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

We have reported that inhibition of protein phosphatase 2A (PP2A) by expression of SV40 small t stimulates the mitogenic MAP kinase cascade. Here, we show that SV40 small t can substitute for tumor necrosis factor-alpha (TNF-alpha) or serum and stimulate atypical protein kinase C zeta (PKC zeta) activity, resulting in MEK activation, cell proliferation and NF-kappaB-dependent gene transcriptional activation in CV-1 and NIH 3T3 cells. These effects were abrogated by co-expression of kinase-deficient PKC zeta and inhibition of phosphatidylinositol 3-kinase p85alpha-p110 by wortmannin, LY294002 and a dominant-negative mutant of p85alpha. In contrast, expression of kinase-inactive ERK2 inhibited small t-dependent cell growth but was unable to abolish small t-induced NF-kappaB transactivation. Our results provide the first in vivo evidence for a critical regulatory role of PP2A in bifunctional PKC zeta signaling pathways controlled by phosphatidylinositol 3-kinase. Constitutive activation of PKC zeta and NF-kappaB following inhibition of PP2A supports new mechanisms by which SV40 small t promotes cell growth and transformation. By establishing PP2A as a key player in the response of cells to growth factors and stress signals like TNF-alpha, our findings could explain why PP2A is a primary target utilized during SV40 infection to alter cellular behavior.
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PMID:Protein phosphatase 2A is a critical regulator of protein kinase C zeta signaling targeted by SV40 small t to promote cell growth and NF-kappaB activation. 931 25

A novel member of the tumor necrosis factor (TNF) cytokine family, designated TRANCE, was cloned during a search for apoptosis-regulatory genes using a somatic cell genetic approach in T cell hybridomas. The TRANCE gene encodes a type II membrane protein of 316 amino acids with a predicted molecular mass of 35 kDa. Its extracellular domain is most closely related to TRAIL, FasL, and TNF. TRANCE is an immediate early gene up-regulated by TCR stimulation and is controlled by calcineurin-regulated transcription factors. TRANCE is most highly expressed in thymus and lymph nodes but not in nonlymphoid tissues and is abundantly expressed in T cells but not in B cells. Cross-hybridization of the mouse cDNA to a human thymus library yielded the human homolog, which encodes a protein 83% identical to the mouse ectodomain. Human TRANCE was mapped to chromosome 13q14 while mouse TRANCE was located to the portion of mouse chromosome 14 syntenic with human chromosome 13q14. A recombinant soluble form of TRANCE composed of the entire ectodomain induced c-Jun N-terminal kinase (JNK) activation in T cells but not in splenic B cells or in bone marrow-derived dendritic cells. These results suggest a role for this TNF-related ligand in the regulation of the T cell-dependent immune response.
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PMID:TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinase in T cells. 931 32

Nitric oxide produced by inducible nitric-oxide synthase (iNOS) in different cells including brain cells in response to proinflammatory cytokines plays an important role in the pathophysiology of stroke and other neurodegenerative diseases. The present study underlines the importance of protein phosphatase (PP) 1 and 2A in the regulation of the differential expression of iNOS in rat primary astrocytes and macrophages. Compounds (calyculin A, microcystin, okadaic acid, and cantharidin) that inhibit PP 1 and 2A were found to stimulate the lipopolysaccharide (LPS)- and cytokine-mediated expression of iNOS and production of NO in rat primary astrocytes and C6 glial cells. However, these inhibitors inhibited the LPS- and cytokine-mediated expression of iNOS and production of NO in rat resident macrophages and RAW 264.7 cells. Similarly, okadaic acid, an inhibitor of PP 1/2A, stimulated the iNOS promoter-derived chloramphenicol acetyltransferase activity in astrocytes and inhibited the iNOS promoter-derived chloramphenicol acetyltransferase activity in macrophages, indicating that okadaic acid also differentially regulates the transcription of the iNOS gene in astrocytes and macrophages. The observed stimulation of the expression of iNOS in astrocytes and the inhibition of the expression of iNOS in macrophages with the inhibition of PP 1/2A activity clearly delineate a novel role of PP 1/2A in the differential regulation of iNOS in rat astrocytes and macrophages. Because the activation of NF-kappaB is necessary for the induction of iNOS and the expression of tumor necrosis factor (TNF)-alpha also depends on the activation of NF-kappaB, we examined the effect of okadaic acid on the LPS-mediated activation of NF-kappaB and production of TNF-alpha in rat primary astrocytes and macrophages. Interestingly, in both cell types, okadaic acid stimulated the LPS-mediated DNA binding as well as transcriptional activity of NF-kappaB and production of TNF-alpha. This study suggests that the stimulation of iNOS expression in astrocytes by inhibitors of PP 1/2A is possibly due to the stimulation of NF-kappaB activation; however, activation of NF-kappaB is not sufficient for the induction of iNOS in macrophages and that apart from NF-kappaB some other signaling pathway(s) sensitive to PP 1 and/or PP 2A is/are possibly involved in the regulation of iNOS in macrophages. This differential induction of iNOS as compared with similar activation of NF-kappaB by inhibitors of PP 1/2A indicates the involvement of different intracellular signaling events for the induction of iNOS in two cell types of the same animal species.
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PMID:Inhibitors of protein phosphatase 1 and 2A differentially regulate the expression of inducible nitric-oxide synthase in rat astrocytes and macrophages. 957 70

