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)

As the somatostatin analog octreotide suppresses pituitary GH secretion and circulating IGF-1 levels, we examined its effects on human hepatoma (hep G2) cells which selectively express IGFBP-1. Octreotide (60 nM) stimulated IGFBP-1 up to 4.1-fold (p < 0.001 after 24 hrs). Induction of IGFBP-1 was first detectable after 12 hrs of 6 nM octreotide (1.5-fold, p < 0.03), and was confirmed by ligand blotting. Cholera toxin and forskolin induced IGFBP-1 independently and were also additive with octreotide. IGFBP-1 mRNA expression was induced 2.7-fold by octreotide. Thus, octreotide induces basal and stimulated IGFBP-1 in hepatocytes independently of insulin and GH. As IGFBP-1 may regulate peripheral IGF-1 action, induction of IGFBP-1 represents a novel pituitary-independent mechanism for octreotide action.
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PMID:Somatostatin analog induces insulin-like growth factor binding protein-1 (IGFBP-1) expression in human hepatoma cells. 138 3

The liver is an epithelioid organ that can regenerate following partial hepatectomy. Although it is composed mainly of hepatocytes, it has a complex, multicellular architecture, implying that intercellular communications must exist during regeneration. As in other mitogen-stimulated cells, immediate-early growth response genes induced in the absence of prior protein synthesis are likely to play an important regulatory role in the regenerative process. Through differential screening of regenerating liver cDNA libraries, we found that one of the most highly expressed immediate-early genes in liver regeneration encodes the rat homolog of the low-molecular-weight insulinlike growth factor (IGF)-binding protein (IGFBP-1). This protein has been implicated in enhancing the mitogenic effect of IGF on tissues. IGFBP-1 gene induction is transcriptionally mediated and specific to regenerating liver, as the gene is not expressed in mitogen-stimulated fibroblasts. IGFBP-1 expression has been shown to increase under low-insulin conditions such as diabetes, and the complex regulation of expression is indicated by our finding that insulin treatment of H35 rat hepatoma cells, which induces proliferation, also causes a rapid decrease in transcription and expression of the IGFBP-1 gene. Of note, IGFBP-1 mRNA is abundant in fetal rat liver, implying that it participates in normal liver growth and development. Although regenerating liver cells continue to produce IGF-I, we did not detect IGF-I receptor mRNA during the first 24 h after hepatectomy. However, some IGFBPs may act to enhance the activity of IGF-I independently of IGF-I receptors. Thus, IGF-1 and IGFBPs may interact with hepatocytes or nonparenchymal liver cells, through either IGF-I or novel receptors. In this way, IGFBP-I and IGF-I could act in a paracrine and/or autocrine fashion in maintaining normal liver architecture during regeneration.
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PMID:The gene encoding rat insulinlike growth factor-binding protein 1 is rapidly and highly induced in regenerating liver. 170 4

We have studied the biosynthesis of the insulin receptor in a human hepatoma cell line, HepG2. As previously reported, these cells synthesize a disulphide-bonded alpha 2 beta 2 tetrameric insulin receptor. Labelling of HepG2 cells with [3H]palmitate or [3H]myristate followed by immunoprecipitation with a polyclonal antireceptor antibody revealed the incorporation of palmitate, but not myristate, into the beta-subunit and alpha beta-precursor of the receptor in a hydroxylamine-sensitive linkage. The extracellular alpha-subunit was not labelled, demonstrating the specificity of incorporation. Acylation of the insulin receptor was an early event as judged by fatty acid incorporation into the alpha beta-precursor and prevention by protein synthesis inhibitors. Pulse-chase studies demonstrated the expected processing of the alpha beta-precursor to mature alpha- and beta-subunits, but no evidence for preferential turnover of the fatty acid moiety was found. The site of acylation appears to be in the transmembrane or cytoplasmic domain since proteolytic treatment of intact cells produced a truncated beta-subunit still containing label. Binding studies showed that HepG2 cells contain approximately half as many insulin-like growth factor-1 receptors as insulin receptors, raising the possibility that this receptor may also be acylated. Indeed, immunoprecipitation with the antiinsulin receptor serum of MDCK cells expressing IGF-1 receptors, but not insulin receptors, revealed bands corresponding to the alpha beta-precursor, alpha- and beta-subunits, of which the alpha beta-precursor and beta-subunits incorporated [3H]palmitate but the alpha-subunit did not.
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PMID:Insulin and IGF-1 receptors contain covalently bound palmitic acid. 284 52

