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)

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

This study assessed the possibility that the intraovarian insulin-like growth factor I (IGF-I) system interacts with the intraovarian interleukin-1 (IL-1) system, the central role of which has been the subject of increasing attention. To this end, whole ovarian dispersates from immature rats were cultured for 48 h in the absence or presence of IGF-I or IGF-binding protein-3 (IGFBP-3), with or without IL-1beta. Cellular RNA content was subjected to a solution hybridization, RNase protection assay with gel-purified [32P]-UTP-labelled antisense riboprobes for rat IL-1beta, type I IL-1 receptor (IL-1R) and secretory phospholipase A2 (sPLA2). PLA2 activity in conditioned media was assayed by measuring the release of [3H]-labelled palmitic acid from the sn-2 position of [3H]-labelled phosphatidylcholine dipalmitoyl (PCDP) substrate. Treatment with IGF-I resulted in a significant (P< 0.01) decrease in type I IL-1R transcripts (an effect which was reversed by co-treatment with IL-1beta), was without effect on IL-1beta transcripts, and significantly (P < 0.05) increased sPLA2 gene expression (an effect which was further enhanced by co-treatment with IL-1beta). Treatment with IGF-I resulted in a significant increase in extracellular PLA2 activity over untreated control. These observations suggest that IGF-I may down-regulate ovarian IL-1 action by decreasing type I IL-1R gene expression, while up-regulating sPLA2 gene expression and activity. These findings are consistent with a role for IGF-I in suppressing IL-1 actions while promoting the generation of prostaglandins. It is tempting to speculate that IGF-I, an intraovarian regulator concerned with promoting folliculogenesis, may be also entwined with priming the prostaglandin-producing potential in anticipation of subsequent ovulation.
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PMID:Insulin-like growth factor I affects the intraovarian interleukin-1 system: evidence for suppression of type I interleukin-1 receptor expression and enhancement of secretory phospholipase A2 expression and activity. 946 54

To investigate specific effects of androgens on whole body metabolism, we studied six healthy lean men (mean +/- SEM age, 23.2 +/- 0.5 yr) before and after gonadal steroid suppression with a GnRH analog (Lupron), given twice, 3 weeks apart. Primed infusions of [13C]leucine, indirect calorimetry, isokinetic dynamometry, growth factor measurements, and percutaneous muscle biopsies were performed at baseline (D1) and after 10 weeks of treatment (D2); each subject served as his own control. Testosterone concentrations were markedly suppressed after 10 weeks of treatment (D1, 535 +/- 141 ng/dL; D2, 31 +/- 9). Leucine's rate of appearance (index of proteolysis) was markedly suppressed after 10 weeks of hypogonadism (-13%; P = 0.01) as well as the nonoxidative leucine disposal, an index of whole body protein synthesis (-13%; P = 0.01) without any changes in plasma amino acid concentrations. All subjects studied after 10 weeks showed a decrease in fat-free mass, as measured by skinfold calipers and dual emission x-ray absortiometry scans (D1, 56.5 +/- 2.9 kg; D2, 54.4 +/- 2.5; P = 0.005), and an increase in percent fat mass (D1, 19.2 +/- 2.5%; D2, 22.2 +/- 2.5; P = 0.001). Rates of lipid oxidation decreased (-31%; P = 0.05) after treatment, with parallel changes in resting energy expenditure (-9%; P = 0.05). Mean and peak GH concentrations (measured every 10 min for 6 h) and GH production rates did not decrease after testosterone deficiency, with an actual increase in basal secretion (P < 0.02). Plasma insulin-like growth factor I (IGF-I) concentrations did not change significantly after 10 weeks of treatment (D1, 227 +/- 44 micrograms/L; D2, 291 +/- 60; P = 0.08). Isokinetic dynamometry of leg extensors at 60 degrees and 180 degrees/s was also decreased after 10 weeks of hypogonadism. Total ribonucleic acid (RNA) was isolated from muscle biopsy samples, and ribonuclease protection assays were performed using human complementary DNA clones for IGF-I, IGF-binding protein-4, myosin, and actin. Ten weeks after Lupron treatment, messenger RNA (mRNA) concentrations of IGF-I decreased significantly, whereas there was a trend toward higher IGF-binding protein-4 concentrations, with no change in myosin or actin mRNA concentrations. In conclusion, testosterone deficiency in young men is associated with a marked decrease in measures of whole body protein anabolism, decreased strength, decreased fat oxidation, and increased adiposity. These effects of testosterone deficiency are independent of changes in peripheral GH production and IGF-I concentrations, even though im IGF-I mRNA concentrations decrease. These data suggest a direct effect of androgens on whole body lipid and protein metabolism.
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PMID:Testosterone deficiency in young men: marked alterations in whole body protein kinetics, strength, and adiposity. 962 14

