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:3.1.26.9 (ribonuclease)
6,589 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

Insulin-like growth factor binding proteins (IGFBPs) constitute a family of at least six secreted proteins that bind insulin-like growth factors I and II (IGF-I and -II) and are capable of modifying IGF actions on target cells. We previously have purified an approximately 29-kDa IGFBP that is secreted by myoblasts during their terminal differentiation, have identified the protein as mouse IGFBP-5, and have cloned its cDNA (James et al., 1993). In this study, we have characterized the mouse IGFBP-5 gene, established its pattern of expression in the adult mouse, and defined its chromosomal location. The 17-kb gene was isolated on overlapping cosmid and lambda clones, and the four exons encoding the 5914-bp mRNA were sequenced. The 5' end of the gene was mapped by solution-hybridization ribonuclease protection assay to two discrete sites in exon 1 that were separated by 21 bp. The relative use of each transcription start site was found to vary among different mouse tissues. By interspecies backcross mapping using progeny derived from matings of [(C57BL/6J X Mus spretus)F1 x C57BL/6J] mice, the IGFBP-5 gene was localized to the proximal region of chromosome 1 in tight linkage with fibronectin 1 (0 recombinants in 168 mice analyzed). Since this part of chromosome 1 shares homology with human chromosome 2q, and since fibronectin has been mapped to 2q34-q36, it is likely that human IGFBP-5 will reside on 2q as well. Characterization of the mouse IGFBP-5 gene now provides a starting point for studying the roles and regulation of this protein in development.
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PMID:Organization, expression, and chromosomal location of the mouse insulin-like growth factor binding protein 5 gene. 751 10

We have investigated changes in the synthesis and localization of insulin-like growth factor (IGF)-I and IGF binding proteins (IGFBPs) in thyroid tissues during the induction of goitre in iodine-deficient rats, and during the subsequent involution of the gland following goitrogen withdrawal. Goitre was induced in adult rats by acute (1 or 2 weeks) or chronic (4 or 10 weeks) administration of methimazole together with a low iodine diet. After twelve weeks the goitrogenic stimuli were removed and thyroids examined 4 weeks later. Circulating T4 levels became undetectable within two weeks of goitrogen administration while thyroid weight had increased five-fold. The thyroids continued to increase in size up to 10 weeks, but at a slower growth rate. IGF-I mRNA, detected by ribonuclease protection assay, was present in the control rat thyroid and increased in abundance after both 1 and 2 weeks of goitrogen administration. Levels of IGF-I mRNA showed a relative decline with prolonged goitrogen administration, and following thyroid involution the hybridization signal was similar to that seen in control glands. Northern blot hybridization showed that IGFBP-2, -3 and -5 mRNAs were all present in growth-quiescent, control thyroids and those encoding IGFBP-2 and -3 were elevated in the goitrous glands and remained so as long as goitrogen was administered, thereafter declining during thyroid involution. IGF-I and IGFBP-2 and -3 mRNAs and synthesized peptides, detected by in situ hybridization and immunohistochemistry respectively, were found to co-localize predominantly in follicular epithelial cells. IGFBP-5 mRNA abundance was unaltered during goitre formation, but was increased in the involuting thyroid. Both IGFBP-5 mRNA and peptide were localized to the parafollicular cells (C-cells) which were increased in number during involution. The results suggest that an increased expression of IGF-1 may contribute to early goitre formation, but that a relative increase in the abundance of IGFBP-2 and -3 may limit IGF availability at later times, and facilitate a slowing of thyroid growth rate. The discrete expression of IGFBP-5 by C-cells suggests that it could contribute indirectly to goitre formation or involution by acting in a paracrine fashion.
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PMID:Altered expression of insulin-like growth factor-I (IGF-I) and IGF binding proteins during rat thyroid hyperplasia and involution. 752 74

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

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

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

Although expression of the IGF-II has been demonstrated within the central nervous system (CNS), past studies have failed to reveal its precise roles or responses subsequent to a traumatic injury. To demonstrate that IGF-II, IGFBP, and IGF receptor (-R) expression alters in response to a penetrating CNS injury, we used the techniques of ribonuclease protection assay, in situ hybridization, immunohistochemistry, Western blotting, and RIA. Under normal physiology, IGF-II expression is restricted to the mesenchymal support structures of the brain, including the choroid plexus, where its expression is coincident with that of IGFBP-2. Between 1-7 days post lesion (dpl), in the acute phase following a penetrant wound to the CNS, IGF-II and IGF-IIR protein, but not messenger RNA, were colocalized, with IGF-I, IGF-IR, and IGFBP-1, -2, -3, and -6, to neurons, macrophages, astrocytes, and microglia within the damaged tissue. Within the cerebrospinal fluid (CSF), levels of IGF-II peptide increased to peak at 7 dpl. IGFBP-2, -3, and -6 were also observed within the CSF, with IGFBP-2 predominating and exhibiting an increase in binding efficiency from 7-10 dpl. In the chronic phase of injury (7-14 dpl), an increase in both IGF-II, IGF-IIR and IGFBP-5 messenger RNA and protein was observed specifically and focally in the marginal astrocytes forming the limiting glial membrane of the wound. Thus, our evidence suggests that there are two mechanisms of action for IGF-II within the injured rat brain. During the acute phase, the secretion of IGF-II from the choroid plexus into the CSF is up-regulated, resulting in increased transport of the peptide to the wound. In the CSF, transported IGF-II is complexed to IGFBP-2 and essentially demonstrates an endocrine mode of action with a balance of locally produced IGFBPs modulating its bioactivity in the wound. Later in the wounding response, levels of IGF-II decline in the CSF and the wound neuropil, possibly with the aid of increased IGFBP-5 levels that may help to locally sequester and down-regulate IGF-II activity. Hence, in the chronic phase of the injury response, IGF-II reasserts itself to a predominantly autocrine/paracrine role restricted to the mesenchymal support structures, including the glia limitans, which may help reestablish and maintain tissue homeostasis.
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PMID:Distinct sites of insulin-like growth factor (IGF)-II expression and localization in lesioned rat brain: possible roles of IGF binding proteins (IGFBPs) in the mediation of IGF-II activity. 988 65

PTH has diverse effects on bone metabolism: anabolic when given intermittently, catabolic when given continuously. The cellular mechanisms underlying the varying target cell response are not clear yet. PTH induces RGS-2, a member of the Regulator of G-protein Signaling protein family, via cAMP/PKA, and inactivates PKC-mediated signaling. To investigate intracellular signaling pathways with different PTH concentration-time patterns, we treated UMR 106-01 osteoblast-like cells in a perfusion system. PTH was administered intermittently (4 min/h, 10(-7) M) or continuously at an equivalent cumulative dose (6.6 x 10(-9) M). cAMP was measured using radioimmunoassay, mRNA levels using real-time rtPCR and ribonuclease protection assay, and protein levels using Western immunoblotting. A single PTH pulse transiently increased cAMP levels by 2000% +/- 1200%. In contrast to continuous PTH exposure, cAMP induction remained unchanged with intermittent PTH, ruling out desensitization of the PTH receptor. In continuously perfused cells, RGS-2 abundance was three to five times higher than in cells intermittently exposed to PTH for up to 12 h. MKP-1 and -3 were significantly less induced with pulsatile PTH; exposure-mode-dependent differences in MMP-13 and IGFBP-5 were small. Pulsatile but not continuous PTH administration prevents PTHrP receptor desensitization and accumulation of RGS-2 in osteoblasts, which should preserve PKC-dependent signaling.
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PMID:Differential regulation of RGS-2 by constant and oscillating PTH concentrations. 1922 8

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