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 signal transduction pathways that mediate GH-dependent regulation of IGF-I gene expression remain poorly defined. To establish a GH-responsive in vitro model system to study the effect of GH on the expression of the endogenous IGF-I gene, primary hepatocytes from adult male rats were prepared. These cells expressed both the GH receptor and the IGF-I gene, as demonstrated using a ribonuclease protection assay. Western blot analyses using antibodies directed against the phosphorylated forms of the ERKs, signal transducer and activator of transcription-5, and Akt/protein kinase B, a protein kinase that is downstream of PI3K, demonstrated GH-dependent phosphorylation of these signaling molecules. These signaling molecules are components of the major signal transduction pathways that are activated by GH. To determine whether GH-responsive IGF-I gene expression could be demonstrated in these cells, hepatocytes were treated without or with 50 ng/ml GH for 3--48 h. IGF-I mRNA levels increased within 3 h, and a maximal 2.2-fold increase was observed after 24 h of GH treatment. To determine whether ERK activation contributes to GH-induced IGF-I gene expression, hepatocytes were treated for 12 h without or with 50 ng/ml GH and 50 microM PD98059, an inhibitor of MAPK kinase-1 and -2. Treatment with PD98059 did not have a significant effect on GH-induced IGF-I gene expression. Similar studies were performed using 50 microM LY 294002, an inhibitor of PI3K. These studies demonstrated that treatment with LY 294002 completely abrogated GH-induced IGF-I gene expression. In contrast, PI3K-specific doses of another inhibitor of PI3K, wortmannin, failed to inhibit the GH-induced increase in IGF-I mRNA levels. In summary, rat hepatocytes in primary culture provide a good model system to study GH-induced IGF-I gene expression, and the results of these studies suggest that a signaling pathway inhibited by LY 294002, possibly a PI3K-dependent pathway, is important for GH-stimulated IGF-I gene expression in hepatocytes.
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PMID:LY 294002, an inhibitor of phosphatidylinositol 3-kinase, inhibits GH-mediated expression of the IGF-I gene in rat hepatocytes. 1151 77

To examine the role of insulin-like growth factor-1 (IGF-1) in renal atrophy of rats with two-kidney, one-clip (2K1C), in which the clipped kidney atrophies, and in the one-kidney, one-clip (IK1C) model of renovascular hypertension, in which it hypertrophies, we studied levels of IGF-I, mRNA, and protein in 2K1C, IK1C, and unilateral nephrectomy (NPX) in rats by solution-hybridization RNase protection, and radioimmunoassay, respectively, both cross-reactively and longitudinally at 3, 10, and 30 days after clipping. Three days after clipping, there were no differences in blood pressure or kidney size; however, 10 and 30 days postoperation, the clipped kidney shrank in the 2K1C model. The nonclipped 2K1C and the clipped lK1C and unilateral nephrectomy kidneys increased in weight (P < .05. At day 3 the IGF-I levels were lower (557 +/- 54, 335 +/- 61 ng/g in control and clipped 2K1C, P < .05, v 1,074 +/- 186, 1,109 +/- 54, and 1,154 +/- 200 ng/g kidney, nonclipped 2K1C, 1K1C, and NPX, respectively). At 30 days the IGF-I levels were 300 +/- 24 ng/g in control (P < .05) v clipped 2K1C, 160 +/- 19, 218 +/- 20 ng/g in nonclipped 2K1C and 406 +/- 33 and 470 +/- 34 ng/g in 1K1C and NPX, respectively (P < .05) v control and clipped 2K1C. Kidney mRNA was increased in the clipped 2K1C. In conclusion, the kidney that had higher IGF-I levels early in nonclipped 2K1C, 1K1C, and nephrectomy hypertrophied, and the kidney (clipped 2K1C) that failed to increase IGF-I atrophied. IGF-I levels are dissociated from the local mRNA message.
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PMID:Atrophy or hypertrophy in chronic renal ischemia: role of the IGF-I system. 1177 29

