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

---

Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We recently reported that tumor necrosis factor (TNF) induced the production of nitric oxide (NO) by TNF-sensitive, but not-resistant, tumor cells. Paradoxically, NO thus produced does not appear to be involved in the mechanism of TNF-mediated cytotoxicity as inhibitors of NO production and NO scavengers did not block cytotoxicity. Because the immunosuppressive drug cyclosporin A (CsA) inhibits several types of immune-mediated killing, we were interested in what effect CsA would have on TNF-mediated cytotoxicity as well as NO production. Treatment with CsA had no effect on the sensitivity L929 cells to TNF-mediated cytotoxicity, either in the presence or absence of interferon-gamma (IFN-gamma). In the presence of IFN-gamma alone, L929 cells were slightly less sensitive to the cytotoxic effects of TNF. In contrast to the effect on TNF-mediated cytotoxicity, CsA treatment had a profound effect on the ability of these cells to produce NO in response to TNF and IFN-gamma. Cells treated with CsA produced 75% less NO than did their untreated controls. Inhibition of calmodulin-dependent calcineurin-like phosphatases is one mechanism by which CsA may exert its effects. Therefore, we tested the effect of EGTA, which inhibits calcineurin by chelating calcium, on NO production and found that EGTA treatment resulted in a 15% decrease in the amount of NO produced. In addition, cells treated with the calmodulin antagonist W-13 produced 79% less NO than their untreated controls. Therefore, these results provide further evidence that NO produced by TNF-sensitive cells is not involved in the mechanism of TNF-mediated cytotoxicity because reduction of NO production by CsA has no effect on TNF-mediated killing of these same cells.
...
PMID:Cyclosporin A inhibits nitric oxide production by L929 cells in response to tumor necrosis factor and interferon-gamma. 836 91

Isoforms of heat shock protein (Hsp) 27 were used as intracellular markers to study tumor necrosis factor/interleukin-1 (TNF/IL-1) regulation of protein phosphatases in primary human fibroblasts. These isoforms were rapidly phosphorylated to varying degrees when fibroblasts were treated with either TNF, IL-1, okadaic acid, calyculin A, ARS, epidermal growth factor, fibroblast growth factor, H2O2, buthionine sulfoximine, N-ethylmaleimide, diethylmaleimide, or iodoacetate. However, inhibitors of protein kinases A and C, tyrosyl protein kinases, and general protein kinases had no effect on the enhanced phosphorylation of these isoforms in TNF, IL-1, okadaic acid, or calyculin A-stimulated cells, suggesting that the activation of protein kinases by itself is insufficient to produce these changes. Isoforms of 32P-labeled Hsp27 were dephosphorylated during cold-chases with excess phosphate in the absence but not in the presence of TNF/IL-1 or inhibitors of protein phosphatases suggesting that inactivation of protein phosphatase(s) plays a role in TNF/IL-1 signal transduction. Assays of phosphatase activity of cytosolic fractions from TNF or okadaic acid treated human fibroblasts showed an inactivation of protein phosphatase activity against the 32P-labeled Hsp27 protein substrates. In vitro assays of partially purified phosphatase activity from primary human fibroblasts with Hsp27 substrate also showed the protein phosphatase activity to be inhibited by ARS. Like okadaic acid, ARS mimics TNF in inducing specific patterns of cellular protein phosphorylation. Taken together these findings are consistent with the hypothesis that a SH-dependent protein phosphatase is inactivated during the early events of TNF/IL-1 signal transduction, hence inhibitors of protein phosphatases and SH modifying compounds can mimic the early effects of TNF/IL-1 on cells.
...
PMID:Inactivation of a redox-sensitive protein phosphatase during the early events of tumor necrosis factor/interleukin-1 signal transduction. 838 May 91

Using metabolic radiolabelling of proteins, which are newly synthesized during TCR-triggered T cell activation we were able to visualize distinct patterns of secreted polypeptides (with molecular weights ranging from 6 to 44 kDa) in supernatants of different T helper-1, T helper-2 and cytotoxic T cell clones. Most of these detected proteins are secreted in response to TCR-crosslinking (or to combined action of PMA and A231287), in an extracellular Ca(2+)-dependent manner and their appearance in supernatants was completely blocked by the addition of RNA synthesis or protein synthesis inhibitors or EGTA. Cyclosporin A (CsA) blocks secretion of several detected polypeptides, but does not affect TCR-triggered synthesis and secretion of others reflecting the existence of TCR-triggered, CsA-insensitive protein synthesis and secretion pathway. The insensitivity of secretion of several easily detectable polypeptides to inhibition by CsA offers a promising approach to further define the CsA-resistant and calcineurin-independent molecular pathways of TCR-triggered T cell activation. Several lymphokines (e.g., interferon-gamma, tumor necrosis factor, interleukin-4 and interleukin-10) are identified among the visualized set of secreted polypeptides. Since other, yet unidentified, secreted polypeptides in the same set of secreted proteins share important properties with known lymphokines it seems promising to use described approach in search for new lymphokines.
...
PMID:Detection of distinct sets of newly synthesized polypeptides in supernatants of TCR-triggered T cell clones. Implication for the search for new lymphokines. 848 28