In cirrhosis, as in other conditions of protein catabolism, there is a state of acquired GH resistance, as defined by high circulating GH levels with low insulin-like growth factor I levels. However, patients with end-stage liver failure respond to supraphysiological doses of GH with an increase in circulating insulin-like growth factor I levels. The present study represents a detailed analysis of GH receptor (GHR) expression in cirrhotic liver from 17 patients with end-stage liver disease. Specific binding of labeled GH was identified in all cirrhotic livers studied. The binding affinity for the GHR was similar in cirrhotic and normal livers, but the number of binding sites per mg protein of liver membrane was variable in both normal and cirrhotic liver, although it were generally lower in cirrhotic liver. GHR expression was identified in cirrhotic liver by Northern blotting, RT-PCR, and ribonuclease protection assay. On Northern blotting, a single transcript of 4.8 kb was identified in normal and cirrhotic tissues. RT-PCR identified expression of both full-length GHR and a truncated form of the GHR; this was confirmed by ribonuclease protection assay. In situ hybridization and immunohistochemistry confirmed the expression of GHR in regenerating hepatocytes and isolated cells in fibrous tissue. In conclusion, 1) the low level of GHR in cirrhotic liver may contribute to the acquired GH resistance found in cirrhotic patients; 2) the reduced expression of both full-length and truncated GHR is compatible with the low level of GH-binding protein found in cirrhosis, as this truncated receptor has previously been reported to generate large amounts of GH-binding protein; and 3) the demonstration of GH binding to cirrhotic liver explains why these patients with GH resistance may still respond to supraphysiological doses of GH.
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PMID:Cirrhotic liver expresses low levels of the full-length and truncated growth hormone receptors. 966 39

The mechanisms by which fasting decreases liver insulin-like growth factor I (IGF-I) messenger RNA (mRNA) abundance have not been defined completely. In the present study, we have examined the effects of fasting in rats on hepatic IGF-I gene transcription, IGF-I pre-mRNA splicing, and cytoplasmic IGF-I mRNA stability. Using the in vitro nuclear run-on transcription technique, we observed that fasting did not change IGF-I gene transcription activity [76 +/- 32 densitometric units (DU) for fasted vs. 58 +/- 23 DU for control-fed rats; P = 0.1], whereas IGF-binding protein-1 (IGFBP-1) gene transcription, a positive control, was increased more than 2-fold (729 +/- 157 DU for fasted vs. 261 +/- 56 DU for control-fed rats; P < 0.05). This implies that fasting-induced reduction of liver IGF-I mRNA is due to events other than a decreased rate of IGF-I gene transcription. By measuring nonspliced (pre-mRNA) and spliced IGF-I transcripts in liver nuclear RNA using ribonuclease protection assays, we found that IGF-I pre-mRNA was increased in fasted rats (measured as the percentage of beta-actin: 34.0 +/- 5.5% for fasted vs. 8.1 +/- 3.8% for control-fed rats; P < 0.01), whereas spliced IGF-I transcript remained unchanged (measured as the percentage of beta-actin: 60.9 +/- 9.2% for fasted vs. 79.0 +/- 6.2% for control-fed rats; P = 0.75). We then compared this pattern of splicing to IGF-I pre-mRNA splicing in hypophysectomized rats subjected to GH stimulation and to IGFBP-1 pre-mRNA splicing in the same fasting experiment. One hour after GH injection, we observed a coordinate increase in both nonspliced and spliced IGF-I transcripts in liver nuclei of hypophysectomized rats. Fasting increased both IGFBP-1 pre-mRNA and spliced transcript. Taken together, these results indicate that the increase in IGF-I pre-mRNA in liver nuclei during fasting is caused by delayed pre-mRNA splicing, rather than increased IGF-I gene transcription. To examine the possible effect of fasting on hepatic IGF-I mRNA stability, we used an in vitro model of nutrient deprivation (fewer amino acids in culture medium) of rat hepatocyte primary culture. Each of the three major IGF-I mRNA species exhibited a shortened half-life in the amino acid-deprived media. The 7.5-kb IGF-I mRNA, however, was degraded faster than the two smaller IGF-I mRNA species. This may indicate that fasting decreases the stability of liver IGF-I mRNA in vivo. In summary, these results suggest that fasting regulates hepatic IGF-I gene expression mainly at the posttranscriptional level by delaying IGF-I pre-mRNA splicing, which attenuates mature IGF-I mRNA generation, and by accelerating the rate of degradation of IGF-I mRNA in cytoplasm.
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PMID:Reduction of hepatic insulin-like growth factor I (IGF-I) messenger ribonucleic acid (mRNA) during fasting is associated with diminished splicing of IGF-I pre-mRNA and decreased stability of cytoplasmic IGF-I mRNA. 979 61

