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)

Using RNase protection analysis, insulin-like growth factor-II (IGF-II) mRNA levels were measured in various tissues from fetal sheep during late gestation (term, 146 +/- 2 days) and after experimental manipulation of fetal plasma cortisol levels. No gestational trend in IGF-II mRNA levels was observed in the fetal lung, kidney, or skeletal muscle. However, in the fetal liver, there was a marked decline in IGF-II mRNA abundance immediately before term, which closely paralleled the normal prepartum surge in fetal plasma cortisol. This decrease in hepatic IGF-II mRNA levels toward term was prevented when the cortisol surge was abolished by fetal adrenalectomy and was stimulated prematurely in fetuses younger than 130 days by exogenous infusion of cortisol. Hepatic and renal IGF-II mRNA abundances were also reduced when fetal cortisol levels were raised endogenously by maternal fasting in late gestation. Muscle IGF-II mRNA levels were reduced by fetal cortisol infusion, but not by maternal fasting, and were higher in adrenalectomized than in intact fetuses in late gestation. No change in IGF-II mRNA levels were observed in the fetal lung in response to altering the fetal cortisol level either exogenously or endogenously. When the data from all fetuses were combined regardless of treatment or gestational age, there was a significant inverse correlation between the plasma cortisol level in utero and IGF-II mRNA abundance in the fetal liver (P < 0.001), but not in any of the other fetal tissues studied. These findings show that cortisol suppresses IGF-II gene expression in the liver of the sheep fetus and indicate that the developmental change in hepatic IGF status toward term may be due to the prepartum cortisol surge.
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PMID:Insulin-like growth factor-II messenger ribonucleic acid expression in fetal tissues of the sheep during late gestation: effects of cortisol. 847 58

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 insulin-like growth factor-II/cation-independent mannose 6-phosphate receptor (IGF-II/MPR) is a multifunctional protein that binds IGF-II and ligands containing a mannose 6-phosphate recognition marker. Recent studies have shown that this receptor plays a critical role in mammalian development, and that its expression is controlled by both epigenetic and tissue-specific factors. Our laboratory has cloned the 93-kilobase mouse gene and characterized its 48 exons. In this report we describe the structure and function of the IGF-II/MPR gene promoter. To study promoter function, a series of chimeric plasmids linking different segments of IGF-II/MPR 5' flanking DNA to the reporter gene, firefly luciferase, were transiently transfected into HepG2 and C3H 10T1/2 cells. Promoter activity was orientation-specific and was maximal (550- to 4250-fold above promoterless control) with a plasmid containing 266 base pairs (bp) of IGF-II/MPR DNA. The fusion gene accurately directed transcription as measured by ribonuclease protection assay using RNA extracted from transfected cells. DNA-protein binding studies by in vitro DNase I footprinting revealed an extended 54-bp footprint within the proximal promoter that contained two E-boxes and potential binding sites for transcription factors Sp1, NGF-IA, and related proteins. Gel mobility shift experiments with double-stranded oligonucleotides containing this region gave rise to several specific DNA-protein complexes, and the addition of specific antibodies indicated that proteins antigenically related to Sp1 and c-Myc were components of one or more of these bands. Deletion of this 54-bp segment led to an 8-fold decline in promoter activity, and its transfer to a heterologous promoter stimulated gene expression by nearly 7-fold. Mutational analyses indicated that each E box contributed to more than half of the enhancer's activity. These results define a strong minimal IGF-II/MPR promoter of no more than 266 bp and identify a 54-bp enhancer within this promoter fragment. Our observations thus represent a first step toward characterizing the developmental, epigenetic, and tissue-specific factors that control IGF-II/MPR gene expression.
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PMID:Control of insulin-like growth factor-II/mannose 6-phosphate receptor gene transcription by proximal promoter elements. 858 25

