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: EC:3.1.27.5 (RNase)
17,967 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oestradiol is important in the growth of uterine leiomyomata and may act primarily or secondarily through mediators such as growth factors, including the insulin-like growth factors (IGF-I and IGF-II), mitogenic peptides. IGF binding proteins (IGFBPs) modulate IGF actions at their target cells. The objective of this study was to examine the possible steroid dependence of IGF, IGFBP and IGF receptor gene expression and IGFBP synthesis in uterine leiomyomata, using tissues from women cycling normally and made hypo-oestrogenic by a gonadtrophin-releasing hormone agonist (GnRHa). Using a solution hybridization ribonuclease protection assay, anti-sense RNA probes for IGF-I, IGF-II and beta-actin (control) were hybridized with total RNA isolated from leiomyomata exposed in vivo to a range of serum oestradiol (< 40-240 pg/ml) and progesterone (0-10 ng/ml) concentrations. IGF-I gene expression was most abundant in leiomyomata obtained during the late proliferative phase of the cycle and was undetectable in leiomyomata from hypo-oestrogenic patients. IGF-II gene expression was not dependent on endogenous steroid concentrations or cycle stage. IGFBP gene expression was investigated by Northern blotting. The order of relative abundance of IGFBP mRNAs was IGFBP-4 >>> IGFBP-3 >> IGFBP-5 > IGFBP-2 and was not dependent on the in-vivo oestrogen status. Type I and type II IGF receptor gene expression was investigated by polymerase chain reaction using gene-specific primers. Type I and type II IGF receptor mRNAs were detected in leiomyomata and were not dependent on cycle stage or in-vivo oestrogen status. Explant cultures of leiomyomata and myometrium synthesized IGFBP-3 (mol. wt = 38-43 kDa), IGFBP-4, and binding proteins of mol. wt = 34 and 31 kDa. Identification of IGFBP-2 was inconclusive, and IGFBP-1 was not detected. These data support the hypothesis that IGF-I, but not IGF-II, may be a mediator of oestradiol action in the growth of uterine leiomyomata, and that IGFBPs may further modulate, by an autocrine or paracrine mechanism, IGF-I action in this tissue.
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PMID:Insulin-like growth factor (IGF), IGF binding protein (IGFBP), and IGF receptor gene expression and IGFBP synthesis in human uterine leiomyomata. 750 28

Bone marrow stromal cells synthesize and secrete insulin-like growth factor (IGF)-I and IGF-binding proteins (IGFBP). IGFBPs may modulate the action of IGF-I or IGF-II on haemopoiesis. However, the specific IGFBPs produced by various stromal cell types have not been identified. We examined six different stromal phenotypes for IGFBP protein and IGFBP-1 to -6 mRNA expression. [125I]IGF-I ligand blot analysis of conditioned medium demonstrate different patterns of IGFBP secretion by each cell type. The most prominent IGFBPs were 24 and 29 kD species, consistent with IGFBP4 and IGFBP5, respectively. RNase protection assays demonstrate that, overall, stromal cells express IGFBP-2 to -6 mRNAs, with IGFBP4, IGFBP5 and IGFBP6 mRNAs predominating. Since agents that modulate cAMP levels may influence haemopoiesis via the release of stromal-derived cytokines, we determined the effect of forskolin, a cAMP agonist, on IGFBP4 expression in TC-1 cells. Forskolin (10(-5) M) up-regulated IGFBP4 mRNA and protein secretion in a time-dependent manner. These findings suggest that IGFBP-4, -5 and -6 released by stromal cells may be key modulators of the haemopoietic response to IGFs. Release of IGFBP4 by agents that increase cAMP may be an important mechanism involved in regulating IGF bioavailability in the marrow microenvironment.
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PMID:Characterization of insulin-like growth factor binding proteins (IGFBP) and regulation of IGFBP-4 in bone marrow stromal cells. 754 Aug 52

Recently a family of six distinct insulin-like growth factor binding proteins (IGFBPs) have been identified and the gene structures of the first five (IGFBP-1, -2, -3, -4 and -5) characterized. We now isolated the IGFBP-6 gene from a rat genomic library and determined its organization as well as the DNA sequence at the 5' flanking region of the gene. The rat IGFBP-6 gene spans 5.1 kb of the genomic sequence and contains four exons interrupted by three introns of approximately 2.4, 0.2 and 1.2 kb in length, respectively. Primer extension analysis and ribonuclease protection assay using RNA from rat lung tissues demonstrated two transcriptional start sites located at 85 and 82 nucleotides upstream of the ATG translational initiation codon. The promoter region of the rat IGFBP-6 gene is devoid of a TATA or a CAAT consensus sequence motif, but putative regulatory cis elements, including a Sp1, an estrogen receptor binding site and a retinoic acid responsive element, are present in the promoter region.
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PMID:Structural characterization of the rat insulin-like growth factor binding protein-6 gene. 768 65