CD134 (OX40) is involved in T cell costimulation and T cell-dependent antibody production. We show strongly increased T cell expression of CD134 in a model of T helper 2-mediated systemic autoimmunity, induced by HgCl2. Regulation of CD134 expression on CD4+ T cells was further studied in vitro, identifying CD134 as an early marker of T cell activation. CD134 expression could be induced by interleukin-4, but not by interferon-gamma or tumor necrosis factor-alpha. Effects of interleukin-4 and of phorbol 12-myristate 13-acetate on CD134 expression could be blocked by the protein kinase inhibitor staurosporin. Combination of these stimuli with ionomycin resulted in a strongly synergistic increase of CD134 expression, which was blocked by the calcineurin-inhibitor cyclosporin A. The results demonstrate the involvement of two synergistically acting pathways in induction of CD134 expression. Furthermore, they suggest a role for interleukin-4 in induction of CD134 expression in vivo.
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PMID:Strong expression of CD134 (OX40), a member of the TNF receptor family, in a T helper 2-type cytokine environment. 976 31

1. In human epithelial-like DLD-I cells, nitric oxide synthase (NOS) II expression was induced by interferon-gamma (100 u ml(-1)) alone and, to a larger extent, by a cytokine mixture (CM) consisting of interferon-gamma, interleukin-1beta (50 u ml(-1)) and tumor necrosis factor-alpha (10 ng ml(-1)). 2. CM-induced NOS II expression was inhibited by tyrphostin B42 (mRNA down to 1%; nitrite production down to 0.5% at 300 microM) and tyrphostin A25 (mRNA down to 24%, nitrite production down to 1% at 200 microM), suggesting the involvement of janus kinase 2 (JAK-2). Tyrphostin B42 also blocked the CM-induced JAK-2 phosphorylation (kinase assay) and reduced the CM-stimulated STAT1alpha binding activity (gel shift analysis). 3. CM reduced the nuclear binding activity of transcription factor AP-1. A heterogenous group of compounds, that stimulated the expression of c-fos/c-jun, enhanced the nuclear binding activity of AP-1. This group includes the protein phosphatase inhibitors calyculin A, okadaic acid, and phenylarsine oxide, as well as the inhibitor of translation anisomycin. All of these compounds reduced CM-induced NOS II mRNA expression (to 9% at 50 nM calyculin A; to 28% at 500 nM okadaic acid; to 18% at 10 microM phenylarsine oxide; and to 19% at 100 ng ml(-1) anisomycin) without changing NOS II mRNA stability. In cotransfection experiments, overexpression of c-Jun and c-Fos reduced promoter activity of a 7 kb DNA fragment of the 5'-flanking sequence of the human NOS II gene to 63%. 4. Nuclear extracts from resting DLD-1 cells showed significant binding activity for transcription factor NF-kappaB, which was only slightly enhanced by CM. The NF-kappaB inhibitors dexamethasone (1 microM), 3,4-dichloroisocoumarin (50 microM), panepoxydone (5 microg ml(-1)) and pyrrolidine dithiocarbamate (100 microM) produced no inhibition of CM-induced NOS II induction. 5. We conclude that in human DLD-1 cells, the interferon-gamma-JAK-2-STAT1alpha pathway is important for NOS II induction. AP-1 (that is downregulated by CM) seems to be a negative regulator of NOS II expression. NF-kappaB, which is probably important for basal activity of the human NOS II promoter, is unlikely to function as a major effector of CM in DLD-1 cells.
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PMID:Cytokine induction of NO synthase II in human DLD-1 cells: roles of the JAK-STAT, AP-1 and NF-kappaB-signaling pathways. 977 60