We characterized mechanisms of growth control involving insulin-like growth factor-1 (IGF-1), IGF-2, and IGF-1 receptor (IGF-1R) by investigating their expression in human cervical cancer cell lines, primary cervical tumor cell cultures, and normal ectocervical epithelial cells maintained in short-term culture. By reverse transcription followed by PCR, IGF-1 mRNA was not detected in any of the cell lines, whereas IGF-2 mRNA transcripts were detected in all of them. Using the RNase protection assay, low levels of IGF-2 mRNA were also detected in all of the cervical cancer cell lines, primary cervical tumor cell cultures, and normal ectocervical cultures tested, but no IGF-1 transcripts were detected. Scatchard analysis revealed 3- and 5-fold increases in IGF-1R expression by the primary cervical cancer cell cultures and cervical cancer cell lines, respectively, compared with the normal ectocervical cells. In proliferation assays, epidermal growth factor (EGF) consistently enhanced cervical cancer cell growth, but an antisense oligonucleotide to IGF-2 uniformly inhibited the EGF-induced mitogenic effect. These studies suggest that autocrine production of IGF-2 and overexpression of the IGF-1R are important components controlling the proliferation of cervical carcinoma cells, and that autocrine IGF-2 production in cervical cancer cells may participate in the mitogenic signaling of EGF.
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PMID:Overexpression of the insulin-like growth factor-1 receptor and autocrine stimulation in human cervical cancer cells. 862 Apr 90

Expression of genes encoding insulin-like growth factor I (IGF-I), insulin-like growth factor II (IGF-II) and type I insulin-like growth factor receptor (IGFr) was measured in theca and granulosa cells from the ovary of the laying hen, using an RNase protection assay. Expression of genes encoding IGF-I and -II was confined to theca tissue and expression was not detected in granulosa cells. In contrast, expression of genes encoding IGFr in granulosa cells was significantly greater than that in theca tissue. The 98 base IGF-II probe was similar to a region of the second coding exon of chicken IGF-II and produced multiple RNase-protected RNA hybrids. Theca RNA from follicles at all stages of development produced RNase-protected hybrids of size 98, 96 and 90 bases; however, an additional band (66 bases) was also observed in theca RNA from small yellow follicles. The stage of follicular development during which maximum amounts of the 66 base RNase-protected fragment was detected correlates with the stage at which small follicles are selected for recruitment into the follicular hierarchy. The results provide evidence for the involvement of IGFs in the intraovarian control of ovarian function in a non-mammalian species, and highlight the importance of IGF-II in this process.
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PMID:Insulin-like growth factor I (IGF-I), IGF-II and type-I IGF receptor gene expression in the ovary of the laying hen. 866 33

We have studied the insulin-like growth factor-II gene (IGF2) promoter usage in normal human liver from fetal to late adult life by quantifying the specific transcripts by RNase protection assays using exon-specific probes. While the fetal liver uses only three promoters (P2, P3, P4) for the transcription of IGF2, all four promoters can be used from the age of 2 months after birth. The levels of the individual promoter transcripts vary substantially during development and the P3 promoter, which is a highly active fetal promoter, was not used by all the investigated adult patients but was detected in 30% of the adult group as a whole. The P1 promoter, which has previously been considered as the only one responsible for IGF2 transcription in the postnatal/adult liver, displayed a trend of increasing relative and absolute activity throughout life, but in some adult cases it was found to be less active than the P4 promoter. The P4 promoter displayed an age-related trend of decreasing activity from a very high fetal level, but individual exceptions were apparent. The P2 promoter transcript, peaking at the age of 2 months, showed a relatively even absolute amount from 18 months onwards. Thus, while P2 and P3 were both found to reach their highest activity after birth, the P4 promoter displayed its highest transcription at the fetal stage. The total IGF2 transcription, primarily from P2, P3 and P4, was found to peak shortly after birth. After this age, the P3 promoter transcript declined most rapidly and a low or zero amount was detected in adulthood. From the age of 18 months to old adulthood the total IGF2 mRNA, derived primarily from P1, P2 and P4, displayed a relatively even amount (approximately one tenth) of that seen at the peak at 2 months. This data may be important in relation to translatability of the various IGF2 transcripts.
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PMID:Expression levels of the insulin-like growth factor-II gene (IGF2) in the human liver: developmental relationships of the four promoters. 867 43

