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:3.1.27.1 (RNase)
16,360 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mitogenic and metabolic effects of insulin-like growth factor-II (IGF-II) can be modulated by six distinct IGF binding proteins (IGFBPs). As a first step toward understanding the role of IGFs and their binding proteins in intestinal epithelial cell differentiation, the expression of IGF-II and IGFBPs was characterized in the human colon adenocarcinoma Caco-2 cell line. Northern blot analysis revealed two IGF-II transcripts of 5.4 and 4.5 kb, and ribonuclease protection assays indicated that IGF-II mRNA levels are regulated during Caco-2 differentiation. A specific radioimmunoassay detected IGF-II in serum-free conditioned medium, the level of which was three- to fivefold higher in proliferating cells than in differentiated cells. Immunoprecipitation and ligand blot analyses of conditioned medium demonstrated that IGFBP-2, IGFBP-3, IGFBP-4, and IGFBP-6 are synthesized by Caco-2 cells, with IGFBP-2 and IGFBP-4 being the major IGFBPs secreted, and that the levels of IGFBP-2 and IGFBP-6 decreased as differentiation proceeded. These results indicate that the expression of IGF-II, IGFBP-2, and IGFBP-6 is regulated in a differentiation-dependent manner in Caco-2 cells.
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PMID:Expression of IGF-II and IGF binding proteins in differentiating human intestinal Caco-2 cells. 749 29

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

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

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 insulin-like growth factors (IGF-I and IGF-II), their receptors and binding proteins (IGFBPs) are endogenously expressed in a number of tissues including the lung during fetal and neonatal development. This endogenous autocrine/paracrine IGF 'system', together with endocrine sources, contributes to the regulation of lung cell proliferation. We investigated the expression of the mRNAs encoding IGF-I, IGF-II, the type 1 IGF receptor (IGF-T1R) and two IGF-binding proteins (IGFBP-2 and IGFBP-4) in rat lung during the perinatum. These were compared in lung with surfactant apoprotein A (Sp-A) mRNA levels. mRNA in extracts of fetal tissues collected between day 17 of gestation (17f) and day 9 after birth (9d) was estimated by Northern blot or RNase protection analysis. At day 20 of gestation IGF-I, IGF-T1R and IGFBP-4 mRNA levels were higher in lung than liver (all P < 0.01), whereas IGF-II and IGFBP-2 mRNA levels were higher in liver than lung (each P < 0.02). The expression of IGF-1, IGFBP-2 and IGFBP-4 in lung was high before birth (days 17-20f) but decreased to low levels at days 21f, 22f or at birth (1d) but increased in the neonatal lung. IGF-II expression in lung was high at 17f but decreased before birth and remained low after birth. The IGF-T1R was expressed at moderate levels before birth, decrease before birth but peaked at days 2-5 after birth. The decrease in expression of these growth regulators before birth expression of these growth regulators before birth was matched by an increased in Sp-A expression which was clearly seen at day 20f, peaked at 1d and then was clearly seen at day 20f, peaked at 1d and then was maintained at high levels after birth. Primary cell cultures of 18f lung epithelia express IGFBP-2 while fibroblasts from the same animals express only IGFBP-4. Cells grown from 22f lung tissue express IGFBP-2 and IGFBP-4 at lower levels, behaving in vitro as they do in vivo. The contrasting levels of expression of different components of the IGF system in the fetal lung and liver indicate organ-specific regulation. IGFBP-2 and IGFBP-4 expression in different cell types within lung but with similar temporal changes suggests cell-specific regulation, perhaps by a common agent. The patterns by a common agent. The patterns of expression of IGF-I, IGF-T1R, IGFBP-2 and IGFBP-4, but not IGF-II, in developing lung correspond to previously described phasic changes in lung cell proliferation rates. The nadir in expression of these four major components of the lung IGF system occurs in the saccular phase when the lung begins to differentiate, probably under the influence of certain endocrine agents.
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PMID:Developmental changes in the expression patterns of IGFs, type 1 IGF receptor and IGF-binding proteins-2 and -4 in perinatal rat lung. 880 Jun 36

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

Cultured hepatic stellate cells (HSCs), the cell type primarily involved in the progression of liver fibrosis, secrete insulin-like growth factor-I (IGF-I) and IGF binding protein (IGFBP) activity. IGF-I exerts a mitogenic effect on HSCs, thus potentially contributing to the fibrogenic process in an autocrine fashion. However, IGF-I action is modulated by the presence of specific IGFBPs that may inhibit and/or enhance its biologic effects. Therefore, we examined IGFBP-1 through IGFBP-6 mRNA and protein expression in HSCs isolated from human liver and activated in culture. Regulation of IGFBPs in response to IGF-I and other polypeptide growth factors involved in the hepatic fibrogenic process was also assessed. RNase protection assays and ligand blot analysis demonstrated that HSCs express IGFBP-2 through IGFBP-6 mRNAs and release detectable levels of IGFBP-2 through IGFBP-5. Because IGF-I, platelet-derived growth factor-BB (PDGF-BB), and transforming growth factor-beta (TGF-beta) stimulate HSC proliferation and/or matrix production, we tested their effect on IGFBPs released by HSCs. IGF-I induced IGFBP-3 and IGFBP-5 proteins in a time-dependent manner without an increase in the corresponding mRNAs. IGFBP-4 protein levels decreased in response to IGF-I. TGF-beta stimulated IGFBP-3 mRNA and protein but decreased IGFBP-5 mRNA and protein. In contrast, PDGF-BB failed to regulate IGFBPs compared with controls. Recombinant human IGFBP-3 (rhIGFBP-3) was then tested for its effect on IGF-I-induced mitogenesis in HSCs. rhIGFBP-3 inhibited IGF-I-stimulated DNA synthesis in a dose-dependent manner, with a peak effect observed at 25 nM IGFBP-3. Because TGF-beta is highly expressed in cirrhotic liver tissue, we determined whether IGFBP-3 mRNA expression is increased in liver biopsies obtained from patients with an active fibroproliferative response due to viral-induced chronic active hepatitis. In the majority of these samples, IGFBP-3 mRNA was increased compared with normal controls. These findings indicate that human HSCs, in their activated phenotype, constitutively produce IGFBPs. IGF-I and TGF-beta differentially regulate IGFBP-3, IGFBP-4, and IGFBP-5 expression, which, in turn, may modulate the in vitro and in vivo action of IGF-I.
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PMID:Characterization and regulation of insulin-like growth factor binding proteins in human hepatic stellate cells. 942 10

The components of the insulin-like growth factor (IGF) axis have been investigated in the normal human thymus. Using ribonuclease protection assays (RPA), IGF-II transcripts were detected in the normal human thymus. By reverse transcriptase polymerase chain reaction (RT-PCR) analyses, promoters P3 and P4 were found to be active in the transcription of IGF2 gene within human thymic epithelial cells (TEC). No IGF-II mRNA could be detected in human lymphoid Jurkat T cells with 30 cycles of RT-PCR. By Northern blot analyses, IGFBP-2 to -6 (but not IGFBP-1) were found to be expressed in TEC with a predominance of IGFBP-4. Interestingly, Jurkat T cells only express IGFBP-2 but at high levels. The type 1 IGF receptor was detected in Jurkat T cells but not in human TEC. The identification of the components of the IGF axis within separate compartments of the human thymus adds further evidence for a role of this axis in the control of T-cell development. The precise influence of thymic IGF axis upon T-cell differentiation and immunological self-tolerance however needs to be further investigated.
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PMID:Characterization of the insulin-like growth factor axis in the human thymus. 1033 24


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