Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.27.1 (RNase)
 16,360 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

cDNAs encoding a mouse gene closely related to human bone morphogenetic protein-1 (BMP-1) have been isolated from an 8.5-day p.c. embryo cDNA library. Analysis of the predicted amino acid sequence shows that the protein contains a putative zinc-binding astacin metalloendopeptidase domain, five Clr/s domains, and two potential Ca(2+)-binding EGF-like repeats. In overall domain organization it more closely resembles the Drosophila tolloid gene product than human BMP-1. By RNase protection, transcripts can be detected in the embryo at 6.5 days p.c. and persist at least until 16.5 days p.c. By in situ hybridization, transcripts are seen at high levels in the maternal deciduum and in the late-gastrulation stage embryo at low levels throughout the mesoderm. This low level of mesodermal expression continues through development but somewhat higher levels are seen in developing membranous and endochondral bone, in the submucosa of the intestine, the dermis of the skin, and the mesenchyme of the spleen and lung. High levels of BMP-1 transcripts are also seen from 9.5 days p.c. in the floorplate region of the developing neural tube. Potential therefore exists for the interaction of BMP-1 protein with products of TGF-beta-related genes expressed during embryogenesis.
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PMID:Embryonic expression of mouse bone morphogenetic protein-1 (BMP-1), which is related to the Drosophila dorsoventral gene tolloid and encodes a putative astacin metalloendopeptidase. 817 72

Although the action of bone morphogenetic protein (BMP) on osteoblast differentiation has been extensively investigated, its effect on osteoclast differentiation remains unknown. In the present study, in vitro effects of BMP-2 on osteoclast-like cell formation and bone resorption were examined. BMP-2 (1-100 ng/ml) significantly stimulated bone resorption by preexistent osteoclast-like cells in mouse bone cell cultures containing stromal cells, whereas it did not affect the bone-resorbing activity of isolated rabbit osteoclast-like cells. When BMP-2 was added to unfractionated bone cells after degeneration of preexistent osteoclast-like cells, BMP-2 dose-dependently stimulated osteoclast-like formation at a minimal effective concentration of 10 pg/ml. BMP-2 also enhanced the osteoclast-like cell formation induced by 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). Moreover, osteoclast-like cells newly formed by BMP-2 from unfractionated bone cells possessed the ability to form pits on dentine slices. Because these results indicated that BMP-2 directly or indirectly stimulated osteoclast differentiation and activity, we next examined the direct effect of BMP-2 on osteoclast precursors in the absence of stromal cells using hemopoietic blast cells derived from spleen cells. The mRNA for BMP-2/4 receptor was detected in hemopoietic blast cells supported by granulocyte-macrophage colony-stimulating factor (GM-CSF) as well as osteoblastic MC3T3-E1 cells and MC3T3-G2/PA6 stromal cells by RNase protection assay. BMP-2 dose-dependently stimulated osteoclast-like cell formation from hemopoietic blast cells supported by GM-CSF at a minimal effective concentration of 10 pg/ml. BMP-2 also enhanced 1,25(OH)2D3-induced osteoclast-like formation from hemopoietic blast cells. The present data are the first to indicate that BMP-2 stimulates bone resorption through both direct stimulation of osteoclast formation and activation of mature osteoclasts, possibly via stomal cells, in vitro.
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PMID:Stimulatory effect of bone morphogenetic protein-2 on osteoclast-like cell formation and bone-resorbing activity. 859 44

Long-term sensitization training, or procedures that mimic the training, produces long-term facilitation of sensory-motor neuron synapses in Aplysia. The long-term effects of these procedures require mRNA and protein synthesis (Montarolo et al., 1986; Castellucci et al., 1989). Using the techniques of differential display reverse transcription PCR (DDRT-PCR) and ribonuclease protection assays (RPA), we identified a cDNA whose mRNA level was increased significantly in sensory neurons by treatments of isolated pleural-pedal ganglia with serotonin for 1.5 hr or by long-term behavioral training of Aplysia. The effects of serotonin and behavioral training on this mRNA were mimicked by treatments that elevate cAMP. The aplysia mRNA increased by serotonin and behavioral training was 41-45% identical to a developmentally regulated gene family which includes Drosophila tolloid and human bone morphogenetic protein-1 (BMP-1). Both tolloid and BMP-1 encode metalloproteases that might activate TGF-beta (transforming growth factor beta)-like molecules or process procollagens. Aplysia tolloid/BMP-1-like protein (apTBL-1) might regulate the morphology and efficacy of synaptic connections between sensory and motor neurons, which are associated with long-term sensitization.
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PMID:A developmental gene (Tolloid/BMP-1) is regulated in Aplysia neurons by treatments that induce long-term sensitization. 898 97