Congenital GH insensitivity (Laron's syndrome, LS) is often associated with a dysfunctional GH receptor (GHR) causing complete insensitivity to GH and absent serum GH-binding protein (GHBP). However, a proportion of children with LS have normal GHBP levels. We have identified four girls from two families with this condition (height SD score, -3.4 to -6.8) and undertaken studies on 1) their GHR genes and 2) their GH responses in cultured skin fibroblasts to define the etiology of their GH insensitivities. No GHR gene mutations were identified in one family. In the other family, the affected siblings, an unaffected brother, and the father were heterozygous for a point mutation within exon 6 (D152H). In addition, use of intron 9 haplotypes to determine linkage to the GHR gene implied inheritance of different maternal GHR alleles in the two affected girls of the latter family. It is unlikely, therefore, that the D152H mutation alone could account for the LS phenotype. End points of GH action [DNA synthesis, insulin-like growth factor-binding protein-3 (IGFBP-3) messenger RNA (mRNA) and peptide production] in skin fibroblast cultures established from three of the LS subjects and four normal children were examined. Whereas normal fibroblasts incorporated [3H]thymidine dose dependently in response to 10-1000 ng/ml GH (increment at 1000 ng/ml, 77 +/- 19%), LS fibroblasts failed to respond significantly above basal levels (P < 0.01). In normal fibroblasts, IGFBP-3 mRNA and peptide increased maximally at 48 h in response to 200 ng/ml GH, as determined by ribonuclease protection assay, Western ligand blotting, and RIA. In comparison, LS fibroblasts produced significantly less IGFBP-3 peptide than normal fibroblasts in response to GH, whereas IGFBP-3 mRNA failed to increase above basal levels. These studies have shown that 1) cultured human skin fibroblasts can be used to define the end points of GH action; 2) fibroblast cultures from the LS children show absent or reduced responses to GH; and 3) GH insensitivity in these children does not appear to be caused exclusively by GHR mutations, but is probably due to dysfunctional GHR signalling. Such patients may prove particularly important to elucidation of the key events in GH signaling.
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PMID:Human skin fibroblasts as a model of growth hormone (GH) action in GH receptor-positive Laron's syndrome. 897 85

Embryonic lung maturation in the H-2 congenic pair, B10.A and B10, proceeds at different rates. The dependence of this heterochronic development on maternal haplotype suggests the involvement of a parentally imprinted gene. Since B10.A (H-2a) and B10 (H-2b) mice are genetically identical except for a 3-18 cM region of chromosome 17 that includes the H-2 complex, we sought a promising candidate gene(s) involved in regulating the rate of lung development from genes encoded in this region. The best candidate is the gene encoding the type II insulin-like growth factor receptor (IGF-IIR), whose ligand is the growth factor IGF-II. Only the maternal copy of this gene is expressed in postimplantation embryos. This receptor does not appear to transduce mitogenic signals; instead, IGF-IIR appears to regulate the levels of its ligand available to the growth-promoting type I IGF receptor (IGF-IR). Using in situ hybridization and indirect immunofluorescence, we demonstrate that IGF-IIR mRNA and protein are localized throughout the pulmonary mesenchyme, as well as in branching epithelia of the pseudoglandular and canalicular stages. We also examined the levels of IGF-IIR mRNA and protein expression by RNase protection assay and ligand blotting during the embryonic period of lung development in B10.A and B10 mice, and found that there is a highly significant positive correlation of IGF-IIR levels with progressive development in both strains. Further, slower-developing B10.A lungs contain significantly higher levels of IGF-IIR mRNA and protein than the more rapidly developing B10 lungs. These results suggest that haplotype-dependent elevation of IGF-IIR levels reduces the available concentration of IGF-II, resulting in a decreased rate of morphogenesis in B10.A mice. Heterochronic lung maturation, then, appears consequent to variable extracellular levels of this important growth factor. These results may be of clinical importance to predicting susceptibility to Respiratory Distress Syndrome in prenatal newborns.
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PMID:Developmental expression of insulin-like growth factor II receptor (IGF-IIR) in congenic mouse embryonic lungs: correlation between IGF-IIR mRNA and protein levels and heterochronic lung development. 911 13