The insulin-like growth factors (IGFs) have been implicated in the growth regulation of human breast cancer. Since the IGFs are associated with specific binding proteins (IGFBPs) which may modulate receptor/ligand interactions, production of IGFBPs by breast cancer cells could alter their IGF-dependent growth. This study examined the expression of IGFBPs 4, 5, and 6 in eight breast cancer cell lines (BCCLs) using ribonuclease (RNase) protection assays. IGFBP-4 mRNA was detected in all BCCLs studied. IGFBP-5 expression was higher in estrogen receptor (ER) positive cells, while IGFBP-6 mRNA was detected in only two ER negative BCCLs. We also found that E2 treatment enhanced the expression of IGFBPs 2, 4, and 5 in T47-D cells. We next studied IGFBP mRNA expression in 40 primary breast tumors. All tumors expressed mRNA for IGFBPs 2-6 but none expressed IGFBP-1 message. IGFBP-3 expression was higher in ER negative tumors, while that of IGFBP-4 and -5 was higher in ER positive specimens. These differences were statistically significant (P < .05). Ligand blot analysis of tumor extracts confirmed the presence of IGFBPs in breast cancer tissues. Thus, differential IGFBP expression in ER positive and negative tumors suggests an important role for this protein in breast cancer biology.
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PMID:Expression of insulin-like growth factor binding proteins in human breast cancer correlates with estrogen receptor status. 769 42

In this study, we examined the expression of insulin-like growth factor (IGF) ligands, receptors, (IGFR1, IGFR2), and binding proteins (IGFBPs) in the human prostate cancer cell line DU145, as well as its mitogenic response to the IGFs. Using RNase protection assays, we found expression of IGF-II, IGFR1, and IGFR2 but failed to detect IGF-I messenger RNA. Distinct binding protein species as well as immunoreactive IGF-II were detected in conditioned media using radioligand and immunoblotting assays. Compared with controls, treatment with exogenous IGF-I and IGF-II resulted in stimulation of monolayer and anchorage-independent growth. Recombinant human IGFBP-1, which binds IGF-II with high affinity, inhibited IGF-II-induced monolayer growth and both baseline and IGF-II-induced anchorage-independent growth in this cell line. Our data suggest IGF-II is as an autocrine growth factor in DU145 cells, and that inhibition of IGF-II-dependent growth of human prostate cancer cells may represent a new therapeutic strategy for this disease.
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PMID:Proliferation of cultured human prostate cancer cells is inhibited by insulin-like growth factor (IGF) binding protein-1: evidence for an IGF-II autocrine growth loop. 853 May 86

The cellular effects of insulin-like growth factor I (IGF-I) are modified by a family of binding proteins (IGFBPs) that act as reservoirs in serum for the growth factor and are produced locally by tissues, including the kidney. Because regulation of these proteins may influence renal repair, either directly or by their interactions with IGF-I, we studied gene expression during the recovery from renal failure induced by folic acid and during the compensatory increase in renal function following uninephrectomy (UNX). Expression of IGF-I, the IGF-I receptor (IGF-IR), and all six IGFBPs was detected using an ribonuclease protection assay. IGFBP-5 was the most abundant binding protein mRNA present in kidney, whereas IGFBP-2 and -6 were the least abundant. During regeneration following folic acid-induced acute renal failure, IGF-I, IGFBP-3, and IGFBP-5 mRNAs declined in abundance approximately two- to threefold. On the other hand, IGF-IR, IGFBP-1, and IGFBP-2 were increased (approximately 2-, 6-, and 6-fold, respectively) in the first 24 h. IGFBP-1 mRNA remained elevated for at least 3 days. Despite the known increase in cellular RNA content following UNX, little difference in specific expression of mRNAs was observed. Because IGFBP-1 has been shown to stimulate cell migration and has previously been localized to the distal nephron, the site of greatest injury in the folic acid model, these data are compatible with the notion that this protein may function either directly to affect cellular repair or act as a reservoir for IGF-I under conditions of cellular damage.
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PMID:Differential mRNA expression of insulin-like growth factor system during renal injury and hypertrophy. 859 75

