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)

In human breast carcinoma MCF-7 cells, phorbol diesters inhibit proliferation and induce cell maturation. We investigated the involvement of TGF-beta 1 in the PCK-mediated inhibition of breast cancer cell proliferation. Using an RNase protection assay, we showed that TPA induced a dose-dependent increase in levels of TGF-beta 1 mRNA that paralleled the inhibitory effect on MCF-7 proliferation. Similar results were obtained with another TPA-sensitive breast cancer cell line (BT-20). TPA did not increase TGF-beta 1 mRNA levels in the MCF-7:RPh-4 and T47D cell lines, which are both insensitive to the growth inhibitory effects of phorbol esters. In addition, the increase in TGF-beta 1 mRNA level was not observed after treatment of the MCF-7 cell with other inducers of cell differentiation such as forskolin, DMF, HMBA and sodium butyrate. The induction of TGF-beta 1 mRNA by TPA along with its inhibitory effect on cell proliferation suggests that TGF-beta 1 mediates, at least in part, the inhibitory effect of PKC activation.
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PMID:[Regulation by protein kinase C of TGF-beta 1 expression in cultured cells of breast adenocarcinoma]. 142 93

Transforming growth factor (TGF)-beta and interleukin (IL)-10 inhibited lipopolysaccharide (LPS)-induced macrophage production of the inflammatory cytokines tumor necrosis factor-alpha (TNF), IL-1 alpha, and IL-1 beta by contrasting post-transcriptional mechanisms. TGF-beta acted slowly and late, as it required 12-16 h to exert a suppressive effect, and inhibited TNF production even when added 6 h after LPS. TGF-beta affected neither the level of TNF mRNA, the release of preformed TNF nor the degradation of TNF. Thus, TGF-beta appeared to inhibit translation of TNF mRNA. IL-10 not only suppressed TNF release to a 25-fold greater extent than TGF-beta, but also inhibited release of IL-1. In contrast to TGF-beta, IL-10 acted on an early step in cytokine production, its effect being maximal 3 h after addition of LPS. Unlike TGF-beta, IL-10 markedly suppressed TNF, IL-1 alpha, and IL-1 beta mRNA levels. However, this was accomplished without suppressing transcription of the corresponding genes. Moreover, cycloheximide antagonized the IL-10-dependent reduction in cytokine mRNA levels. Thus, IL-10 may induce a ribonuclease active on cytokine transcripts or may induce a protein that enhances the susceptibility of TNF, IL-1 alpha, and IL-1 beta mRNAs to ribonucleolytic action. We conclude that IL-10 and TGF-beta induce different phenotypes of macrophage deactivation, and deactivate macrophages by different mechanisms: IL-10 promotes degradation of cytokine mRNA, while TGF-beta primarily suppresses translation.
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PMID:Contrasting mechanisms for suppression of macrophage cytokine release by transforming growth factor-beta and interleukin-10. 142 77

Transforming growth factor beta (TGF-beta) inhibits proliferation of normal keratinocytes, and this response is retained, to variable extents, in benign tumors of the skin (S. Haddow, D. J. Fowlis, K. Parkinson, R. J. Akhurst, and A. Balmain, Oncogene, 6: 1465-1470, 1991). To investigate the profile of TGF-beta biosynthesis during various stages of chemical carcinogenesis of the skin, we used a combination of ribonuclease protection assay, in situ hybridization with gene-specific probes for TGF-beta 1, -beta 2, and -beta 3, and immunohistochemistry with isoform-specific antibodies against TGF-beta 1. Following 12-O-tetradecanoylphorbol-13-acetate treatment of adult mouse skin, there was a rapid induction of TGF-beta 1 protein. Intracellular TGF-beta 1 protein was localized to suprabasal keratinocytes, and the extracellular form was localized predominantly to the dermis. Despite ubiquitous induction of TGF-beta 1 protein by 12-O-tetradecanoylphorbol-13-acetate in various mouse strains, we noted strain-specific differences in the quantitative induction of TGF-beta 1 RNA. Papillomas and carcinomas induced in vivo had elevated levels of TGF-beta 1 RNA within the basal keratinocyte compartment but did not contain significant levels of TGF-beta 1 protein within the tumor. We postulate that the tumor evades TGF-beta 1-controlled negative growth regulation by altered translational and/or posttranslational processing mechanisms of this growth factor. Levels of TGF-beta 2 and -beta 3 RNA were not elevated at any stage of chemical carcinogenesis of the skin.
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PMID:Discordant transforming growth factor beta 1 RNA and protein localization during chemical carcinogenesis of the skin. 150 19