The tumor necrosis factor (TNF) alpha level is elevated in patients with advanced heart failure, and the phosphorylation of contractile regulatory proteins is reduced in the human heart. We hypothesized that TNFalpha affects the phosphorylation of proteins involved in regulating contraction; phospholamban (PLB), myosin light chain 2 (MLC2) and troponin I (TnI). Spontaneously beating rat neonatal cardiac myocytes, prelabelled with [32P]orthophosphate, were treated with TNFalpha for 30 min, and stimulated with isoproterenol for 5 min. 32P-labelled myofibrillar proteins were isolated by 15% SDS-PAGE. Baseline phosphorylation levels of PLB, TnI and an unknown 23kDa phosphoprotein were decreased by TNFalpha in a dose-dependent manner. Moreover, TNFalpha attenuated the phosphorylation levels of PLB and TnI increased by a concentration of 0.01 microM isoproterenol, but not by 1 microM of isoproterenol. Although TNFalpha had no effect on the cAMP content or cAMP-dependent protein kinase activity in the presence or absence of isoproterenol, an inverse relationship was observed between the concentration of TNFalpha and the cGMP content in cardiac myocytes, and treatment with TNFalpha resulted in a concentration-dependent increase in type 2A protein phosphatase activity. The observation that TNFalpha decreases phosphorylation levels of PLB and TnI in cardiac myocytes suggests that the reduction of these protein phosphorylation levels is partially responsible for alterations of intracellular Ca2+-cycling and the force of contraction in TNF alpha-treated cardiac myocytes. Furthermore, TNFalpha reduces myocyte contraction and protein phosphorylation states possibly via cAMP-independent mechanisms, at least in part, by the activation of type 2A protein phosphatase.
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PMID:Tumor necrosis factor-alpha decreases the phosphorylation levels of phospholamban and troponin I in spontaneously beating rat neonatal cardiac myocytes. 1007 33

This study investigates the second messengers involved in NF-kappaB activation by the bisperoxovanadium (bpV) phosphotyrosyl phosphatase inhibitors. We first initiated a time course analysis of bpV-mediated activation of the human immunodeficiency virus type-1 long terminal repeat- and NF-kappaB-driven reporter gene. Our results showed a slower and more transient activation of both kappaB-regulated luciferase-encoding vectors by bpV compounds when compared with the action of tumor necrosis factor-alpha (TNF). Time course analyses of NF-kappaB translocation by shift assay experiments further confirmed these results, hence implying distinct pathways of NF-kappaB activation for bpV compounds and TNF. Attempts to characterize the bpV-dependent signaling cascade revealed that the src family protein tyrosine kinase p56(lck) was critical for NF-kappaB induction by bpV. Furthermore, p56(lck) interaction with the intracytoplasmic tail of CD4 markedly enhanced such induction. Optimal activation of NF-kappaB following bpV treatment necessitated downstream effectors of p56(lck) such as the syk family protein tyrosine kinase ZAP-70 and the molecular adaptor SLP-76. Importantly, reduced NF-kappaB activation was observed when capacitative calcium entry was deficient but also upon pharmacological inhibition of calmodulin and calcineurin. Altogether, these results suggest that induction of NF-kappaB by phosphotyrosyl phosphatase bpV inhibitors necessitates both proximal and distal effectors of T cell activation.
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PMID:p56(lck), ZAP-70, SLP-76, and calcium-regulated effectors are involved in NF-kappaB activation by bisperoxovanadium phosphotyrosyl phosphatase inhibitors in human T cells. 1057 81

