 cells), were studied. In this cell line but not in untransfected HTC cells, monoclonal antibodies activated S6 kinase without stimulating either insulin receptor autophosphorylation or the tyrosine phosphorylation of pp 185. These data indicate, therefore, that monoclonal antibodies can activate S6 kinase and then increase S6 phosphorylation. Moreover, they suggest that activation of receptor tyrosine kinase and subsequent tyrosine phosphorylation of cellular proteins may not be crucial for activation of S6 kinase by the insulin receptor.
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PMID:Monoclonal antibodies mimic insulin activation of ribosomal protein S6 kinase without activation of insulin receptor tyrosine kinase. Studies in cells transfected with normal and mutant human insulin receptors. 255 27

Glucocorticoids regulate the trafficking of mouse mammary tumor virus (MMTV) glycoproteins to the cell surface in the rat hepatoma cell line M1.54, but not in the immunoselected sorting variant CR4. To compare the localization of MMTV glycoproteins to another proteolytically processed glycoprotein, both wild type M1.54 cells and variant CR4 cells were transfected with a human insulin receptor (hIR) expression vector, pRSVhIR. The production of cell surface hIR was monitored in dexamethasone-treated and -untreated wild type M1.54 and variant CR4 cells by indirect immunofluorescence, direct plasma membrane immunoprecipitation, and by [125I] insulin binding. In both wild type and variant rat hepatoma cells, hIR were localized at the cell surface in the presence or in the absence of 1 microM dexamethasone. In contrast, the glucocorticoid-regulated trafficking of cell surface MMTV glycoproteins occurred only in wild type M1.54 cells. We conclude that the hIR, which undergoes posttranslational processing reactions similar to MMTV glycoproteins, does not require glucocorticoids to be transported to the plasma membrane and is representative of a subset of cell surface glycoproteins whose trafficking is constitutive in rat hepatoma cells. Thus, MMTV glycoproteins and hIR provide specific cell surface markers to characterize the glucocorticoid-regulated and constitutive sorting pathways.
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PMID:Glucocorticoid-regulated and constitutive trafficking of proteolytically processed cell surface-associated glycoproteins in wild type and variant rat hepatoma cells. 255 98

Anti-phosphotyrosine antibody and anti-insulin receptor antibody were used to study insulin-stimulated phosphorylation of the beta-subunit of the insulin receptor in [32P]orthophosphate-labeled Fao hepatoma cells. Without insulin, the receptor contained both phosphoserine and phosphothreonine and could be immunoprecipitated with anti-receptor antibody but not with the anti-phosphotyrosine antibody. After incubation of these cells with insulin, both antibodies immunoprecipitated the phosphorylated receptor. The beta-subunit of the receptor precipitated with anti-phosphotyrosine antibody from cells stimulated with insulin (100 nM) for 1 min contained predominantly phosphotyrosine, whereas, after 10 min with insulin, the amounts of phosphotyrosine and phosphoserine were nearly equal. These results suggest that insulin-stimulated tyrosine phosphorylation preceded insulin-stimulated serine phosphorylation of the beta-subunit. Sequential immunoprecipitation of receptor with anti-phosphotyrosine antibody followed by precipitation of the remaining proteins with anti-receptor antibody suggests that insulin receptors which contain phosphoserine in the basal state are tyrosine phosphorylated more slowly than the dephosphorylated receptors or not at all after the addition of insulin. The beta-subunit of the insulin receptor was the major phosphorylated protein precipitated by the anti-phosphotyrosine antibody from insulin-stimulated Fao cells. These results confirm our notion that insulin initially stimulated tyrosine autophosphorylation and subsequently serine phosphorylation of the insulin receptor in intact cells and suggests that this sequence of reactions occurs faster on receptors that are dephosphorylated before the incubation with insulin.
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PMID:Predominance of tyrosine phosphorylation of insulin receptors during the initial response of intact cells to insulin. 258 63

Analysis of mouse Swiss/3T3 fibroblasts and rat hepatoma H35 cells using the affinity cross-linking method revealed multiple forms of 125I-insulin binding components (Mr greater than 300,000) in the absence of reducing agents. The same analysis, in the presence of reducing agents, revealed two major components (Mr = 125,000 and Mr = 30,000). The Mr = 125,000 component appeared to be the alpha-subunit of the high-affinity insulin receptor, whereas the small insulin-binding component of Mr = 30,000 was not a degradation product of the alpha-subunit but was apparently associated with the insulin receptor. We suggest that it is likely a novel component for regulating the function of insulin receptor.
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PMID:A novel insulin-binding protein with a molecular weight of 30,000 daltons. 267 52


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