A radiation-inducible immediate-early gene, IEX-1, was identified and characterized in human squamous carcinoma cells. Sequence analysis revealed 156-amino acid nucleotides, encoding a protein of Mr 20,000. The protein is glycosylated (Mr approximately 27,000) in the presence of microsomal membranes. Northern analysis reveals a 1.2-kb transcript. Treatment with cycloheximide was associated with superinduction of this transcript suggesting that it is an immediate-early gene. The abundance of IEX-1 mRNA increased rapidly after exposure of the cells to ionizing radiation (2-10 Gy), reaching a maximum by 15 min and returning subsequently to basal levels by 4 h. Expression of IEX-1 was also induced significantly by the protein kinase C (PKC) activator 12-O-tetradecanoylphorbol-13-acetate (TPA), the protein phosphatase inhibitor okadaic acid, and tumor necrosis factor-alpha, whereas treatment of cells with UV light and H2O2 had little effect on IEX-1 expression. Cells depleted of PKC by prolonged incubation with TPA showed no attenuated IEX-1 response to tumor necrosis factor-alpha. This is the first report of IEX-1, a radiation-inducible glycosylated human protein, whose expression can be mediated through multisignal transduction pathways.
...
PMID:Identification and characterization of a radiation-inducible glycosylated human early-response gene. 860 92

In this study, the acute effects of tumor necrosis factor (TNF)-alpha on insulin-stimulated glucose uptake, glycogen synthesis, and protein phosphatase-1 (PP-1) activation were examined in cultured rat skeletal muscle cell line, L6. Exposure of L6 cells to low concentrations of TNF-alpha (10 ng/ml for 60 min) inhibited basal and insulin stimulated 2-deoxyglucose uptake (40-50% decrease in basal and insulin stimulated glucose uptake respectively, when compared with controls, P < 0.05). The effect of TNF-alpha was more pronounced when the incubation period was extended to 6 and 12 h. TNF-alpha also blocked insulin activation of glycogen synthase (GS) and inhibited glycogen synthesis (measured as [14C]-glucose incorporated into glycogen). Because GS is activated by dephosphorylation via protein phosphatase-1 (PP-1), we examined the effect of TNF- alpha on PP-1 activation. As reported by us earlier (Srinivasan, M., and N. Begum, J Biol Chem 269:16662-16667, 1994), insulin rapidly stimulated PP-1 and concomitantly inhibited PP-2A activities in L6 cells. Pretreatment with TNF- alpha for 10-60 min blocked subsequent insulin-induced activation of PP-1. The impaired activation of PP-1 was accompanied by a reduction in insulin-stimulated phosphorylation of the regulatory subunit of PP-1. cAMP-Rp diastereomer, a cAMP antagonist failed to prevent the detrimental effects of TNF-alpha on PP-1. Cell permeable ceramide analogs, C2, C6, and Sphingomyelinase mimicked the effects of TNF-alpha on PP-1 inhibition. Furthermore, TNF-alpha treatment was accompanied by an increase in cellular ceramide levels, with concomitant reductions in sphingomyelin. We conclude that TNF-alpha blocks insulin-stimulated glycogen synthesis by inhibiting PP-1 activation via ceramide release.
...
PMID:Effect of tumor necrosis factor-alpha on insulin action in cultured rat skeletal muscle cells. 864 Nov 97

Changes in patterns of gene induction by myeloid lineage cells following multiple exposures to endotoxin (lipopolysaccharide; LPS) is a feature of LPS tolerance. To further understand the mechanism of this phenomenon we describe studies using stably transfected Chinese hamster ovary cell lines that express human CD14 (CHO-hCD14). Using NF-kappa B activation as a measure of LPS-induced cell activation we show that a single treatment with LPS renders CHO-hCD14 cells tolerant to subsequent challenge with LPS, but not with other stimuli such as tumor necrosis factor. Tolerance may result from the induction of gene(s) that control LPS-induced signaling pathways and here we suggest that such genes may be found in the group of immediate, early response genes characterized by the protein phosphatase 3CH134. The CHO-hCD14 cell lines provide a novel model system to further explore the mechanism of endotoxin tolerance.
...
PMID:Endotoxin tolerance is induced in Chinese hamster ovary cell lines expressing human CD14. 869 83