The activation of proliferation of rat liver hepatic stellate cells (HSC) in cooperation with hepatocytes (PC) was studied using a coculture system and cell-conditioned media, respectively. The proliferation of HSC was followed by incorporation of [3H] thymidine and BrdU into DNA and by DNA content per culture. Strong stimulation of HSC proliferation was noticed under reduced fetal calf serum (FCS) conditions (0.2%) during a 48-hour coculture with PC, rat hepatoma, human hepatoma, and transforming growth factor (TGF)-alpha-transgenic mouse PC, respectively. The extent of stimulation was frequently higher than that observed by the addition of 10% FCS. Transformed HSC (myofibroblasts) could also be stimulated by cocultured PC, but the magnitude of activation was lower than that of (untransformed) HSC. Using radioreceptor assays, we could demonstrate significant concentrations of insulinlike growth factor (IGF)-1 (300 ng/10(6) cells x 48 hours) and quite lower concentrations of bFGF and TGF-alpha in the hepatocyte-conditioned media (PCcM), whereas IGF-2 was not detectable. With anti-IGF-1 neutralizing antibody, the stimulatory activity of PCcM could be reduced by approximately 50%. PCcM, which mimics the effects of cocultures and supports strongly the action of exogenous IGF-1 on HSC proliferation, leaving that of other cytokines (TGF-alpha, IL-1 alpha, bFGF, aFGF, TNF-alpha), added either separately or in various combinations, uninfluenced. The latter cytokines were without significant effects on HSC proliferation. The mitogenic activity of cytokine combinations containing IGF-1 could be enhanced severalfold by limiting amounts of PCcM. Maximum stimulation of cell proliferation of 40-fold above control cultures was reached by IGF-1 in combination with TGF-alpha and bFGF in presence of diluted PCcM, which is approximately 6-fold higher than in the absence of PCcM. [125I] IGF-1 added to PCcM was bound by more than 90% to carrier proteins. The results confirm in cocultures strong mitogenic activation of HSC by PC. It is suggested that IGF-1 and respective IGF-binding proteins are of great importance in the mitogenic signal transfer between hepatocytes and hepatic stellate cells.
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PMID:Molecular dissection of the mitogenic effect of hepatocytes on cultured hepatic stellate cells. 759 Jun 70

In humans and rabbits, the circulating GH binding protein (GHBP) is released from the GH receptor by cleavage at a site proximal to the cell surface. There is evidence that GHBP status is predictive of GH responsiveness, presumably because it reflects GH receptor status. This assumes that GHBP release is not a regulated step. Here we report a model for study of GHBP release that provides some insight into this question. Human HepG2 cells were stably transfected with rabbit GH receptor and shown to be responsive to nonprimate (bovine) GH, indicating functionality of the transfected receptor. These cells released GHBP of the expected size, and this release could be increased by incubation with a phorbol ester, which stimulated receptor synthesis through the cytomegalovirus promoter. We surveyed a wide range of protease inhibitors both with and without streptolysin-O permeabilization, with the intention of defining the endogenous protease. Of 16 inhibitors, only benzamidine proved an effective inhibitor of release, indicating the existence of a novel protease. We could increase GHBP release with a membrane impermeable thiol blocker, suggesting activation of a membrane protease. We examined the ability of IGF-1, insulin, dexamethasone, sex steroids, and T4 to influence GHBP release. Although these agents are known to be effective in the parent hepatoma line, none were effective in modulating GHBP release, although GH itself decreased release by around 30% as assessed with a ligand immunofunctional assay. We conclude that GHBP release appears to be constitutive in this model and driven by receptor availability. This is consistent with an in vivo situation where circulating GHBP provides an index of hepatic receptor expression.
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PMID:Control of growth hormone (GH) binding protein release from human hepatoma cells expressing full-length GH receptor. 783 99