A critical process during early heart development is the formation of mesenchymal cells which will contribute to valves and septa of the mature heart. These cells arise by an epithelial-mesenchymal transformation of endothelial cells in the atrioventricular (AV) canal and outflow tract areas of the heart. Adjacent endothelial cells in the atrium and ventricle remain epithelial. A three-dimensional collagen gel culture system has been exploited to examine the interactions that mediate this transformation. The AV canal myocardium produces a stimulus that is transmitted through an intervening extracellular matrix to the AV canal endothelium. This interaction is regionally specific, such that ventricular myocardium does not provide an adequate stimulus and ventricular endothelium does not respond to the AV canal myocardial stimulus. Exogenous TGF-beta 1 (or TGF-beta 2) can complement ventricular myocardium to produce transformation by AV canal endothelium. A blocking antibody, effective against several TGF-beta, prevents cell transformation. To identify the specific member of the TGF-beta family that functions in situ, antisense oligonucleotides for each of the numbered TGF-beta were topically added to AV canal explant cultures. Only the oligonucleotide targeted to TGF-beta 3 was an effective inhibitor of mesenchymal cell formation. Studies have been undertaken to localize specific mRNas by in situ hybridization and RNase protection assays. These assays have concentrated on the regional and temporal appearance of TGF-beta 2 and 3. Surprisingly, RNase protection assays with a TGF-beta 3 sense probe showed the presence of a transcript complementary to TGF-beta 3.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:TGF-beta 3-mediated tissue interaction during embryonic heart development. 163 53

Transforming growth factor-beta 1 (TGF-beta 1) has previously been implicated as a potential negative autocrine or paracrine growth regulator of certain cell types (Arteaga, C. L., R. J. Coffey, Jr., T. C. Dugger, C. M. McCutchen, H. L. Moses, and R. M. Lyons. 1990. Cell Growth & Differ. 1:367-374; Hafez, M. M., D. Infante, S. Winawer, and E. Friedman. 1990. Cell Growth & Differ. 1:617-626; Glick, A. B., K. C. Flanders, D. Danielpour, S. H. Yuspa, and M. B. Sporn. 1989. Cell Regulation. 1:87-97). This is based mainly on experiments assessing the effects of exogenous TGF-beta 1 or neutralizing antibodies to TGF-beta 1 on normal or tumor cell proliferation in vitro. However, direct evidence demonstrating such a negative regulation of tumor cell growth in vivo is still lacking. To overcome this problem we have constructed and used an antisense expression vector for TGF-beta 1 as a means of regulating endogenous TGF-beta 1 expression in tumor cells. Antisense-transfected FET human colon carcinoma cells showed a fivefold reduction in TGF-beta 1 mRNA and 15-fold reduction in TGF-beta 1 secretion. Antisense mRNA was detected in transfected cells by an RNase protection assay. Compared to control cells, cultured antisense-transfected cells showed a reduction in lag phase time rather than a change in doubling time. Cloning efficiencies of transfected cells were four times greater than control cells in anchorage-independent assays. Control cells did not form tumors at 5 x 10(5) in athymic nude mice. Antisense-transfected cells formed tumors in 40% of animals injected. At higher inocula (1 x 10(6) cells) antisense-transfected cells formed tumors in 100% of animals injected, but control cells still failed to form tumors. These results show that TGF-beta 1 acts as a negative growth regulator of human colon carcinoma cells in vivo as well as in vitro. Acquisition of partial or full resistance to such inhibitory effects may therefore contribute to tumor development and progression.
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PMID:TGF-beta 1 is an autocrine-negative growth regulator of human colon carcinoma FET cells in vivo as revealed by transfection of an antisense expression vector. 173 Jul 43

Granulocyte-macrophage CSF (GM-CSF) is a potent stimulator of macrophages and neutrophils and is produced by rheumatoid arthritis (RA) synovium. We now report studies that identify some of the synovial cells and cytokines responsible for local GM-CSF production and gene expression in RA. GM-CSF was assayed by ELISA in supernatants from cultured RA fibroblast-like synoviocytes stimulated with various cytokines (IL-1 beta, TNF-alpha, macrophage-CSF, IFN-gamma, IL-6, and TGF-beta). Immunoreactive GM-CSF was detected in IL-1 beta and TNF-alpha-stimulated cultures, but not in cells cultured in medium or stimulated with any of the other cytokines. IL-1 and TNF-alpha had a synergistic effect on GM-CSF production. GM-CSF gene expression by fibroblast-like synoviocytes was analyzed by ribonuclease protection assay, Northern blot analysis, and in situ hybridization. Both IL-1 beta and TNF-alpha induced GM-CSF mRNA accumulation, with a maximum effect after 4 h of stimulation. We then studied GM-CSF production by macrophage-like synoviocytes (MLS) isolated from fresh synovial specimens by flow microfluorimetry. Fresh MLS spontaneously secreted the cytokine and exogenous IL-1 beta or TNF-alpha had no effect. After 1 wk in culture, additional stimulation with IL-1 beta or TNF-alpha was required for GM-CSF production. Finally, in situ hybridization performed on freshly isolated subpopulations of synovial cells, identified GM-CSF RNA transcripts in MLS.
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PMID:Cytokines in chronic inflammatory arthritis. VI. Analysis of the synovial cells involved in granulocyte-macrophage colony-stimulating factor production and gene expression in rheumatoid arthritis and its regulation by IL-1 and tumor necrosis factor-alpha. 202 69

