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)

Platelet-derived growth factor (PDGF) is a potent mitogen in human serum which specifically stimulates the proliferation of mesenchymal cells. We have now examined normal human mammary epithelial cells (HMEC) derived from reduction mammaplasties and grown in a serum-free defined medium. Medium conditioned by HMEC contained a PDGF-like activity that competed with [125I]PDGF for binding to PDGF receptors in normal human fibroblasts. When conditioned media were incubated with antiserum specific for either PDGF-A or PDGF-B, only PDGF-A antiserum was capable of inhibiting binding of conditioned media to PDGF receptors. Using an RNase protection assay, mRNA from normal HMEC was probed for both the PDGF-A and PDGF-B chains. Little or no PDGF-B was found in HMEC strains, while a strong signal was seen with the PDGF-A probe. When HMEC were grown in the presence of transforming growth factor-beta (TGF beta) for 48 h, inhibition of growth was observed in association with a 20- to 40-fold stimulation of PDGF-B mRNA and a 2-fold stimulation of PDGF-A mRNA. This mRNA induction was extremely rapid (within 1 h), and secreted PDGF activity was induced 2- to 3-fold. Two other HMEC growth inhibitors and differentiating agents, sodium butyrate and phorbol ester 12-O-tetradecanoylphorbol-13-acetate, had no effect on PDGF mRNA regulation. The current study suggests that PDGF gene induction is an extremely rapid and specific indicator of TGF beta function regardless of whether TGF beta is acting in a growth stimulatory or inhibitory manner. Any role of PDGF-B in TGF beta modulation of differentiation of normal or malignant mammary gland remains to be determined.
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PMID:Transforming growth factor-beta induces platelet-derived growth factor (PDGF) messenger RNA and PDGF secretion while inhibiting growth in normal human mammary epithelial cells. 217 25

Rat liver tumors initiated with N-nitrosodiethylamine (DEN) followed by promotion with phenobarbital (PB) were examined for expression of transforming growth factor-beta (TGF beta) type I, II and III receptors. RNase protection and TGF beta 1 affinity labeling assays were used to determine TGF beta receptor steady-state mRNA and protein levels, respectively. We have demonstrated that all three TGF beta receptors are expressed in both normal and malignant hepatic tissues. Long-term PB administration did not alter TGF beta receptor mRNA or protein levels in normal liver. However, type I, II and III TGF beta receptor mRNA and protein levels were decreased by approximately 50% in the DEN-initiated/PB-promoted liver tumors as compared to the receptor levels in normal liver tissue surrounding the tumors. In contrast, TGF beta receptor mRNA and protein levels were unchanged in liver tumors initiated with DEN but not PB-promoted. These data demonstrate that PB promotes the formation of a tumor phenotype that is characterized by a significantly reduced number of TGF beta type I, II and III receptors. This suggests that the down-regulation of TGF beta receptors in PB-promoted hepatic tumors may provide a selective growth advantage to the tumor cells by reducing the ability of TGF beta to inhibit their growth.
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PMID:Transforming growth factor-beta receptors type I, II and III in phenobarbital-promoted rat liver tumors. 800 Dec 32

Although a great deal is known about the cellular effects of exogenous transforming growth factor-beta (TGF-beta) treatment and the effects of various exogenous agents (including TGF-beta's themselves) on TGF-beta expression, studies of cellular controls for autocrine TGF-beta expression and function have been rare. Since exogenous TGF-beta treatment blocks progression through the cell cycle, it seemed likely that autocrine TGF-beta activity would be induced by growth states in which there was little or no cell division such as confluency or quiescence. Specific TGF-beta 1 or beta 2 neutralizing antibody treatment of a colon carcinoma cell line designated CBS showed that autocrine TGF-beta activity could be demonstrated in quiescent cells but not in preconfluent cells. Studies of kinetics of TGF-beta 1 and beta 2 mRNA levels during the establishment of quiescence revealed a significant increase of both isoforms in quiescent cells. The quiescent cells also secreted three- to fourfold and four-to fivefold higher levels of total (latent plus active) TGF-beta 1 and beta 2 protein in the conditioned media than the confluent cells and preconfluent cells, respectively. There was no detectable active form of either TGF-beta isoform in the conditioned media of preconfluent cells, whereas a significant amount of active TGF-beta 1 and beta 2 was detected in the conditioned media of quiescent cells. Quantitative RNase protection assays were developed to compare the effects of cell crowding vs quiescence on TGF-beta expression. TGF-beta 1 was primarily induced by quiescence. TGF-beta 2 was induced by both quiescence and cell crowding. Increased TGF-beta 1 mRNA levels appeared to be exclusively due to an increase in stability, while increased TGF-beta 2 mRNA levels were due to increased transcription. This growth state-related induction of TGF-beta's was also observed in two other colon carcinoma cell lines. These studies show that TGF-beta 1 and beta 2 are autocrine-negative factors which can be situationally expressed by cells as a function of their growth state. Autocrine expression of the TGF-beta's in this model system appears not to affect exponentially growing cells, but rather to function by maintaining a quiescent state and/or by blocking progression through the cell cycle.
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PMID:Autocrine transforming growth factor-beta 1 and beta 2 expression is increased by cell crowding and quiescence in colon carcinoma cells. 808 24