Benign prostatic hyperplasia (BPH) is a common proliferative disorder of unknown etiology. We have previously documented that the insulin-like growth factor (IGF) axis is critical for prostate cell growth and is abnormal in BPH. The type 1 IGF receptor (IGF-1R) is constitutively expressed by most body tissues and plays a significant role in regulating cell proliferation, consistent with the role of its ligands (IGF-I and IGF-II) as important mitogenic factors. The Wilms' tumor gene product (WT-1) is a tumor suppressor that has been shown to be altered in rare kidney tumors and is known to regulate IGF-II and IGF-1R. We investigated the possibility that the expression of prostatic WT-1, IGF-1R, and IGF-II genes is altered in patients with BPH. We utilized primary cultures of prostatic stromal cells grown from normal (n = 9) and hyperplastic (n = 9) surgical specimens and analyzed WT-1, IGF-1R, and IGF-II messenger RNA levels. In all of the BPH cell strains, WT-1 expression (measured by RT-PCR and RNase protection assays) was strikingly lower than that found in normal strains (0-20% of normal, mean 14% of normal, P < 0.01). The expression of both the IGF-1R (300% of normal, P < 0.05) and IGF-II (1000% of normal, P < 0.01) messenger RNAs was higher in BPH strains as compared with normal strains. No changes were seen in stromal cell strains derived from prostatic adenocarcinoma. Thus, in cultured human prostatic stromal cell strains from patients with BPH, decreased WT-1 gene expression is associated with increases in the expression of the IGF-1R and IGF-II genes that are known transcriptional targets of WT-1. These findings indicate that reduced expression of the WT-1 tumor suppressor gene and elevated IGF-1R and IGF-II gene expression may be involved in the pathophysiology of prostatic hyperplasia, implying a new role for the Wilms' tumor gene in nonmalignant states.
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PMID:Decreased expression of Wilms' tumor gene WT-1 and elevated expression of insulin growth factor-II (IGF-II) and type 1 IGF receptor genes in prostatic stromal cells from patients with benign prostatic hyperplasia. 921 94

Relaxin promotes growth of reproductive tissues, including the uterus. Although we have evidence of a role for insulin-like growth factor I (IGF-I) in mediating relaxin-induced growth of porcine granulosa cells in vitro, the mechanism of action by which relaxin enhances uterine growth has not been identified. To investigate a role for the uterine insulin-like growth factor (IGF) system in relaxin-induced uterine growth, we monitored the effects of relaxin on porcine IGFs and IGF-binding proteins (IGFBPs) in vivo. The trophic effects of relaxin on the uterus were elicited by administering relaxin or saline to prepubertal gilts every 6 h for 54 h. Three hours after the last injection, uterine flushes, uteri, follicular fluid, and ovaries were collected. Estradiol was measured in plasma and follicular fluid to confirm the prepubertal status of each animal. Significantly higher concentrations of uterine lumen IGF-I (P < 0.05) and IGF-II (P < 0.01) were observed in animals treated with relaxin. However, relaxin administration did not affect uterine IGF-I and -II gene expression, as determined by a ribonuclease protection assay and Northern analysis, respectively. In uterine flushes, relaxin treatment increased an IGFBP doublet (33 and 34.5 kDa) and IGFBP-3. The uterine IGFBP doublet was identified as IGFBP-2 by immunoprecipitation. Plasma or follicular fluid IGFs and IGFBPs were unaffected by relaxin administration. In addition, relaxin did not influence IGF-I binding to its uterine receptor. This is the first study to demonstrate regulation of the pig uterine IGF system by relaxin. In conclusion, the data point to IGF-I, IGF-II, IGFBP-2, and IGFBP-3 as putative mediators of relaxin-induced uterine growth in the pig.
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PMID:Relaxin increases insulin-like growth factors (IGFs) and IGF-binding proteins of the pig uterus in vivo. 927 49


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