12-Tetradecanoylphorbol-13-acetate (TPA)-induced differentiation of U937 promonocytes leads to a 30-fold increase in transforming growth factor beta 1 (TGF-beta 1) gene expression, and this effect results from a stabilized mRNA. Similar up-regulation was detected in TPA-treated K562 erythroblasts but was absent from cell lines that do not differentiate in response to TPA. Related studies in vitro showed that postnuclear extracts of U937 promonocytes contain a ribonuclease system that degrades TGF-beta 1 mRNA selectively and that this system is completely blocked by prior treatment of the cells with TPA. These data identify a new mechanism for regulating TGF-beta 1 mRNA levels and allow us to establish the overall basis for control of TGF-beta 1 gene expression by activation of protein kinase C. Our results also provide a new basis for understanding the long-term up-regulation of TGF-beta 1 gene expression that can accompany hematopoietic cell differentiation.
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PMID:A phorbol ester-regulated ribonuclease system controlling transforming growth factor beta 1 gene expression in hematopoietic cells. 223 28

Transforming growth factor (TGF)-beta is a potent regulator of many cell functions and a growth inhibitor for mammary epithelial cells. We now know of three highly homologous members of the human TGF-beta gene family. We have studied the expression of TGF-beta 1, -beta 2, and -beta 3 mRNA in four human breast cancer cell lines. Using the RNase protection assay, we have detected mRNA expression of TGF-beta 1, -beta 2, and -beta 3 by T-47D cells, TGF-beta 1 and -beta 3 by ZR-75-1 cells, and TGF-beta 1 by MCF-7 cells. Treatment of these estrogen receptor-positive cells with 10 nM estradiol for 48 h resulted in decreased mRNA levels of TGF-beta 2 and -beta 3 but did not affect mRNA levels of TGF-beta 1. Expression of TGF-beta 1 and -beta 2 mRNA by an estrogen receptor-negative cell line, MDA-MB-231, was not changed by estradiol treatment. Treatment of cells with the antiestrogen tamoxifen (1 microM) did not significantly alter mRNA levels for any of the three TGF-beta species. We have further determined that estradiol treatment of T-47D was associated with diminished secretion of TGF-beta into the medium. Both TGF-beta 1 and -beta 2 inhibited the proliferation of MCF-7 cells, and neither protein affected the growth of T-47D cells. TGF-beta 1 was at least 10-fold more potent than TGF-beta 2 at inhibiting the growth of MCF-7 cells.
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PMID:Differential regulation of expression of three transforming growth factor beta species in human breast cancer cell lines by estradiol. 229 70

Acid/ethanol extracts of normal rat liver and rat ascites hepatoma cells (AH 130) were found to inhibit the epidermal growth factor (EGF)-dependent colony formation of Balb/c 3T3 cells. The extracts did not inhibit the growth of the 3T3 cells in monolayer culture. The inhibitory activities were heat- and acid-stable and were not inactivated by the treatment with pronase, RNase and DNase. Upon ultrafiltration, a considerable fraction of the inhibitory activities were found in the fraction corresponding to the molecular size ranging from 3.5 to 10 Kd, in which no appreciable TGF-beta activity was detected.
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PMID:Anchorage-independent cell growth-inhibiting factor(s) from normal rat liver and ascites hepatoma. 349 Sep 20

Transforming growth factor beta 1 (TGF-beta 1), a product of marrow stromal cells, inhibits the proliferation and differentiation of hematopoietic progenitor cells within the hematopoietic microenvironment. Steel factor (SF), also a product of marrow stromal cells, is an essential positive regulator of hematopoiesis in vivo. TGF-beta 1 has been shown to repress human and murine leukemic cell and murine lin- bone marrow mononuclear cell expression of the receptor for SF (c-kit). We speculated that TGF-beta 1 might exert its inhibitory effect on hematopoiesis in part by decreasing SF/c-kit interactions. Therefore, we tested the hypothesis that TGF-beta 1 inhibits both stromal cell expression of SF and hematopoietic progenitor cell expression of c-kit. We measured stromal cell expression of SF protein and hematopoietic progenitor cell expression of membrane-bound c-kit before and after exposure to recombinant human TGF-beta 1. Both stromal cell expression of SF protein and hematopoietic progenitor cell expression of c-kit protein were inhibited 50% to 80% by TGF-beta 1. Using Northern blot and ribonuclease protection assays, we determined that TGF-beta 1 repressed stromal cell SF mRNA, but did not alter SF transcript stability. TGF-beta 1 was also found to repress c-kit mRNA in human leukemic myeloblasts as well as in normal lin- hematopoietic progenitor cells. In contrast with its effect on SF mRNA, TGF-beta 1 accelerated the degradation of c-kit mRNA. We conclude that TGF-beta 1 inhibits stromal cell production of SF by repression of SF gene transcription and represses hematopoietic progenitor cell expression of c-kit by decreasing the stability of c-kit transcripts. Taking into account the importance of SF and c-kit in maintaining steady-state hematopoiesis in vivo, the dual effect of TGF-beta 1 on both SF and c-kit gene expression is likely to be one of the major mechanisms by which TGF-beta 1 inhibits hematopoiesis in vivo.
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PMID:Transforming growth factor beta 1 inhibits expression of the gene products for steel factor and its receptor (c-kit). 753 88


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