Wilms' tumor, or nephroblastoma, arises from metanephric blastema and caricatures renal organogenesis. An alteration in at least one of the genes involved in control of renal differentiation is therefore a likely event in tumorigenesis, and indeed some of the genes involved in renal development, for example, hepatocyte growth factor (HGF) and its receptor c-met, the transcription factor Wilms' tumor gene (WT1), and transforming growth factor-beta family member bone morphogenetic protein (BMP)-7, have also been implicated in various models of tumorigenesis. In a comparison of mRNA expression patterns for these genes in normal rat embryonic or fetal kidney and nephroblastoma, we found that the patterns for HGF, met, and WT1 detected by in situ hybridization or ribonuclease protection assay (RPA) in the nephroblastomas were similar to those of normal developing kidney. BMP-7 expression, on the other hand, was lower in most tumors examined both by in situ hybridization and RPA than in normal tissues. This deficiency in a defined inductive factor that has been shown to function in renal tubulogenesis may play a role in tumorigenesis by allowing the accumulation of blastemal populations typical of nephroblastomas.
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PMID:Deficient expression of mRNA for the putative inductive factor bone morphogenetic protein-7 in chemically initiated rat nephroblastomas. 980 58

Osteogenic protein-1 (OP-1) or bone morphogenetic protein-7 (BMP-7) stimulates cartilage formation in mouse bone rudiments in vitro but arrests terminal differentiation of prehypertrophic chondrocytes into hypertrophic chondrocytes. In this study we report that these effects of OP-1 depend on the developmental stage of the bone rudiment, early stages (E14 and E15 metatarsals) being most responsive. E17 metatarsals that already contained a hypertrophic area that had initiated mineralization were no longer affected by OP-1. We then investigated whether the sensitivity of the early long bone rudiments to OP-1 correlated with high expression of the OP-1 binding type I serine/threonine kinase receptors (activin receptor-like kinase: ALK-2/ActR-I, ALK-3/BMPR-IA or ALK-6/BMPR-IB) at this early stage. We did not find any significant difference in overall mRNA levels of these ALKs between stages E14 through E17 as assessed by RNase protection assays. However, by immunohistochemistry we found that ALK-6 staining was strong in E14 early cartilage primordium and its future perichondrium but dropped sharply to low levels in these cell types until onset of chondrocyte (pre)hypertrophy at E16. By contrast, ALK-2 and ALK-3 immunostainings in E14 were barely detectable. We also examined by immunohistochemistry the local synthesis of OP-1. OP-1 was present in E14 early chondrocytes and forming perichondrium but in low amounts; however, production of OP-1 increased in these cell types with age. All three receptor types as well as OP-1 were present in significant amounts in prehypertrophic chondrocytes and late hypertrophic chondrocytes including those undergoing mineralization. The temporary high immunostaining for ALK-6 in the early proliferating chondrocytes and future perichondrium of E14 bone rudiments, and its absence in older bones correlated with the sensitivity of chondrocytes and perichondrium to (exogenous) OP-1. We therefore propose that the effects of OP-1 on these cells in vitro are mediated by ALK-6/BMPR-IB. We furthermore conclude that locally produced OP-1 is a potential autocrine/paracrine growth factor. Increased local production of OP-1 may be partially responsible for the age-related decrease in responsiveness to exogenous OP-1 with respect to hypertrophy and mineralization of cartilage.
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PMID:Correlation between ALK-6 (BMPR-IB) distribution and responsiveness to osteogenic protein-1 (BMP-7) in embryonic mouse bone rudiments. 1070 76