Mechanical forces are well known to modulate smooth muscle cell growth and synthetic phenotype. The signals controlling this process are complex and potentially involve changes in the expression of peptide growth factor genes such as those of the insulin-like growth factor (IGF) system. This study was designed to investigate the mechanical regulation of IGF-I and the binding proteins for IGF (IGFBPs) in smooth muscle cells cultured on a deformable surface and subjected to cyclic stretch. Using the RNase protection assay, we found that the application of a cyclic biaxial strain to cells induced a 2.5- to 4-fold increase in IGF-I mRNA levels after 8 h and an even greater increase after 16-24 h of stretch. This change was not affected by variations in the magnitude of the applied strain but was attenuated ( approximately 40%) when cells were treated with antagonists for angiotensin II receptors. Furthermore, the transcript levels of the three major IGF binding proteins produced in smooth muscle cells, e.g., IGFBP-2, IGFBP-4, and IGFBP-5, varied between stretched and control cells. Both IGFBP-2 and IGFBP-4 mRNA levels were consistently reduced in stretched cells but remained comparable to those of the control cells when the angiotensin II transducing pathway was blocked by inhibitors prior to the application of mechanical strain. Conversely, the gene expression of IGFBP-5 was upregulated in stretched cells, and neutralizing antibodies to IGF-I blocked this activation. Similarly, pharmacologic inhibition of the phosphatidylinositol 3-kinase, an important component of the IGF receptor transduction pathway, inhibited IGFBP-5 gene expression in stretched cells. These results suggest that the downstream effects of mechanical strain on IGF-I and IGFBP transcript levels are mediated, to greater or lesser extent, either through an angiotensin II tranducing pathway or via a feedback loop involving the autocrine secretion of IGF-I itself.
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PMID:Mechanical regulation of IGF-I and IGF-binding protein gene transcription in bladder smooth muscle cells. 1178 55

The aim of this work was to study the influence of the endocrine balance between thyroid hormones, insulin and growth hormone (GH) on the regulation of insulin-like growth factor binding proteins (IGFBPs), complementing a study previously reported for insulin-like growth factors (IGFs) in similar populations. Serum concentrations of IGFBPs-1 to -3 were assayed by Western ligand blot and their mRNA expression in the liver assayed by RNase protection assay in the hypothyroid populations: thyroidectomized and mercapto-1-methylimidazole (MMI)-treated neonates, and thyroidectomized adult rats at different periods after thyroidectomy. Serum concentrations of insulin, GH and IGF-I were increased in thyroidectomized neonates and decreased in the other populations. IGFBPs-1 and -2 increased 79% and 50% respectively in thyroidectomized neonatal rats compared with control at 15 days after thyroidectomy, whereas only IGFBP-2 increased (87%) in MMI-treated neonates, which had low serum insulin and GH compared with control on the same days. In thyroidectomized adult rats, IGFBPs-1 and -2 decreased 60% compared with controls on all days studied. Furthermore, when streptozotocin was administered to thyroidectomized neonates and insulin was given to thyroidectomized adult rats to restore insulin to control values in both groups, a differential regulation was found for IGFBPs-1 and -2. The transcriptionally induced decrease in IGFBP-3 (20-25% compared with control in neonates and 50% in adult rats), however, seemed to be regulated by GH and IGF-I. The similarity of changes in IGFBPs found in hypothyroid, undernourished and streptozotocin-induced diabetic neonatal rats suggests that the regulatory effect of insulin or GH on the IGFBPs requires the reduced biologically active thyroid hormone that is found in these three populations.
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PMID:Influence of hypothyroidism on circulating concentrations and liver expression of IGF-binding proteins mRNA from neonatal and adult rats. 1183 54

The inflammatory response of the lung to noxious factors contributes to the pathogenesis of chronic lung injury. Inflammatory mediators regulate the insulin-like growth factor (IGF) system, a key modulator of lung fibroblast proliferation. The activity of IGFs is regulated by IGF-binding proteins (IGFBPs) secreted by lung cells. To investigate the regulation of lung fibroblast IGFBPs by cytokines, we exposed 19-d fetal rat lung fibroblasts to various pro- and anti-inflammatory mediators. IGFBP abundance in conditioned medium (CM) was measured by ligand blot and RNA transcript abundance by RNase protection assays. Fetal rat lung fibroblasts exposed to interleukin (IL)-1beta or tumor necrosis factor (TNF)-alpha for 48 h demonstrated increased abundance of CM IGFBP-3 (5.9- and 4.7-fold increases for IL-1beta and TNF-alpha, respectively) and IGFBP-4 (5.7- and 7.4-fold increases for IL-1beta and TNF-alpha, respectively) that was accompanied by a small increase in IGFBP-4 mRNA and a larger increase in IGFBP-3 mRNA abundance. IGFBP-4 specific proteolysis was examined in CM collected from fetal rat lung fibroblasts after incubation with serum-free medium (SFM), IL-1beta, or TNF-alpha for 48 h. Cell-free aliquots of SFM-CM incubated at 37C for 24 h showed a 65% decrease in IGFBP-4 abundance that was inhibited by 1,10-phenanthroline. In contrast, CM from cells exposed to IL-1beta or TNF-alpha incubated at 37 degrees C for 24 h did not show a significant decrease in IGFBP-4 abundance unless IGF-I was present during the cell-free incubation. Addition of IGFBP-3 to aliquots of SFM-CM reversed the IGF-I-mediated acceleration of IGFBP-4 proteolysis. Similarly, addition of IGFBP-3 to cells in culture increased the accumulation of CM IGFBP-4. These results demonstrate that cytokines regulate IGFBP production and clearance by fetal lung cells and suggest a mechanism by which cytokines regulate cell proliferation following lung injury.
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PMID:Pro- and anti-inflammatory cytokines regulate insulin-like growth factor binding protein production by fetal rat lung fibroblasts. 1186 36