In vitro studies have shown that insulin and IGF-1 releases the fibrinolytic inhibitor plasminogen activator inhibitor-1 (PAI-1) from cells of hepatic origin. To investigate the effects of IGF-1 on fibrinolysis: 1) cultured hepatoma cells were grown in the presence of IGF-1 and media collected for secreted PAI-1 and cells probed for PAI-1 mRNA, 2) 8 hypopituitary patients were treated with recombinant human growth hormone (rhGH) and 3) 5 type 2 diabetic patients were treated with recombinant human IGF-1 (rhIGF-1). Treatment of Hep G2 cells with IGF-1 (1000 ng/ml) increased secretion of PAI-1 from a median value of 80 ng/10(6) cells (range 21-91) to 144 ng/10(6) cells (range 128-169) after 24 h (p < 0.01). Synthesis of PAI-1 mRNA increased in a similar fashion. Treatment of hypopituitary patients with rhGH led to an increase in circulating IGF-1 from a mean value of 166 (range 41-324) ng/ml at baseline to 322 (77-575) ng/ml at 4 weeks and 259 (104-533) ng/ml after 8 weeks (p < 0.02). Despite this, no changes in circulating PAI-1 or fibrinolysis occurred. Type II diabetic patients treated with rhIGF-1 showed an increase in circulating IGF-1 from a mean value of 120 ng/ml (range 109-196), at baseline to 823 ng/ml (585-894) after 5 days. This also was not associated with changes in circulating PAI-1 or in fibrinolysis. The results confirm that IGF-1 induces the synthesis of PAI-1 in Hep G2 cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effects of insulin-like growth factor-1 on plasminogen activator inhibitor-1 synthesis and secretion: results from in vitro and in vivo studies. 816 92

Insulin receptors have been characterized in a cell line recently isolated from a chicken hepatoma (LMH). The binding of 125I-insulin to LMH cells or membranes displayed the expected criteria for insulin receptors: affinity, temperature dependency, curvilinearity of Scatchard plot, rank order of potency for insulin analogs and insulin induced down-regulation. The alpha-subunit of LMH cell insulin receptors exhibited a normal size of 135 kDa. Following autophosphorylation, LMH WGA-purified receptors revealed a 95 kDa beta-subunit and a 72 kDa protein (pp72). Both proteins were phosphorylated in a time-, insulin- (and insulin-like growth factor 1; IGF-1) and manganese-dependent manner, and were precipitated by antiphosphotyrosine and two anti-insulin receptor antibodies. The 72 kDa protein was not present under non-reducing condition PAGE or in normal chicken liver. These results strongly suggest that pp72 is either a truncated form of the insulin receptor beta-subunit specific to LMH cells or a degradation product. Lectin-purified insulin receptors from LMH cells or chicken liver membranes exhibited similar tyrosine kinase activity, using artificial substrate poly(Glu-Tyr) 4:1. Finally, amino acid uptake by LMH cells was insulin stimulatable.
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PMID:Insulin receptor and insulin sensitivity in a chicken hepatoma cell line. 827 26

Insulin receptor substrate-1 (IRS-1), a substrate of various receptor tyrosine kinases transmits mitogenic signals initiated by extracellular ligands. This protein is involved in normal hepatocyte growth and has been found to be overexpressed in human hepatocellular carcinoma. Expression of a carboxy-terminal truncated IRS-1 molecule containing the pleckstrin homology and phosphotyrosine-binding domains associates with the insulin receptor and prevents tyrosyl phosphorylation of endogenous IRS-1 and Shc proteins. Thus, subsequent activation of downstream signaling molecules induced by insulin and IGF-1 such as phosphatidylinositol-3 kinase and mitogen activated protein kinase is inhibited. The morphologic features of transformed human hepatocellular carcinoma cells change to a differentiated hepatocyte appearance and characteristics of the malignant phenotype as manifested by anchorage independent cell growth and tumor formation in nude mice are lost. These studies demonstrate that signal transduction pathways mediated through or by IRS-1 are important in hepatocyte and human hepatocellular carcinoma cell growth.
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PMID:A carboxy-terminal truncated insulin receptor substrate-1 dominant negative protein reverses the human hepatocellular carcinoma malignant phenotype. 890 30