Stimulation of [3H]serine-labeled A431 cells with tumor necrosis factor-alpha (TNFalpha) or bacterial sphingomyelinase (SMase) resulted in a rapid decrease (approximately 50% by 15 min) in cellular [3H]sphingomyelin content and generation of the lipid moiety [3H]ceramide, which remained elevated 60 min later. Sphingomyelin hydrolysis in response to TNFalpha or bacterial SMase resulted in a time-dependent decrease in the phosphorylation state of c-Jun protein, an effect that was also observed in cells treated with the membrane-permeable ceramide analogue N-hexanoylsphingosine (C6-ceramide). The rapid dephosphorylation of the c-Jun gene product in response to TNFalpha, SMase, or C6-ceramide was not observed in A431 cells treated with the serine-threonine phosphatase inhibitor okadaic acid. After the initial steps of previously described methods for the purification of a ceramide-activated protein phosphatase termed CAPP (Dobrowsky, R. T., Kamibayashi, C., Mumby, M. C., and Hannun, Y. A. (1993) J. Biol. Chem. 268, 15523-15530), we obtained a cytosolic fraction from A431 cells that specifically dephosphorylated 32Pi-labeled c-Jun protein used as substrate in an immunocomplex phosphatase assay. Phosphatase activity in vitro was apparent only in the presence of ceramide (5 micro) and was specifically abrogated when okadaic acid (1 n) was included in the immunocomplex phosphatase assay. These results provide strong evidence for c-Jun as a downstream target for CAPP activated in response to post-TNF signaling in A431 cells.
...
PMID:c-Jun is a downstream target for ceramide-activated protein phosphatase in A431 cells. 870 18

Transcription-modulating drugs achieve their therapeutic effects through the modulation of gene transcription. To understand how selectivity is achieved, four groups of such drugs - including immunosuppressants, estrogen analogs, the antidiabetic thiazolidinediones, and the anti-inflammatory salicylates - will be discussed. The immunosuppressants cyclosporin A and FK506, when complexed with immunophilins, inactivate the protein phosphatase calcineurin, resulting in the inhibition of interleukin-2 gene activation. Another immunosuppressant, rapamycin, binds to the same immunophilin as FK506 but inactivates a protein kinase p70(s6k). Estrogen analogs tamoxifen and rolaxifene antagonize one estrogen receptor transactivation function (AF-2) and agonize another (AF-1). They modulate expression of a wide variety of genes, including transforming growth factor-alpha, insulin-like growth factor-1, and transforming growth factor-beta3, which are important for breast and endometrial cancer proliferation and bone maintenance respectively. The antidiabetic drugs thiazolidinediones bind and activate peroxisome proliferator-activated receptor gamma and suppress insulin resistance mediated by tumor necrosis factor-alpha. Salicylates inhibit transcription factor NFkappaB, which is important for immune and inflammatory responses. Continuing understanding of molecular mechanisms of such drugs not only helps to identify better drugs for these targets but should also provide an insight into developing future transcription-modulating drugs with better selectivity and reduced toxicity.
...
PMID:Transcription-modulating drugs: mechanism and selectivity. 893 43

Sphingolipid metabolites participate in key events of signal transduction and cell regulation. In the sphingomyelin cycle, a number of extracellular agents and insults (such as tumor necrosis factor, Fas ligands, and chemotherapeutic agents) cause the activation of sphingomyelinases, which act on membrane sphingomyelin and release ceramide. Multiple experimental approaches suggest an important role for ceramide in regulating such diverse responses as cell cycle arrest, apoptosis, and cell senescence. In vitro, ceramide activates a serine-threonine protein phosphatase, and in cells it regulates protein phosphorylation as well as multiple downstream targets [such as interleukin converting enzyme (ICE)-like proteases, stress-activated protein kinases, and the retinoblastoma gene product] that mediate its distinct cellular effects. This spectrum of inducers of ceramide accumulation and the nature of ceramide-mediated responses suggest that ceramide is a key component of intracellular stress response pathways.
...
PMID:Functions of ceramide in coordinating cellular responses to stress. 894 89

Exposure of cells to ionizing radiation (IR) or tumor necrosis factor-alpha (TNF-alpha) results in the stimulation of the DNA binding activities of transcription factors, AP-1 and NF-kappaB. HVH1/CL100, a dual specificity protein phosphatase, may attenuate the AP-1 response by dephosphorylating a key upstream element, mitogen-activated protein kinase (MAPK). The members of IkappaB family of proteins regulate the NF-kappaB response. We examined the effects of IR and TNF-alpha on HVH1 and IkappaB alpha gene expression. Our data demonstrate that IR or TNF-alpha treatment of head and neck squamous carcinoma cells (PCI-04A) increased the steady-state levels of HVH1 and IkappaB alpha mRNAs; however, the induction patterns were different. TNF-alpha treatment led to a relatively prolonged stimulation of HVH1 and IkappaB alpha mRNAs lasting at least 7 h, while IR caused a transient stimulation of these mRNAs and the expression returned to basal levels within 6 h post-IR treatment. Treatment of cells with cycloheximide did not prevent the IR orTNF-alpha-inducible expression of HVH1 and IkappaB alpha genes, indicating that these responses were independent of the new protein synthesis. These data imply that protein phosphatase HVH1 and regulatory factor IkappaB alpha may play important roles in cellular response to IR and TNF-alpha. In addition, the kinetics of responsiveness indicates that the mechanisms of IR and TNF-alpha-induced signalling are distinct.
...
PMID:Ionizing radiation and TNF-alpha stimulate gene expression of a Thr/Tyr-protein phosphatase HVH1 and inhibitory factor IkappaB alpha in human squamous carcinoma cells. 927 72


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---