Nutritional status is a critical factor that modulates the responsiveness of the liver to GH and the resulting production of endocrine (mostly liver-derived) IGF-I. Using a conditional Cre/lox P system, we have established a liver-specific IGF-I-deficient mouse model. Despite the reduction in the circulating IGF-I (75%), the growth parameters are normal, except for the reduced spleen size, providing a unique model to study the effect of protein restriction on the autocrine/paracrine GH/IGF-I axis. To determine the effects of protein calorie malnutrition on the spleen, liver-specific IGF-I-deficient mice were assigned to one of four isocaloric diets, differing in the protein content (20, 12, 4, and 0%), for a period of 10 d. A low protein intake decreased the nonhepatic IGF-I secretion into the circulation, whereas it caused an increase in the level of circulating GH. This supports the view that nonhepatic IGF-I production contributes to circulating IGF-I levels. The lack of dietary protein led to an up-regulation of GH and IGF-I receptors expression in the spleen, whereas the IGF-I mRNA remained unchanged, as was demonstrated by flow cytometry and ribonuclease protection assay. B lymphocytes seem to be responsible for the up-regulated GH/IGF-I receptor expression. Northern blot analysis showed an up-regulation of IGF-binding protein-3 mRNA levels, which suggests that the protein deprivation may lead to an increased sequestration of circulating or locally synthesized IGF-I. These results support the hypothesis that the splenic GH/IGF-I axis responds to the nutritional stress caused by a low protein intake, to maintain the tissue homeostasis.
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PMID:Protein calorie restriction affects nonhepatic IGF-I production and the lymphoid system: studies using the liver-specific IGF-I gene-deleted mouse model. 1202 Nov 87

Insulin-like growth factor (IGF)-I has an important role in myogenesis but its developmental regulation in skeletal muscle before birth remains unknown. In other tissues, cortisol modulates IGF gene expression and is responsible for many of the prepartum maturational changes essential for neonatal survival. Hence, using RNase protection assays and ovine riboprobes, expression of the IGF-I and growth hormone receptor (GHR) genes was examined in ovine skeletal muscle during late gestation and after experimental manipulation of fetal plasma cortisol levels by fetal adrenalectomy and exogenous cortisol infusion. Muscle IGF-I, but not GHR, mRNA abundance decreased with increasing gestational age in parallel with the prepartum rise in plasma cortisol. Abolition of this cortisol surge by fetal adrenalectomy prevented the prepartum fall in muscle IGF-I mRNA abundance. Conversely, raising cortisol levels by exogenous infusion earlier in gestation prematurely lowered muscle IGF-I mRNA abundance but had no effect on GHR mRNA. When all data were combined, plasma cortisol and muscle IGF-I mRNA abundance were inversely correlated in individual fetuses. Cortisol is, therefore, a developmental regulator of IGF-I gene expression and is responsible for suppressing expression of this gene in ovine skeletal muscle near term. These observations have important implications for muscle development both before and after birth, particularly during conditions which alter intrauterine cortisol exposure.
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PMID:Control of growth hormone receptor and insulin-like growth factor-I expression by cortisol in ovine fetal skeletal muscle. 1204 62

