Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The conversion of androstenedione to estrone, the reaction mediated by the aromatase enzyme complex, may make an important contribution to the synthesis of estrogens in breast tissues. In the present study, the effect of the cytokine. TNF alpha, on aromatase activity was examined in breast fibroblasts derived from normal and malignant breast tissue. TNF alpha (2.5-10.0 ng/ml), in the presence of stripped fetal calf serum and dexamethasone, significantly stimulated fibroblast aromatase activity in a dose-dependent manner. IL-1 and IL-6 also stimulated fibroblast aromatase activity, but no marked synergism between TNF alpha and IL-1 or IL-6 was detected. Using a specific radioimmunoassay, significant concentrations of TNF alpha were detected in samples of breast cyst fluid and breast tumor cytosol, which had previously been shown to stimulate aromatase activity, but not in conditioned medium from breast tumor-derived fibroblasts. As TNF alpha may be preferentially expressed and produced in the adipose tissue component of the breast, this cytokine may have an important role in regulating estrogen synthesis in normal and malignant breast tissues.
Mol Cell Endocrinol 1994 Dec
PMID:Stimulation of aromatase activity in breast fibroblasts by tumor necrosis factor alpha. 789 4

Since several genes expressed in the pituitary can bind the transcription factor NF-KB, its presence and regulation was examined in the GH3 pituitary cell line. An electrophoretic mobility shift assay using nuclear extracts and an oligonucleotide probe corresponding to the Ig KB binding site was employed to identify activated NF-KB. One complex possessed properties characteristic of NF-KB: co-migration with an NF-KB complex and binding specificity restricted to NF-KB binding DNA sequences. Antibodies to the NF-KB subunits NFKB1p50 (p50) and RelA (p65) interacted with the extract-DNA complex. Activation of NF-KB in GH3 cells was increased by PMA or the cytokine tumor necrosis factor alpha. A synergy between PMA and TNF or a calcium mobilizing agent was seen in NF-KB activation. Further TNF activation was enhanced by TRH. These observations indicate the presence of NF-KB in GH3 cells and demonstrate its activation by hormones/second messengers that act on pituitary cells.
Mol Cell Endocrinol 1994 Dec
PMID:Activation of the transcription factor NF-KB in GH3 pituitary cells. 789 18

Ribozymes are RNA molecules that cleave other RNA molecules. Thus, ribozymes offer a new way of inhibiting expression of specific genes whose nucleotide sequences are known. Intracellular stability of ribozymes is an important factor for their efficacy. We previously showed that hammerhead ribozyme directed against mRNA of tumour necrosis factor alpha (TNF alpha) slowly acquires resistance to degradation in cultured human cells. In order to explain this resistance, we now report on endogenous cellular protein(s) that bind to TNF alpha-ribozyme (TNF alpha-Rz) in solution to form stable complexes during native gel electrophoresis. Suppression of the effects of ribonucleases in the cytoplasmic extracts allowed approximately 80% of the input ribozyme RNA to be recovered in the form of complexes, indicating that complex formation protected the ribozyme from degradation. Treatment of the ribozyme-protein complexes with proteinase K prior to electrophoresis led to the recovery of full-length ribozyme. Interestingly, ribozyme-protein complexes retained cleavage activity, suggesting that the binding is in reversible equilibrium. Analysis of protein cytoplasmic extracts for binding to sub-fragments of TNF alpha-Rz demonstrated that protein binds to a conformational epitope formed by an interaction between the 5' end of TNF alpha-Rz and its catalytic domain. Competition of the ribozyme-protein binding with a ribozyme construct containing DNA instead of RNA at the 5' end, indicated that the ribose phosphate backbone of the 5' end is required for strong binding. The protein responsible for the formation of the complex with low electrophoretic mobility was found to be specific for the TNF alpha-Rz, since ribozyme for HIV-1 integrase gene (Int-Rz), or for human interleukin-2 (IL2-Rz) did not compete significantly with the TNF alpha-Rz binding. Covalent linkage of the IL2-Rz to the 3' end of TNF alpha-Rz, or to the proposed RNA protein binding site conferred protein binding and enhanced the stability and activity of the chimeric molecules. The RNA epitope identified in this study, through its endogenous protein binding, may serve as an oligonucleotide cassette for enhancing the in vivo stability and activity of other RNA molecules in general. This RNA epitope will also be useful in the study of RNA-protein interactions.
J Mol Biol 1994 Oct 07
PMID:Interaction between tumour necrosis factor alpha ribozyme and cellular proteins. Involvement in ribozyme stability and activity. 793 19