The decrease in cancellous bone formation after estrogen treatment is generally thought to be coupled with a prior decrease in bone resorption. To test the possibility that estrogen has rapid tissue-specific actions on bone metabolism, we determined the time course (1-32 h) effects of diethylstilbestrol on steady-state mRNA levels for immediate-response genes, extracellular matrix proteins, and signaling peptides in the proximal tibial metaphysis and uterus by using Northern blot and RNase protection assays. The regulation of signaling peptides by estrogen, although tissue specific, followed a similar time course in bone and uterus. The observed rapid decreases in expression of insulin-like growth factor I, a growth factor associated with bone formation; decreases in mRNA levels for bone matrix proteins; evidence for reduced bone matrix synthesis; failure to detect rapid increases in mRNA levels for signaling peptides implicated in mediating the inhibitory effects of estrogen on bone resorption (interleukin-1 and -6) as well as other cytokines that can increase bone resorption; and the comparatively long duration of the bone remodeling cycle in rats indicate that estrogen can decrease bone formation by a mechanism that does not require a prior reduction in bone resorption.
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PMID:Estrogen has rapid tissue-specific effects on rat bone. 1036 61

During development, the insulin-like growth factor I (IGF-I) gene is expressed in a tissue specific manner; however, the molecular mechanisms governing its developmental regulation remain poorly defined. To examine the hypothesis that expression of the growth hormone (GH) receptor accounts, in part, for the tissue specific expression of the IGF-I gene during development, the developmental regulation of IGF-I and GH receptor gene expression in rat tissues was examined. The level of IGF-I and GH receptor mRNA was quantified in RNA prepared from rats between day 17 of gestation (E17) and 17 months of age (17M) using an RNase protection assay. Developmental regulation of IGF-I gene expression was tissue specific with four different patterns of expression seen. In liver, IGF-I mRNA levels increased markedly between E17 and postnatal day 45 (P45) and declined thereafter. In contrast, in brain, skeletal muscle and testis, IGF-I mRNA levels decreased between P5 and 4M but were relatively unchanged thereafter. In heart and kidney, a small increase in IGF-I mRNA levels was observed between the early postnatal period and 4 months, whereas in lung, minimal changes were observed during development. The changes in GH receptor mRNA levels were, in general, coordinate with the changes in IGF-I mRNA levels, except in skeletal muscle. Interestingly, quantification of GH receptor levels by Western blot analysis in skeletal muscle demonstrated changes coordinate with IGF-I mRNA levels. The levels of the proteins which mediate GH receptor signaling (STAT1, -3, and -5, and JAK2) were quantified by Western blot analysis. These proteins also are expressed in a tissue specific manner during development. In some cases, the pattern of expression was coordinate with IGF-I gene expression, whereas in others it was discordant. To further define molecular mechanisms for the developmental regulation of IGF-I gene expression, protein binding to IGFI-FP1, a protein binding site that is in the major promoter of the rat IGF-I gene and is important for basal promoter activity in vitro, was examined. Gel shift analyses using a 34-base pair oligonucleotide that contained IGFI-FP1 did not demonstrate changes in protein binding that paralleled those in IGF-I gene expression, suggesting that protein binding to IGFI-FP1 does not contribute to the developmental regulation of IGF-I gene expression, at least in brain and liver. In summary, the present studies demonstrate coordinate expression of the IGF-I gene and GH receptor during development and suggest that GH receptor expression contributes to the tissue specific expression of the IGF-I gene during development.
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PMID:Developmental regulation of insulin-like growth factor-I and growth hormone receptor gene expression. 1043 30