In an attempt to analyze the cellular and molecular basis of the capacity of bone marrow stromal cells to support hematopoiesis in culture, we developed a series of murine stromal cell lines from a single long-term bone marrow culture (BMC). The cytokines produced by these cells were analyzed using immunohistochemical techniques, ribonuclease protection assays (RPA) and RT-PCR. We examined the capacity of these cloned cell lines to replace primary bone marrow-derived stromal cells in long-term bone marrow cultures (LT-BMC) and sought correlations between the capacity to support hematopoiesis in culture with the production of known cytokines. These immortalized lines replicate many of the functions of the hematopoietic microenvironment. They express cytokines known to play a role in hematopoiesis. All of the lines constitutively express mRNA for PBSF (SDF-1), macrophage colony-stimulating factor (M-CSF), stem cell factor (SCF), FLT-3, thrombopoietin (TPO), interleukin 7 (IL-7), leukemia inhibitory factor (LIF), tumor necrosis factor-beta (TNF-beta), and interferon-gamma (IFN-gamma). Most lines also express granulocyte-macrophage colony-stimulating factor (GM-CSF) and G-CSF. They vary in their expression of IL-6, tumor growth factor-beta1 (TGF-beta1), TGF-beta2, and TNF-alpha. Growing these lines in the presence of cytokines that influence hematopoiesis alters the levels of cytokine message. The most striking effects were produced by TNF-alpha. In addition to the cytokine mRNAs, the cell lines express factors associated with bone formation such as osteoblast-specific factor-2 (OSF-2) and bone morphogenetic protein-1 (BMP-1). They also express the neural cell-adhesion molecule neuropilin and neurotrophic factors including nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). Several of the lines can maintain hematopoiesis in culture, as measured by the continuous production of myeloid colony-forming cells (CFU-c), for months. This capacity to support hematopoiesis does not correlate with any pattern of cytokine expression. Several of these lines also support the growth of human hematopoietic cells, and human CFU-c can be detected in the cultures in which CD34(+) bone marrow cells (BMC) are cultured on murine stromal cells. No correlation between the production of any of the known cytokines and the ability to support murine hematopoiesis was detected. In addition, there was no correlation between the capacity to support murine hematopoiesis and the capacity to maintain human HSC. Despite repeated cloning, the lines remain heterogeneous and are capable of producing cells with the properties of fibroblasts, osteoblasts, adipocytes, and myoblasts. In addition to the cytokine mRNAs, the cell lines express factors associated with bone formation such as OSF-2 and BMP-1. They also express the neural cell-adhesion molecule neuropilin and neurotrophic factors including NGF and BDNF.
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PMID:Immortalized multipotential mesenchymal cells and the hematopoietic microenvironment. 1127 66

We have previously established the presence of a functional bone morphogenetic protein (BMP) system in the ovary by demonstrating the expression of BMP ligands and receptors as well as novel cellular functions. Specifically, BMP-4 and BMP-7 are expressed in theca cells, and their receptors by granulosa cells. These BMPs enhanced and attenuated the stimulatory action of FSH on estradiol and progesterone production, respectively. To investigate the underlying mechanism of the differential regulation, we analyzed mRNA levels for key regulators in the steroid biosynthetic pathways by RNase protection assay. BMP-7 enhanced P450 aromatase (P450(arom)) but suppressed steroidogenic acute regulatory protein (StAR) mRNAs induced by FSH, whereas mRNAs encoding further-downstream steroidogenic enzymes, including P450 side-chain cleavage enzyme and 3beta-hydroxysteroid dehydrogenase, were not significantly altered. These findings suggest that BMP-7 stimulation and inhibition of P450(arom) and StAR mRNA expression, respectively, may play a role in the mechanisms underlying the differential regulation of estradiol and progesterone production. To establish the physiological relevance of BMP functions, we investigated the in vivo effects of injections of recombinant BMP-7 into the ovarian bursa of rats. Ovaries treated with BMP-7 had decreased numbers of primordial follicles, yet had increased numbers of primary, preantral, and antral follicles, suggesting that BMP-7 may act to facilitate the transition of follicles from the primordial stage to the pool of primary, preantral, and antral follicles. In this regard, we have also found that BMP-7 caused an increase in DNA synthesis and proliferation of granulosa cells from small antral follicles in vitro. In contrast to the stimulatory activity, BMP-7 exhibited pronounced inhibitory effects on ovulation rate and serum progesterone levels. These findings establish important new biological activities of BMP-7 in the context of ovarian physiology, including folliculogenesis and ovulation.
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PMID:Effect of bone morphogenetic protein-7 on folliculogenesis and ovulation in the rat. 1156 18

Addition of dexamethasone (Dex) to human mesenchymal stem cells (hMSCs) resulted in a 16-fold increase in human bone morphogenetic protein-6 (hBMP-6) mRNA levels 24 h after treatment. Evaluation of luciferase expression after transfection of HeLa cells with hBMP-6 promoter/luciferase reporter constructs indicated that the hBMP-6 promoter activity was contained in a 268-bp region (-1051 to -784 where +1 is the translation start site) over 600 bases 5' to that previously published. It further showed that the promoter activity is regulated by glucocorticoid treatment. Analysis of RNA from hMSCs and HeLa cells by primer extension, RNase protection, and 5' RACE further narrowed the location of the transcription start site to an 84-bp region (-940 to -857). To determine whether this start site was regulated in hMSCs, hBMP-6 mRNA levels in control and Dex-treated cells were quantitated by RT-PCR using one primer set in the translated region of the gene and one located just 3' of the 84-bp region. Both primer sets showed hBMP-6 mRNA levels approximately 16- to 22-fold higher in the Dex-treated cells, demonstrating that hBMP-6 transcription is being regulated by glucocorticoids in the pluripotent hMSCs at the upstream transcription start site.
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PMID:Glucocorticoid regulation of human BMP-6 transcription. 1533 3