Cyclin and cyclin-dependent kinase(cdk) complexes, and their inhibitors (CKIs) play important roles in growth regulation on the cells. p27/kip1 is a CKI associated with G1 arrest induced by cell to cell contact, transforming growth factor-beta and cyclic AMP. The abnormality of p27/Kip1 genes in human tumors usually appears as a steady level defect of expression, since mutations in them is rare. Thus it is important to estimate the expression level of this gene. To detect the change of p27/Kip1 mRNA level in blood cells, we developed the ribonuclease protection assay using nonradioactive riboprobe which was produced by reverse transcriptase-polymerase chain reaction (RT-PCR) with T7 promoter-added antisense primer and the in vitro transcription system. Our assay may be useful for clinical evaluation of the mRNA level.
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PMID:[Detection of p27/kip1 mRNA in blood cells by nonradioactive ribonuclease protection assay]. 867 70

The invasive property of trophoblast cells is dependent on the activity of proteolytic enzymes of the metallo- and serine proteases family. Interleukin-1 (IL-1) was found to be involved in the regulation of these proteases in various systems, serving as an important modulator in trophoblast physiology (e.g. induction of hCG beta, cytokines, and others). Therefore, consideration is given in this report to the role of IL-1 in the regulation of metalloprotease activity in human trophoblasts. Human trophoblast cells were isolated from first trimester placentas by trypsin degradation and Percoll fractionation. Primary cell cultures of first trimester trophoblasts constitutively elaborated two species of collagenase type IV (92 and 72 kDa), as assessed in gelatin matrix. Treatment with IL-1 further augmented the 92-kDa type IV collagenase secretion in a dose-dependent manner. Furthermore, IL-1 significantly (P < 0.01) increased 92-kDa collagenase gene expression by trophoblast cells, as determined by solution hybridization/ribonuclease protection assay. Both the increase in gene expression and protein biosynthesis of the 92-kDa collagenase type IV were neutralized by the soluble IL-1 receptor, indirectly suggesting a receptor-mediated response. Interestingly, transforming growth factor-beta a putative modulator of IL-1 induced effects, was shown to induce the 92-kDa collagenase type IV secretion as well. These results provide indirect evidence supporting the idea that IL-1 and transforming growth factor-beta may play an intermediary role in trophoblast invasion at the feto-maternal interface by regulating trophoblast expression of 92-kDa type IV collagenase, a protease of prime importance in trophoblast invasion.
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PMID:Cytokine-mediated regulation of type IV collagenase expression and production in human trophoblast cells. 876 80

Receptor serine-threonine kinases (RSTK) mediate inhibitory as well as stimulatory signals for growth and differentiation by binding to members of the transforming growth factor-beta (TGF-beta) superfamily. Over 12 different RSTKs have been isolated so far, displaying wide expression in peripheral tissues and in the nervous system. Here we report the isolation and characterization of a novel type I RSTK termed activin receptor-like kinase-7 (ALK-7) that, unlike other members of this receptor family, is predominantly expressed in the adult central nervous system. The ALK-7 gene encodes a 55-kDa cell-surface protein that exhibits up to 78% amino acid sequence identity in the kinase domain to previously isolated type I receptors for TGF-beta and activin. In the extracellular domain, however, ALK-7 is more divergent, displaying comparable similarities with all members of the ALK subfamily. RNase protection and in situ hybridization studies demonstrated a highly specific mRNA distribution restricted to neurons in several regions of the adult rat central nervous system, including cerebellum, hippocampus, and nuclei of the brainstem. Receptor reconstitution and cross-linking experiments indicated that ALK-7 can form complexes with type II RSTKs for TGF-beta and activin in a ligand-dependent manner, although direct binding of ALK-7 to ligand in these complexes could not be demonstrated. The specific expression pattern of ALK-7, restricted to the postnatal central nervous system, indicates that this receptor may play an important role in the maturation and maintenance of several neuronal subpopulations.
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PMID:A novel type I receptor serine-threonine kinase predominantly expressed in the adult central nervous system. 894 33