By use of RNase protection assays, hepatic growth hormone receptor (GHR) and insulin-like growth factor I (IGF-I) mRNA abundances were measured in sheep fetuses after experimental manipulation of fetal plasma thyroid hormone concentrations by fetal thyroidectomy (TX) and exogenous infusion of triiodothyronine (T(3)) and cortisol. TX abolished the normal prepartum rise in hepatic GHR abundance but had little effect on hepatic GHR gene expression at 127-130 days (term 145 +/- 2 days). By contrast, it upregulated basal IGF-I expression in immature fetal liver by increasing both Class 1 and Class 2 transcript abundance but had no further effects on IGF-I gene mRNA levels at 142-145 days. Raising plasma T(3) to prepartum values by exogenous infusion of either T(3) or cortisol into immature intact fetuses prematurely raised hepatic GHR and IGF-I mRNA abundances to values similar to those seen in intact fetuses at 142-145 days. In TX fetuses, cortisol infusion increased hepatic GHR mRNA but not total IGF-I mRNA abundance at 127-130 days. These findings show that thyroid hormones have an important role in the regulation of hepatic GHR and IGF-I gene expression in fetal sheep during late gestation and suggest that T(3) mediates the maturational effects of cortisol on the hepatic somatotropic axis close to term.
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PMID:Control of ovine hepatic growth hormone receptor and insulin-like growth factor I by thyroid hormones in utero. 1082 21

A growing body of information now supports the existence of a complete intraovarian insulin-like growth factor I (IGF-I) system. Although the precise role of IGF-I in the context of ovarian physiology remains to be determined, it is likely that IGF-I may engage in the amplification of gonadotrophin hormonal action. These facts and experiments with animals establishing the ovaries of multiple species as a site of growth hormone (GH) reception and action have led to the use of recombinant GH (rGH) as an adjunctive agent to potentiate ovulation induction by exogenous gonadotrophins. Whether intraovarian IGF-I plays an intermediary role in GH hormonal action at the ovarian level remains uncertain at present. The aim of this study was to evaluate whether rGH administration to pre-menopausal women could modify the expression of the IGF-I gene in the ovary. The expression of the IGF-I gene was examined in a time-dependent manner in normal pre-menopausal ovaries obtained from nine women treated with rGH and nine control women treated with placebo, using solution hybridization/RNase protection assays. Ovarian tissue samples were obtained 24 h (six women) and 7 days (12 women) following rGH/placebo injection. Total RNA (20 microg) from whole pre-menopausal ovaries (with or without rGH treatment) as well as from human granulosa cells was hybridized with a human IGF-I antisense RNA. IGF-I peptide, but not oestradiol, serum concentrations increased significantly 24 h after rGH injection. IGF-I gene, however, was not expressed in the luteinized granulosa cells and whole pre-menopausal ovaries irrespectively of rGH treatment in ovarian samples analysed both 1 and 7 days following rGH injection. On the contrary, IGF-II mRNA transcribed from the fetal or fetal-neonatal IGF-II promoter and IGF-I receptor mRNA (both used as hybridization control) were both found in whole pre-menopausal ovary and luteinized granulosa cells. Nevertheless, no changes in the hybridization patterns were seen in the absence or presence of rGH. These studies demonstrate that rGH administration to normal premenopausal women does not change the expression of insulin-like growth factors and their receptor genes in the pre-menopausal human ovary. Furthermore, these results provide further evidence against locally produced IGF-I as responsible for any ovarian effects seen in systemic rGH administration.
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PMID:Growth hormone does not increase the expression of insulin-like growth factors and their receptor genes in the pre-menopausal human ovary. 1083 48

Several studies indicate that systemic GH influences various brain functions. Connexin-43 forms gap junctions that mediate intercellular communication and establish the astroglial syncytium. We investigated the effects of peripheral administration of bovine GH (bGH) and recombinant human insulin-like growth factor I (rhIGF-I) on the expression of connexin-43 in the rat brain. Hypophysectomized female Sprague Dawley rats were substituted with cortisol (400 microg/kg x day) and L-T4 (10 microg/kg x day) and treated with either bGH (1 mg/kg x day) or rhIGF-I (0.85 mg/kg x day) for 19 days. The abundance of connexin-43 messenger RNA (mRNA) and protein in the brainstem, cerebral cortex, hippocampus, and hypothalamus was quantified by means of ribonuclease protection assays and Western blots. Treatment with bGH increased the amounts of connexin-43 mRNA and protein in the cerebral cortex and hypothalamus. No changes were found in the brainstem or hippocampus. Infusion of rhIGF-I did not affect connexin-43 mRNA or protein levels in any of the brain regions studied. These results show that administration of bGH increases the abundance of cx43 in specific brain regions, suggesting that GH may influence gap junction formation and thereby intercellular communication in the brain.
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PMID:Growth hormone increases connexin-43 expression in the cerebral cortex and hypothalamus. 1101 45


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