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 examined the effect of staphylococccal enterotoxin B (SEB)-induced anergy on expression of six different cytokine genes in T cells restimulated with SEB in vitro. We found that although IL-2, IL-3, and IL-4 mRNA levels are substantially reduced in anergic T cells, mRNAs for IL-6, IL-10, IFN-gamma, and TNF-alpha are expressed normally. Thus, there appeared both anergy-sensitive and resistant cytokine mRNA expression in restimulated anergic T cells. The same pattern of cytokine mRNA responses was observed in anergic CD4+ T cells, indicating that the preferential induction of anergy in Th1-like cells is not evident in this in vivo model. Employing TCR V beta 8.2 transgenic mice in which almost all T cells become anergic, we found that the TCR/CD3 complex can transduce both anergy-sensitive and resistant signals. Furthermore, a series of experiments using FK506, A23187, and PMA suggests that signals between TCR and activation of calcineurin and protein kinase C may be blocked in anergic T cells. This is supported by our gel mobility shift assays indicating that calcineurin and/or PMA-inducible NF-ATp, OAP40, and AP-1, but not calcineurin-independent Oct-2, are repressed in anergic spleen T cells upon restimulation with SEB. Taken together, these results suggest that, among signals elicited by stimulation of TCR with SEB, a Ca2+/calcineurin-NF-ATp pathway and other signals, including protein kinase C, are repressed in anergic T cells upstream of their activation, which are essential for the cytokine mRNA expression of the anergy-sensitive type but are dispensible for those of the anergy-resistant type.
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PMID:Effect of staphylococcal enterotoxin B-induced anergy on cytokine gene expression: anergy-sensitive and resistant mRNA expression. 869 45

Prostaglandins of the E series are immunomodulatory agents which exert inhibitory as well as stimulatory effects on a variety of immune responses. Since it is known that PGE2 is able to increase cAMP levels, we investigated whether it can affect gene expression through the activation of the transcription factors which bind enhancer elements in the promoter regions of cAMP-regulated genes. Using electrophoretic mobility shift assay, we demonstrated that a short treatment of human T lymphocytes with PGE2 induces specific binding activity to CRE and AP-2, but not AP-1, DNA elements. Since the okadaic acid, a potent protein phosphatase inhibitor, prolongs the induction of the binding activity, phosphorylation events are likely to occur. This activity seems to be due to increased cAMP levels because forskolin and IBMX mimic the effects of PGE2. More interestingly, transfection experiments with CRE-CAT plasmide show that PGE2 activates the transcription of a CRE-containing promoter. These data support the positive role for PGE2 on some immune functions.
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PMID:Prostaglandin E2 induction of binding activity to CRE and AP-2 elements in human T lymphocytes. 892 59

The immunosuppressant cyclosporin A (CsA) exerts its pharmacologic actions by inhibiting calcineurin function. Here, we investigated the effect of CsA on the DNA-binding activity of the transcription factor, AP-1, in YAC-1 cells. We found that elevation of intracellular Ca2+ by ionomycin increased AP-1 DNA-binding activity in these cells. CsA treatment upregulated the ionomycin-induced, but not the basal AP-1 DNA-binding activity. In contrast, a CsA analog, MeVal4CsA, that does not inhibit calcineurin, failed to enhance ionomycin-induced AP-1 DNA-binding activity. This activity was shown to involve c-Fos, c-Jun and JunB. CsA consistently augmented ionomycin-induced c-fos mRNA expression and more variably that of JunB. Therefore, calcineurin negatively regulates Ca(2+)-stimulated AP-1 activity principally at the c-fos induction level. By inhibiting calcineurin, CsA shifts the balance between positive and negative AP-1 regulation. Since AP-1 controls the transcription of many genes, this finding may have implications for both the immunosuppressive and toxic effects of CsA.
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PMID:Cyclosporin A enhances the calcium-dependent induction of AP-1 complex and c-fos mRNA in a T cell lymphoma. 895 14