Peptides derived from the CDRs of the anti-TNF alpha monoclonal antibody Di62 were tested for inhibition of binding of Di62 to TNF alpha as well as of TNF alpha to its 55 and 75 kDa receptor. A peptide derived from the CDR1 of the light chain was shown to specifically inhibit Di62 binding to TNF alpha with markedly higher activity (Ki = 4 microM) than all other CDR-derived peptides. This peptide also significantly inhibited binding of TNF alpha to its 55 and 75 kDa receptor and protected L929 cells from the cytotoxic effect of TNF alpha (IC50 = 6 microM). The C-terminal region of this peptide, which is homologous to the 55 and 75 kDa TNF receptor, was found to be essential for activity.
Mol Immunol 1994 Oct
PMID:Identification and characterization of a TNF alpha antagonist derived from a monoclonal antibody. 793 97

Several functions of alveolar macrophages (AM) are modified by cigarette smoking. AM are the first line of defense in bronchoalveolar spaces and could be depressed in their cytotoxicity to tumor cells in smokers. An assay using A549 cells (human lung adenocarcinoma) as target cells was performed to assess cytostasis mediated by AM and their supernatants (SN) from healthy smokers (n = 8) and nonsmokers (n = 6). Contact-mediated cytostasis was decreased in AM of smokers (n = 8) relative to nonsmokers (n = 6) (22.9 +/- 5.7% versus 42.7 +/- 6.0% [+/- SEM], P < 0.04) and increased after lipopolysaccharide (LPS) stimulation in both groups (34.5 +/- 5.3% versus 46.8 +/- 5.2%, NS). Cytostasis induced by SN from nonstimulated AM was low in both groups and was still lower in smokers after LPS exposure (19.3 +/- 4.5% versus 34.5 +/- 4.8%, P < 0.04). Among cytotoxic factors produced by macrophages, interleukin (IL)-1 beta, IL-6, and tumor necrosis factor alpha (TNF alpha) may play an important role in cytostasis. Recombinant human (rH) IL-1 beta and rHTNF alpha had a moderate cytostatic activity, which was additive, whereas rHIL-6 had no significant activity on A549 cells. Bioactive IL-1 beta, IL-6, and TNF alpha were therefore measured in macrophage SN. Their levels tended to be lower in smokers than in nonsmokers and were much increased after LPS stimulation. Levels of the three cytokines were also found to correlate with each other; furthermore, a good correlation between cytokine levels in SN and cytostasis was observed.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1994 Nov
PMID:Cytostatic activity of alveolar macrophages from smokers and nonsmokers: role of interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha. 794 92