The action of insulin, IGF-1, and IGF-2 is mediated via two receptor tyrosine kinases, the insulin and IGF-1 receptors. Upon ligand binding, these receptors become active kinases, undergoing autophosphorylation and phosphorylating cellular substrates, including insulin receptor substrate-1 (IRS-1). IRS-1 acts as a docking protein and mediates multiple interactions among other proteins, resulting in transduction of the metabolic and mitogenic signals. The IRS-1 gene has been cloned from four species (human, rat, mouse, and frog). In the present study, the chicken IRS-1 gene was cloned. Chicken, as is true of birds in general, have a higher fasting and fed blood glucose than do mammals. Chicken IRS-1 DNA sequence encodes a 1240 amino acid protein. The most conserved regions were the IRS homology-2 (IH-2), the pleckstrin homology, and the shc and IRS-1 NPXY-binding (SAIN) domains. Twelve of the cIRS-1 tyrosine residues are in sequence motifs that, when phosphorylated, could interact with proteins containing SH2 domains. All twelve of these motifs were conserved. IRS-1 mRNA is expressed during embryogenesis in chicken and persists after hatching. In LMH cells, derived from a chicken hepatoma, two bands were tyrosine phosphorylated in an insulin-dependent manner: IRS-1 (approximately 180 kDa) and the insulin receptor beta subunit (approximately 95 kDa). Chicken IRS-1 is structurally and functionally similar to its human homolog, despite the difference in blood glucose levels and the evolutionary distance between birds and mammals.
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PMID:Cloning of the chicken insulin receptor substrate 1 gene. 892 91

In mammalian cells, the insulin receptor substrate 1 protein (IRS-1) is a specific substrate for insulin and IGF-1 receptor tyrosine kinases which is involved in mediating metabolic and mitogenic actions of insulin and IGFs. In order to determine if IRS-1 is also essential in a chicken derived hepatoma cell line (LMH cells), IRS-1 gene has been invalidated in these cells. For this, we subcloned chicken IRS-1 gene in an antisense orientation into a mammalian expression vector driven by the cytomegalovirus early promoter. LMH cells were stably transfected with this construct or with the empty vector carrying only the neomycin resistance gene and selected for cIRS-1 expression. One subclone, C2, showed a complete repression of cIRS-1 expression at both protein and mRNA levels. Proliferation of C2 cells was dramatically reduced (54%) compared with Neo(r) cells. Furthermore this reduction was accompanied by a decrease in insulin-dependent [3H]thymidine incorporation, indicating a reduction in DNA synthesis. Insulin-dependent [U-14C]glucose incorporation into cellular lipids was also significantly reduced in C2 cell line suggesting an alteration in lipogenesis. In wild type LMH cells, SHC which is involved in Ras pathway, also served as a substrate for insulin receptor tyrosine kinase. In C2 cells, SHC expression, its association with the insulin receptor and its tyrosine phosphorylation were largely increased. Two forms of the regulatory subunit of PI 3-kinase were present: p85 and p55 forms. Furthermore, C2 cells displayed increased basal phosphatidylinositol (PI) 3'-kinase activity. This report demonstrates a role for cIRS-1 in the metabolic and mitogenic actions of insulin in LMH cells. However, the overexpression of cIRS-1 antisense did not completely abolish cell proliferation. This may be explained by the exacerbation of an alternative pathway that only partly compensate for the knocking out of cIRS-1 gene: the overexpression of SHC.
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PMID:Insulin receptor substrate 1 antisense expression in an hepatoma cell line reduces cell proliferation and induces overexpression of the Src homology 2 domain and collagen protein (SHC). 960 20


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