Pharmacological control of interleukin-12 (IL-12) production may be a key therapeutic strategy for modulating immunological diseases dominated by type-1 cytokine responses. In this study, we investigated the effects of pentoxifylline on the production of IL-12 by human blood mononuclear cells and primary human monocytes stimulated with heat-killed Staphylococcus aureus Cowan strain I (SAC) or lipopolysaccharide (LPS). Pentoxifylline potently suppressed production of IL-12 in a concentration-dependent manner. In these same experiments, tumour necrosis factor-alpha (TNF-alpha) production was inhibited and IL-10 and prostaglandin E2 (PGE2) production was enhanced by treatment with pentoxifylline. Suppression of IL-12 production by pentoxifylline was found to be independent of several known endogenous inhibitors of IL-12, such as IL-10, transforming growth factor-beta (TGF-beta), IL-4 and PGE2. RNase protection assays revealed that pentoxifylline inhibited accumulation of both IL-12 p40 and p35 mRNA, suggesting a predominant mRNA locus for pentoxifylline-induced IL-12 inhibition. Low levels of pentoxifylline added to the suppression of IL-12 production by suboptimal inhibiting doses of dexamethasone, suggesting that this drug combination may have therapeutic utility. These results provide a firm rationale for the use of pentoxifylline in clinical trials of immunological disorders characterized by inappropriate type-1 immune responses.
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PMID:Inhibition of human interleukin-12 production by pentoxifylline. 922 17

The renin-angiotensin system (RAS) has been implicated in the development of hypertensive glomerulosclerosis. However, there are no experimental findings clearly demonstrating activation of glomerular RAS in hypertensive nephropathy. Using the stroke-prone spontaneously hypertensive rat (SHRSP) as an animal model of hypertensive glomerulosclerosis, we examined the relationship between the sequential changes in urinary albumin excretion (UAE), renal morphology, and glomerular mRNA expression for transforming growth factor-beta (TGF-beta) and fibronectin (FN) and glomerular mRNA levels for RAS components, and determined the effects of the angiotensin II (Ang II) type 1 (AT-1) receptor antagonist (candesartan) and equihypotensive hydralazine on these parameters. In SHRSP, UAE was normal at nine weeks of age and increased by 12 weeks. Plasma renin activity, plasma Ang II concentration, and angiotensin converting enzyme (ACE) activity were not higher in 9- and 12-week-old SHRSP than in WKY. RNase protection assay revealed higher glomerular mRNA levels for angiotensinogen, ACE, and AT-1a and AT-1b receptors in 9-, 12-, and 14-week-old SHRSP than in WKY. The glomerular mRNA levels for TGF-beta and FN in SHRSP were increased from nine weeks of age. SHRSP had a greater glomerulosclerosis index (GSI) at 24 weeks of age than did WKY. Administration of candesartan for two weeks, but not of hydralazine, markedly reduced UAE and normalized mRNA levels for TGF-beta, FN, and RAS components. Candesartan administration for 12 weeks virtually prevented the progression of glomerulosclerosis in rats. We conclude that in SHRSP, RAS activation and increased sensitivity to Ang II in glomeruli play important roles in the progression of glomerulosclerosis.
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PMID:Candesartan prevents the progression of glomerulosclerosis in genetic hypertensive rats. 940 67