IGF-I regulates renal growth and development. Insulin-like growth factor binding proteins (IGFBPs) are synthesized by the kidney and may modulate the local autocrine and/or paracrine actions of IGF-I. We have previously demonstrated that mesangial cells (MC) release IGF-I and IGF-binding activity; however, the specific IGFBPs produced by these cells and the factors involved in their regulation are unknown. We examined MC for expression of IGFBP-1 to -6 mRNAs and proteins. RNase protection assays using total RNA demonstrated that MC express all of the IGFBPs. [125I]IGF-I Western ligand blot of conditioned medium demonstrated that MC release IGFBPs of 24, 29, 32 kDa, and a doublet at 46 kDa, consistent with IGFBP-4, -5, -2 and -3, respectively. IGFBP species of 28 and 34 kDa were also detected. Since IGF-I and TGF-beta are implicated in glomerular hypertrophy and matrix expansion, we tested their effect on IGFBPs released by MC. IGF-I (100 ng/ml), TGF-beta (2 ng/ml) and forskolin (10(-5) M) differentially regulated the abundance of IGFBPs released in the conditioned medium in a time-dependent manner. IGF-I and TGF-beta were potent inducers of the release of IGFBP3 protein; however, TGF-beta, but not IGF-I, increased IGFBP3 mRNA levels. Recombinant IGFBP3 was tested for its effect on IGF-I-induced mitogenesis. IGFBP3 inhibited IGF-I-stimulated DNA synthesis in a dose-dependent manner with a peak effect observed at 50 nM IGFBP3. Although TGF-beta is a potent inhibitor of IGF-I-stimulated DNA synthesis, this effect is not mediated via IGFBPs. Expression of IGFBP-1 to -6 by MC suggests that these proteins may modulate IGF-I bioavailability in the glomerulus. IGF-I itself, TGF-beta and cAMP agonists may indirectly modulate the effects of IGF-I via the release of IGFBPs by MC.
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PMID:Characterization of insulin-like growth factor binding proteins and regulation of IGFBP3 in human mesangial cells. 869 27

The imbalance between normal insulin-like growth factor-I (IGF-I) and markedly increased IGF binding protein (IGFBP) plasma levels plays a pathogenic role for growth retardation and catabolism in children with chronic renal failure. To investigate the mechanism of these alterations, experiments were performed in an experimental model of uremia in rats (5/6 nephrectomy) and in pair-fed and ad libitum-fed sham-operated controls Using a specific solution hybridization/RNase protection assay, we observed a marked reduction of hepatic IGF-I messenger RNA (mRNA) abundance at steady state in uremic animals (37 +/- 5% of control) compared both with pair-fed (65 +/- 10%) and ad libitum-fed controls (100 +/- 11%) (P < 0.001). Reduced IGF-I gene expression was clearly organ-specific; it was most pronounced in liver (significant vs., pair-fed controls) and lung and muscle tissue (significant vs., ad libitum-fed controls); no change was observed in kidney and heart tissue. To determine a potential mechanism of reduced hepatic IGF-I gene expression in uremia, the hepatic GH receptor gene expression in the same experimental animals was analyzed by specific solution hybridization/RNase protection assay. Uremic animals had a 20-30% reduction of hepatic GH receptor mRNA abundance compared with controls. Hepatic GHBP expression in uremia was decreased in parallel. Despite the reduction of hepatic IGF-I mRNA abundance, plasma IGF-I levels in uremia were not different from ad libitum-fed controls. This discrepancy is explained by an increased concentration of IGFBPs in uremic plasma. By RIA, plasma IGFBP-1 levels in uremia were increased 4-fold; by Western immunoblot, plasma IGFBP-2 levels were increased 7-fold and plasma IGFBP-4 levels were increased 2-fold compared with both control groups. Intact IGFBP-3 (M(r), approximately 48 kDa) and low molecular IGFBP-3 fragments were not significantly different among the three groups. By Northern blot analysis, hepatic IGFBP-1 mRNA levels in uremia were 2-fold higher than in controls. IGFBP-2 mRNA abundance in liver tissue was increased 4-fold, whereas in kidney there was a significant reduction of IGFBP-2 mRNA (30% of control). IGFBP-4 mRNA was increased by 50% in kidney but not in liver. Plasma insulin and corticosterone levels were not different among the groups. Our study shows that hepatic IGF-I gene expression was specifically reduced in uremia, partially as the consequence of a reduced hepatic GH receptor gene expression. One of the mechanisms contributing to increased IGFBP levels in uremia is increased hepatic gene expression of IGFBP-1 and IGFBP-2. The imbalance between reduced hepatic IGF-I production and increased hepatic IGFBP-1 and 2 production is likely to play a pathogenic role for catabolism and growth failure in CRF.
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PMID:Decreased hepatic insulin-like growth factor (IGF)-I and increased IGF binding protein-1 and -2 gene expression in experimental uremia. 904 93