We investigated the effect of increasing nutrient intake on the responsiveness of the GH/IGF-I system in calves fed a high-protein milk replacer. Fifty-four Holstein bull calves were fed one of three levels (low, medium, and high; n = 18 per treatment) of a 30% crude protein, 20% fat milk replacer to achieve target rates of gain of 0.50, 0.95, or 1.40 kg/d, respectively, for low, medium, and high. Six calves per treatment were slaughtered at approximately 65, 85, and 105 kg BW. Additionally, six calves were slaughtered at 1 d of age to provide baseline data. Plasma aliquots from blood samples collected weekly were analyzed for IGF-I, insulin, glucose, NEFA, and plasma urea nitrogen (PUN). Plasma IGF-I and insulin, measured weekly, increased (P < 0.001) with greater nutrient intake from wk 2 of life to slaughter. Plasma glucose and NEFA also increased (P < 0.05) with nutrient intake. In addition, each calf underwent a GH challenge beginning 4 d before the scheduled slaughter. Plasma from blood collected before the first GH injection and 14 and 24 h after the third injection was analyzed for IGF-I and PUN. Response to challenge, calculated as the absolute difference between the prechallenge and 14-h postchallenge plasma IGF-I concentrations, was significant in calves on all three treatments. Plasma urea nitrogen was not different among treatments as measured weekly but decreased (P < 0.001) following GH challenge in all calves. Results of ribonuclease protection assays showed increased expression of hepatic mRNA for GH receptor 1A and IGF-I with increased intake. The amounts of GH receptor and IGF-I mRNA in muscle and adipose, however, were not affected by intake. In summary, plasma IGF-I was elevated in calves with increased nutrient intake, and the elevations in plasma IGF-I following short-term administration of GH were significant in all calves by 65 kg BW. Data demonstrate that in well-managed milk-fed calves the somatotropic (GH/IGF-I) axis is functionally coordinated and sensitive to nutrient intake and GH.
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PMID:Effect of nutrient intake on the development of the somatotropic axis and its responsiveness to GH in Holstein bull calves. 1207 34

Basic fibroblast growth factor (bFGF) stimulates bone formation in vitro and in vivo. The purpose of this study was to determine changes in gene expression for bone matrix proteins, growth factors, and cytokines associated with the stimulatory effects of bFGF on bone formation in aged ovariectomized (ovx) rats. At 3 months of age, female Sprague-Dawley rats were sham-operated (sham) or ovariectomized (ovx), then maintained untreated for 1 year. At 15 months of age, baseline (BSL) sham and ovx rats were killed. All other rats received daily intravenous injections of bFGF (200 microg/kg) or vehicle (veh) for 14 days. Lumbar vertebrae were processed for quantitative bone histomorphometry or molecular analyses. Ovariectomy decreased vertebral cancellous bone volume by approximately 33% and increased most indices of bone turnover. Treatment of aged ovx rats with bFGF for only 14 days significantly increased cancellous bone volume compared with vehicle treatment of ovx rats, but this variable remained lower than in sham + veh rats. Osteoid volume, osteoblast surface, and osteoid surface were markedly increased, and osteoclast surface was significantly decreased in ovx + bFGF rats compared with sham + veh and ovx + veh rats. Northern analyses revealed that mRNA levels for osteocalcin and type I collagen, relative to 18S RNA, were significantly higher in ovx + bFGF rats than in ovx + veh rats by a factor of >10. RNase protection assays revealed that insulin-like growth factor (IGF-I) mRNA levels, relative to L32 housekeeping gene, were also significantly higher, by nearly a factor of 3, in ovx + bFGF rats than in ovx + veh rats. Treatment of ovx rats with bFGF did not appear to affect message levels for transforming growth factor-beta (TGF-beta), interleukin-6 (IL-6), and interferon-gamma (IFN-gamma). These in vivo results suggest that bFGF treatment upregulates gene expression for IGF-I, which may mediate, at least in part, the increased gene expression for bone matrix proteins and the bone anabolic effects of bFGF in aged ovx rats.
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PMID:Changes in gene expression associated with the bone anabolic effects of basic fibroblast growth factor in aged ovariectomized rats. 1211 Apr 27

Seckel syndrome is an autosomal-recessive disorder with a frequency of less than 1/10 000 births in which there are multiple malformations including severe short stature. We report on a patient with Seckel syndrome with a current body height of -7.5 SDS. Laboratory investigations at the age of 19 months revealed high levels of IGF-I, IGF-II and IGFBP-3. These data suggested the existence of IGF-I resistance possibly caused by impairment of the IGF-I receptor (IGF-IR) or altered IGFBPs. The purpose of this investigation was to examine whether the growth retardation in a Seckel syndrome patient is related to an alteration in the IGF system. Analysis of IGF-IR mRNA of patient's and control fibroblasts by solution hybridization/RNase protection assay did not show differences of IGF-IR transcript expression or size. Affinity crosslinking studies using [125I]-IGF-I showed normal-sized IGF-IR-ligand complexes. Mutation analysis of the complete coding regions of the IGF-I and IGF-IR genes showed no evidence of genetic alterations. Ligand blot analysis of IGFBPs secreted by the patient's fibroblasts showed stronger signals than control cells. Quantitative measurement of IGFBP-3 in cell-conditioned media was performed by radioimmunoassay (RIA) and revealed a sixfold increase when compared to control fibroblasts. We conclude that in this patient with Seckel syndrome and severe growth impairment IGF-I resistance is possibly related to altered production of IGFBP-3.
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PMID:Growth failure in a child showing characteristics of Seckel syndrome: possible effects of IGF-I and endogenous IGFBP-3. 1215 10


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