Cyclosporin (CsA) inhibits mitochondrial death signaling and opposes tumor necrosis factor (TNF)-induced apoptosis in vitro. However, CsA is also a potent inhibitor of calcineurin, a phosphatase that may participate in cell death. Therefore, we tested the hypothesis that calcineurin regulates TNF cytotoxicity in rat hepatoma cells (FTO2B). TNF-treated FTO2B cells appeared apoptotic by DNA fragmentation, nuclear condensation, annexin V binding, and caspase activation. We studied two calcineurin inhibitors, CsA and FK506, and found that each potently inhibited TNF cytotoxicity. Western blot demonstrated calcineurin in FTO2B homogenates. In a model of mitochondrial permeability transition (MPT), we found that CsA prevented MPT and cytochrome c release, while FK506 inhibited neither. In summary, we present evidence that calcineurin participates in an apoptotic death pathway activated by TNF. CsA may oppose programmed cell death by inhibiting calcineurin activity and/or inhibiting mitochondrial signaling.
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PMID:Regulation of tumor necrosis factor cytotoxicity by calcineurin. 1104 65

CD58 is the ligand for the CD2 molecule on human T cells and has been shown to provide a co-stimulatory signal for T cell activation. However, its physiological role is still unclear. We studied the effects of co-stimulation by CD58 on the production of T(h)1-type (IL-2- and IFN-gamma) or T(h)2 type (IL-4, IL-5 and IL-10) cytokines in an in vitro culture system of purified human T cells with CD58-transfected P815 cells and with anti-CD3 as the primary stimulus. Co-stimulation of T cells by CD58 potently induced IL-10 and IFN-gamma production (at the protein and at the mRNA level), and transforming growth factor-ss production (at the mRNA level), comparable to what can be found in CD80 co-stimulated T cell cultures. In contrast, we found low to absent IL-2, IL-4, IL-5, IL-13 and tumor necrosis factor-alpha production after CD58 co-stimulation, and this was not due to suppressive effects of endogenously produced IL-10. CD80 co-stimulation strongly induced all these cytokines. Intracellular staining for cytokine expression revealed the existence of a T cell subpopulation induced by CD58 co-stimulation to produce both IFN-gamma and IL-10. We furthermore found that the selective cytokine profile induced by CD58 co-stimulation is further accentuated by rIL-12 and by rIFN-alpha. Using cyclosporin A as an inhibitor of the calcineurin enzyme, we could show that production of all cytokines in this system is calcium dependent. CD58 co-stimulation thus induces a cytokine pattern corresponding to that described for T regulatory (T(r)) 1 cells and to the pattern reported to be induced by the newly identified B7 family member, B7-H1.
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PMID:Effects of co-stimulation by CD58 on human T cell cytokine production: a selective cytokine pattern with induction of high IL-10 production. 1115 51

Cardiotoxicity resulting from detrimental environmental insults has been recognized for a long time. However, extensive studies of the mechanisms involved had not been undertaken until recent years. Advances in molecular biology provide powerful tools and make such studies possible. We are gathering information about cellular events, signaling pathways, and molecular mechanisms of myocardial toxicologic responses to environmental toxicants and pollutants. Severe acute toxic insults cause cardiac cell death instantly. In the early response to mild environmental stimuli, biochemical changes such as alterations in calcium homeostasis occur. These may lead to cardiac arrhythmia, which most often is reversible. Prolonged stimuli activate transcription factors such as activator protein-1 through elevation of intracellular calcium and the subsequent activation of calcineurin. Upregulation by activated transcription factors of hypertrophic genes results in heart hypertrophy, which is a short-term adaptive response to detrimental factors. However, further development of hypertrophy will lead to severe and irreversible cardiomyopathy, and eventually heart failure. From cardiac hypertrophy to heart failure, myocardial cells undergo extensive biochemical and molecular changes. Cardiac hypertrophy causes tissue hypoperfusion, which activates compensatory mechanisms such as production of angiotensin II and norepinephrine. Both further stimulate cardiac hypertrophy and, importantly, activate counterregulatory mechanisms including overexpression of atrial natriuretic peptide and b-type natriuretic peptide, and production of cytokines such as tumor necrosis factor-alpha. This counterregulation leads to myocardial remodeling as well as cell death through apoptosis and necrosis. Cell death through activation of mitochondrial factors and other pathways constitutes an important cellular mechanism of heart failure. Our current knowledge of cardiotoxicity is limited. Further extensive studies are warranted for a comprehensive understanding of this field.
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PMID:Molecular and cellular mechanisms of cardiotoxicity. 1125 Aug 3


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