The mechanisms by which interleukin-1 (IL-1) exerts destructive action on the pancreatic islet beta-cells remain elusive. Fragmentation of DNA leading to the activation of poly(ADP-ribose) synthetase was investigated in the present study, by assessing the nuclear response to cytokines in rat pancreatic islets. Nuclear fractions display Mg(2+)-dependent poly(ADP-ribose) synthetase activity catalyzing the incorporation of [adenine-U-14C]NAD, with Ka and Km for Mg2+ and NAD amounting to 0.86 mM and 0.43 mM, respectively. Exposure of the nuclear fraction to rIL-1 beta (10 IU/ml) provoked DNA strand breaks and increased nuclear poly(ADP-ribose) synthetase activity (148.4%, P < 0.01). In intact islets, this nuclear response was observed after 18 h culture in medium containing rIL-1 beta, with a concomitant decrease in NAD (88.5%). Brief periods of pre-incubation (90 min) with rIL-1 beta were unable to induce any nuclear activity. Under these conditions, the presence of IFN-alpha (24 U/ml) and TNF (120 U/ml) was necessary to induce a response to rIL-1 beta. Under the latter experimental conditions, a decrease in NAD content was also observed. The nuclear effects of IL-1 beta were modified by nicotinamide (10 mM), an inhibitor of poly(ADP-ribose) synthetase. It is thus conceivable that an increase in poly(ADP-ribose) synthetase activity together with DNA break is implicated in the beta cytotoxic effect of interleukin-1 beta.
Mol Cell Endocrinol 1994 Jul
PMID:Nuclear response of pancreatic islets to interleukin-1 beta. 795 97

Mouse models of infection of the central nervous system (CNS) have been used to study retroviral-induced neurologic disease. Ecotropic-neurotropic murine leukemia virus (MuLV) infection of susceptible neonatal mice causes a neurologic disease characterized by progressive hindlimb paralysis. The lesions consist of chronic noninflammatory spongiform change predominantly involving brainstem and spinal cord. Two molecularly cloned strains of MuLV, ts-1, a temperature-sensitive mutant of Moloney MuLV, and pNE-8, derived from a feral mouse isolate Cas-Br-E, were used in this study. Infected mice were sacrificed at regular intervals postinoculation throughout the time-course of disease. The neuropathology was evaluated using standard histological and immunohistopathological techniques. Tissue concentrations of viral proteins and potentially cytotoxic factors were compared with the histopathology in select regions of the CNS. Areas of extensive vacuolation with neuronal and oligodendroglial infection were observed in spinal cord, brainstem, and cerebellum. High titers of infectious virus were observed within CNS lesions, whereas low titers were observed in morphologically uninvolved areas. Western blot analysis revealed abundant production of viral envelope proteins, which correlated well with infectious virus titers. Serum quinolinic acid (QUIN) concentrations in both groups of noninfected and infected mice were similar. However, CNS tissue concentrations of QUIN, TNF alpha, and IL-6 in ts-1 infected mice were significantly higher than in pNE-8 infected or noninfected mice. The difference in concentration of these factors may be the result of greater activation of macrophages/microglia in ts-1 infected mice. During murine retroviral encephalitis, CNS damage may be mediated by direct infection of CNS cells and may be enhanced by indirect effects of neurotoxic factors possibly secreted by infected/activated macrophages.
Mol Chem Neuropathol 1994 Aug
PMID:Viral load and its relationship to quinolinic acid, TNF alpha, and IL-6 levels in the CNS of retroviral infected mice. 799 24

Oestradiol 17 beta-hydroxysteroid dehydrogenase (E2DH) has a pivotal role in the regulation of oestradiol (E2) concentrations in normal and malignant breast tissues. Previous studies have suggested that a number of cytokines can stimulate E2DH activity to increase the conversion of oestrone (E1) to E2. In this investigation we have examined the effect of TNF alpha, interleukin-1 beta (IL-1 beta) and IL-6 on E2DH activity in MCF-7 breast cancer cells. These cytokines may be produced by breast tumours and their presence in conditioned medium (CM) from tumour-derived fibroblasts was also measured to assess their possible contribution to its E2DH stimulatory activity. Treatment of MCF-7 cells with IL-1 beta and TNF alpha (5 ng/ml) significantly increased (P < 0.001) reductive E2DH (red-E2DH, the conversion of E1 to E2) activity. In contrast, IL-6 at a concentration of 100 ng/ml produced little, if any, stimulation of reductive activity. Combinations of all three cytokines acted synergistically to stimulate red-E2DH activity. No cytokine, either alone or in combination, affected oxidative (E2-->E1) activity. Significant concentrations of IL-6 and IL-1 beta were detected in CM, but the stimulation of red-E2DH activity was much greater than that which could be explained by their levels alone. It is concluded that these cytokines may play an important role in regulating E2DH activity in breast cancer cells and may act synergistically in vivo to enhance the formation of E2 in breast tumours.
J Steroid Biochem Mol Biol 1994 May
PMID:The interaction of cytokines in regulating oestradiol 17 beta-hydroxysteroid dehydrogenase activity in MCF-7 cells. 800 40