A precise role for insulin-like growth factors (IGFs), IGF-binding proteins (IGFBPs), and IGF-receptors (IGF-Rs) in damaged central nervous system (CNS) tissue has not been elucidated, although their expression in the ischemic brain has been demonstrated. However, little is known of IGF responses after CNS trauma. In this study, we have used ribonuclease protection assay, in situ hybridization, and immunohistochemistry to demonstrate that IGF-I, IGFBPs, and IGF-1R expression alters in response to a penetrating CNS injury. Within penetrant cerebral wounds in the acute phase of the response (1-7 days post lesion; dpl), increased levels of IGF-I, IGFBP-1, -2, -3, -6, and IGF-1R protein were localized to injury responsive astrocytes, neurons and cells of the monocyte lineage. IGF-I, IGFBP-2, and 3 showed a congruency in sites of messenger RNA (mRNA) and peptide expression, with IGF-I and IGFBP-2 mRNA expression predominating. IGF-I, IGFBP-1, and IGFBP-3 protein were also associated with the microvascular endothelium, which was accompanied by increased levels of IGFBP-3 mRNA. These early changes in IGFBP expression probably facilitate IGF-I action. Later in the wounding response (7-14 dpl), the expression of IGFBP-4 and IGFBP-5 peaked within astrocytes and neurons, with IGFBP-5 mRNA being specifically localized to the glia limitans within the wound, suggesting an inhibitory role for these proteins, down-regulating the effects of IGF-I chronically. Our evidence suggests that within penetrating CNS wounds, IGF-I acts in an autocrine/paracrine manner to regulate cellular responses, with its spatial and temporal availability being modulated by the differential presence of stimulatory vs. inhibitory IGFBPs.
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PMID:Spatial and temporal changes in the insulin-like growth factor (IGF) axis indicate autocrine/paracrine actions of IGF-I within wounds of the rat brain. 920 48

Major changes in serum levels of insulin-like growth factor I (IGF-I) and IGF-binding proteins (IGFBPs) occur in children with end-stage liver disease in association with changes in body composition. We hypothesized that these changes would be associated with changes in hepatic messenger RNA (mRNA) expression. Eleven children with end-stage extrahepatic biliary atresia and 11 controls (liver donors) were studied. Serum samples were obtained from the children with biliary atresia immediately before orthotopic liver transplantation. Serum IGF-I, IGFBP-1, and IGFBP-2 levels were measured by radioimmunoassay, and IGFBP-3 by immunoradiometric assay. In both groups, growth hormone receptor mRNA expression was examined by quantitative reverse transcription-polymerase chain reaction, IGF-I mRNA expression by ribonuclease protection assay, and IGFBP-1 to -4 mRNA expression by Northern analysis. Growth hormone receptor and IGF-I mRNA levels were reduced 1.7-fold (P = .003) and 9.6-fold (P = .0001) in biliary atresia compared with levels in controls. Despite increased serum IGFBP-1 levels and reduced IGFBP-3 levels in biliary atresia, there was no change in either IGFBP-1 or IGFBP-3 mRNA expression. In contrast, serum levels and mRNA expression of IGFBP-2 were increased 1.6-fold (P = .003) and twofold (P = .0001), respectively, compared with controls. Gene expression did not correlate with liver dysfunction or body composition. Changes in growth hormone receptor and IGF-I mRNA expression may account for the reduction in serum IGF-I found in pediatric liver disease. In contrast, the marked alteration in circulating IGFBP levels was not accompanied by changes in hepatic IGFBP gene expression, suggesting that posttranslational mechanisms may be important.
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PMID:Hepatic growth hormone receptor, insulin-like growth factor I, and insulin-like growth factor-binding protein messenger RNA expression in pediatric liver disease. 939 4


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