Cultured hepatic stellate cells (HSCs), the cell type primarily involved in the progression of liver fibrosis, secrete insulin-like growth factor-I (IGF-I) and IGF binding protein (IGFBP) activity. IGF-I exerts a mitogenic effect on HSCs, thus potentially contributing to the fibrogenic process in an autocrine fashion. However, IGF-I action is modulated by the presence of specific IGFBPs that may inhibit and/or enhance its biologic effects. Therefore, we examined IGFBP-1 through IGFBP-6 mRNA and protein expression in HSCs isolated from human liver and activated in culture. Regulation of IGFBPs in response to IGF-I and other polypeptide growth factors involved in the hepatic fibrogenic process was also assessed. RNase protection assays and ligand blot analysis demonstrated that HSCs express IGFBP-2 through IGFBP-6 mRNAs and release detectable levels of IGFBP-2 through IGFBP-5. Because IGF-I, platelet-derived growth factor-BB (PDGF-BB), and transforming growth factor-beta (TGF-beta) stimulate HSC proliferation and/or matrix production, we tested their effect on IGFBPs released by HSCs. IGF-I induced IGFBP-3 and IGFBP-5 proteins in a time-dependent manner without an increase in the corresponding mRNAs. IGFBP-4 protein levels decreased in response to IGF-I. TGF-beta stimulated IGFBP-3 mRNA and protein but decreased IGFBP-5 mRNA and protein. In contrast, PDGF-BB failed to regulate IGFBPs compared with controls. Recombinant human IGFBP-3 (rhIGFBP-3) was then tested for its effect on IGF-I-induced mitogenesis in HSCs. rhIGFBP-3 inhibited IGF-I-stimulated DNA synthesis in a dose-dependent manner, with a peak effect observed at 25 nM IGFBP-3. Because TGF-beta is highly expressed in cirrhotic liver tissue, we determined whether IGFBP-3 mRNA expression is increased in liver biopsies obtained from patients with an active fibroproliferative response due to viral-induced chronic active hepatitis. In the majority of these samples, IGFBP-3 mRNA was increased compared with normal controls. These findings indicate that human HSCs, in their activated phenotype, constitutively produce IGFBPs. IGF-I and TGF-beta differentially regulate IGFBP-3, IGFBP-4, and IGFBP-5 expression, which, in turn, may modulate the in vitro and in vivo action of IGF-I.
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PMID:Characterization and regulation of insulin-like growth factor binding proteins in human hepatic stellate cells. 942 10

The B10/B10.A congenic mouse pair serves as a model for identifying specific genes related to morphogenesis and dysmorphogenesis of the embryonic palate and other organs. The present report describes our initial investigation of the Fraser-Juriloff paradigm, which proposes that susceptibility to malformation results from genetically determined differences in normal developmental patterns. Specifically, we evaluated the relationship between Igf2r gene expression, transforming growth factor-beta (TGF-beta) activation, and cdk4 gene expression. By using in situ hybridization, RNase protection assays, indirect immunofluorescence, Western blots, and bioassays, we show 1) the presence of insulin-like growth factor II (IGF-II), IGF-II receptor (IGF-IIR), IGF-IR, TGF-beta, plasminogen, plasminogen activators [urokinase plasminogen activator (uPA) and tissue plasminogen activator (tPA)], and Cdk4 in developing palates; 2) on embryonic day 14 (E14), which is a critical day for palatal growth, B10.A embryos have 82% greater IGF-IIR mRNA than B10; 3) on E14, B10.A embryonic palates have a 57% greater level of active TGF-beta2 than B10, although the total TGF-beta2 is nearly identical; and 4) on E14, B10 embryonic palates have a 52% greater level of Cdk4 mRNA than B10.A palates, a measure of cell cycle progression. Because cellular activation of latent TGF-beta appears to require binding to the mannose-6-phosphate (M6P) binding site of the IGF-IIR and is plasmin and plasminogen activator dependent, the positive correlation of IGF-IIR levels and active TGF-beta2 levels seems to be key. Thus, the strain variation of TGF-beta2/IGF-IIR-mediated growth inhibition in late G1 phase would appear to account for the slower growth and development of B10.A palates relative to B10. Elevated corticosteroid (CORT) exposure in E14 B10.A embryos significantly increases TGF-beta levels, 87% of which is TGF-beta2, as well as the levels of active TGF-beta, 64% of which is TGF-beta2. Without exogenous CORT, B10.A embryos do not have clefts; hence, we present an outline of pathogenesis: slower growing B10.A embryos have an up-regulation of IGF-IIR, which serves to sequester IGF-II from the growth-promoting IGF-IR and to bind more CORT-up-regulated, latent TGF-beta2 for subsequent plasmin-dependent activation; higher levels of TGF-beta2 signaling down-regulate Cdk4 and result in greater palatal growth inhibition at a critical stage of palatogenesis and, thus, cleft palate. We present an epigenetic model of information processing related to cell proliferation. The model is a dynamical network that uses continuous logic to learn its rules from changing conditions.
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PMID:Insulin-like growth factor II receptor, transforming growth factor-beta, and Cdk4 expression and the developmental epigenetics of mouse palate morphogenesis and dysmorphogenesis. 943 20


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