The blood-brain barrier GLUT1 glucose transporter is localized in brain to the capillary endothelium, which makes up the blood-brain barrier (BBB) in vivo. However, its expression is markedly downregulated in cultured bovine brain capillary endothelium (ECL cells), possibly due to the absence of brain-derived or astrocyte trophic factors in the tissue culture medium. To examine this hypothesis, we studied the effect of a bovine brain homogenate (BBH), and conditioned media and plasma membranes obtained from the rat C6 glioma cell line, on the abundance of the GLUT1 transcript in ECL cells. BBH induced a significant increase in the abundance of both GLUT1 and actin mRNAs, and this effect was dose and time dependent. The increase in the GLUT1 mRNA levels correlated with an increase in the transcriptional rate of this gene measured by nuclear run-on experiments. C6 conditioned media and C6 plasma membranes had no effect on the abundance of either GLUT1 or actin mRNA. To determine whether known growth factors cause BBH-like induction of GLUT1 and actin mRNAs, a series of growth factors was also tested. EGF and PDGF had no effect on the levels of these mRNAs. Basic FGF had a moderate effect and TNF alpha partially mimicked the effect of BBH on both GLUT1 and actin transcripts. The present data suggests that brain-derived trophic factors present in BBH stimulate BBB-GLUT1 glucose transporter gene expression in ECL cells through a transcriptional mechanism. Although this effect was partially mimicked by TNF alpha, C6 cell membranes or C6 conditioned media were unable to induce changes in the abundance of GLUT1 mRNA. Therefore, BBH may be a useful model to study the characterization of soluble brain-derived trophic factors involved in the induction of BBB-GLUT1 gene expression.
Brain Res Mol Brain Res 1994 Mar
PMID:Enhanced expression of the blood-brain barrier GLUT1 glucose transporter gene by brain-derived factors. 801 84

Dietary deficiency of magnesium (Mg) in rodents results in cardiomyopathic lesion formation. In our rat model, these lesions develop after 3 weeks on the Mg-deficient diet; significant elevation of several cytokines, IL-1, IL-6 and TNF alpha also occurs. In probing the mechanisms of lesion formation, we obtained data supporting the participation of free radicals (Freedman AM et al.: Bioch Biophys Res Commun 1990; 170: 1102). Recently, we identified an early elevation of circulating substance P and proposed a role of neurogenic peptides during Mg-deficiency (Weglicki WB, Phillips TM: AM J Phys 1992;262:R734). The present study was designed to evaluate the contribution of neurogenic peptides to the pathogenesis of Mg-deficiency. In the blood, substance-P and calcitonin gene related peptide (CGRP) are elevated during the first week on the diet. During the second week, circulating histamine, PGE2 and TBAR-materials were elevated and red cell glutathione was reduced, all prior to the elevation of the inflammatory cytokines during the third week. When the rats were treated with the substance P-receptor blocker [CP-96,345], the levels of substance P and CGRP remained elevated; however, increases in histamine, PGE2, TBAR-materials, and the decrease in red cell glutathione were inhibited; also, the development of cardiac lesions was inhibited significantly. These data support a central role for neurogenic peptides, especially substance P, in the development of cardiomyopathic lesions during Mg-deficiency.
Mol Cell Biochem 1994 Jan 26
PMID:Neurogenic peptides and the cardiomyopathy of magnesium-deficiency: effects of substance P-receptor inhibition. 802 89


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