Induction of the Epstein-Barr virus (EBV) lytic cycle by crosslinking surface immunoglobulin is inhibited by the immunosuppressants cyclosporin A (CsA) and FK506. This correlates with the ability of CsA to inhibit Ca2+-dependent transcription of the lytic cycle switch gene BZLF1. It is shown here that CsA sensitivity maps to three sites (ZIA, ZIB and ZID) that bind the serum response factor-related protein MEF2D. A synthetic promoter containing multiple copies of a MEF2D site from Zp, in conjunction with a CREB/AP-1 site (ZII) from Zp, exhibits CsA-sensitive inducibility. Furthermore, the Zp MEF2D sites were functionally interchangeable with MEF2 sites derived from heterologous promoters. While no evidence of a NFAT family member binding to either the MEF2 or CREB/AP-1 sites was obtained, it could be demonstrated that CsA-sensitive induction of Zp was mediated by calcineurin and NFATc2 in synergy with either phorbol ester or especially with the EBV-induced Ca2+/calmodulin-dependent kinase type IV/Gr. These studies identify Zp as prototypic of a novel class of CsA-sensitive and NFAT-dependent promoters defined by the presence of MEF2 sites.
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PMID:Cyclosporin A-sensitive induction of the Epstein-Barr virus lytic switch is mediated via a novel pathway involving a MEF2 family member. 900 75

The nuclear factor of activated T cells (NFAT) regulates cytokine gene expression in T cells through cis-acting elements located in the promoters of several cytokine genes. NFATx1, which is preferentially expressed in the thymus and peripheral blood leukocytes, is one of four members of the NFAT family of transcription factors. We have performed domain analysis of NFATx1 by examining the effects of deletion mutations. We found that NFATx1 DNA binding activity and interaction with AP-1 polypeptides were dependent on its central Rel similarity region and that transcriptional activation was reduced by deletions of either its N-terminal domain or its C-terminal domain, suggesting the presence of intrinsic transcriptional activation motifs in both regions. We also identified a potent inhibitory sequence within its N-terminal domain. We show that the inactivation of the inhibition was dependent on the activity of calcineurin, a calcium-calmodulin-dependent phosphatase. We also show that calcineurin associated with the N-terminal domain of NFATx1 at multiple docking sites and caused a reduction of size, indicative of dephosphorylation, in NFATx1. We have mapped the inhibitory activity to less than 60 residues, containing motifs that are conserved in all NFAT proteins. Finally, we demonstrate that deletion in NFATx1 of the mapped 60 residues leads to its nuclear translocation independent of calcium signaling. Our results support the model proposing that the N-terminal domain confers calcium-signaling dependence on NFATx1 transactivation activity by regulating its intracellular localization through a protein module that associates with calcineurin and is a target of its phosphatase activity.
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PMID:Control of NFATx1 nuclear translocation by a calcineurin-regulated inhibitory domain. 912 55

As targets for the immunosuppressive drugs cyclosporin A and FK506, transcription factors of the NFAT (nuclear factor of activated T cells) family have been the focus of much attention. NFAT proteins, which are expressed in most immune-system cells, play a pivotal role in the transcription of cytokine genes and other genes critical for the immune response. The activity of NFAT proteins is tightly regulated by the calcium/calmodulin-dependent phosphatase calcineurin, a primary target for inhibition by cyclosporin A and FK506. Calcineurin controls the translocation of NFAT proteins from the cytoplasm to the nucleus of activated cells by interacting with an N-terminal regulatory domain conserved in the NFAT family. The DNA-binding domains of NFAT proteins resemble those of Rel-family proteins, and Rel and NFAT proteins show some overlap in their ability to bind to certain regulatory elements in cytokine genes. NFAT is also notable for its ability to bind cooperatively with transcription factors of the AP-1 (Fos/Jun) family to composite NFAT:AP-1 sites, found in the regulatory regions of many genes that are inducibly transcribed by immune-system cells. This review discusses recent data on the diversity of the NFAT family of transcription factors, the regulation of NFAT proteins within cells, and the cooperation of NFAT proteins with other transcription factors to regulate the expression of inducible genes.
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PMID:Transcription factors of the NFAT family: regulation and function. 914 5

Human papillomavirus (HPV) DNA sequences are found in most carcinomas originating from the uterine cervix. HPV E6 and E7 oncogenes have been shown to cooperate with ras oncogenes to fully transform human epithelial cells. We investigated the effect of the Ha-ras oncogene on the transcriptional activity of HPV-18 and found that it induced the transcriptional activity of the viral promoter, whereas the normal gene had only a minimal effect. However, transfection of the normal Ha-ras gene and simultaneous inhibition of protein phosphatase sensitive to okadaic acid (OA) resulted in a cooperative transactivation of the viral promoter. When cloned upstream of a minimal promoter, the AP-1 binding sites present in the viral promoter conferred transcriptional responsiveness to Ha-ras and OA. Furthermore, HeLa cell clones permanently expressing the Ha-ras oncogene or high levels of the normal gene exhibited a twofold to threefold increase in E6*E7/E1 and E6*E7 transcripts. We propose that both Ha-ras and a protein phosphatase sensitive to OA regulate HPV oncogene expression through modulation of AP-1 activity and suggest that increased levels of E6 and E7, resulting from activated viral transcription in the presence of ras oncogenes, may in part explain the observed cooperation between these viral and cellular oncogenes in the transformation of human cells.
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PMID:Ha-ras oncogene-induced transcription of human papillomavirus type 18 E6 and E7 oncogenes. 921 Sep 55

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.
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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

The MAP kinase (MAPK) JNK but not ERK is synergistically activated during costimulation of T cells. We examined how protein tyrosine kinases (PTKs) and GTPases differentially regulate JNK and ERK in T cells. While PTKs are not selective, small GTPases display distinct MAPK-activating functions. Whereas Ras activates ERK, Rac activates JNK. Rac cooperates with a Syk-generated signal to enhance JNK activation and appears to be at a nodal point for pathways emanating from CD28, calcineurin, and protein kinase C. AP-1- and NF-AT-dependent reporters are stimulated by Rac and Syk and are dependent on JNK. Unlike Syk, the PTK Lck activates JNK but does not cooperate with Rac, resulting in weak AP-1 and NF-AT activation. Therefore, signals generated by PTKs are functionally distinct and need to be integrated to induce transcriptional responses.
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PMID:Cooperation between Syk and Rac1 leads to synergistic JNK activation in T lymphocytes. 946 9

Recent molecular evidence points to transient and/or stage-specific expression of delta- and kappa-opioid receptors by thymic and peripheral T lymphocytes. Since medical treatments or stress commonly increase opioid levels, it is important to understand the mechanisms by which opioids affect T lymphocyte functions. We therefore created and studied a T cell line expressing the cloned delta-opioid receptor (DOR1). DOR1 ligation by a specific DOR1 agonist, deltorphin, augmented IL-2 secretion by synergizing with signals from TCR-CD3 and CD28. Reporter gene constructs were used to map this effect of deltorphin to the AP-1- and NF-AT/AP-1-binding sites of the IL-2 promoter. Although DOR1 signaling increased [Ca2+]i, deltorphin enhanced transcriptional activity of the NF-AT/AP-1-binding site via a mechanism independent of calcineurin and distinct from the effects of elevated [Ca2+]i. Deltorphin also increased accumulation of AP-1 transcription factor complexes, suggesting that DOR1 augments IL-2 secretion by increasing the AP-1 component of the NF-AT/AP-1 transcription factor. These results advance the molecular understanding of opioid effects on lymphocytes, and in addition, demonstrate regulation of IL-2 synthesis and secretion by the novel mechanism of receptor-mediated AP-1 induction.
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PMID:Delta-opioid receptors expressed by Jurkat T cells enhance IL-2 secretion by increasing AP-1 complexes and activity of the NF-AT/AP-1-binding promoter element. 954 83


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