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)

Cyclosporin A-sensitive promoter activity that is induced by the T cell antigen receptor was identified in the region between base pairs -147 and -17 of the mouse interleukin (IL)-4 gene. Here, we identify a transcriptional factor, NF(P), that binds a sequence from -75 to -69 (ATTTTCC) of the mouse IL-4 gene which corresponds to the human IL-4 gene P sequence. Expression of NF(P) was associated with positive regulation of the IL-4 gene and cyclosporin A sensitivity. The P sequence is homologous to the binding site for the positive transcriptional regulator of the IL-2 gene nuclear factor of activated T cells (NFAT). Binding of NF(P) to the P sequence was completely inhibited by an oligonucleotide corresponding to the NFAT binding site. Like NFAT, NF(P) was also found in the cytosol of resting T cells but translocated to the nucleus via a cyclosporin A-sensitive mechanism after T cell activation. Overexpression of a constitutively active calcineurin caused translocation of NF(P) from the cytosol to the nucleus. NF(P) purified on an oligonucleotide affinity column was 90 kDa, which is smaller than the 120-kDa reported for cNFAT. Purified NF(P) did not bind the NFAT consensus sequence, even in the presence of AP-1 protein. Our results suggest that the NF(P) molecule is not identical to the cNFAT molecule.
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PMID:Activation of the interleukin-4 gene is controlled by the unique calcineurin-dependent transcriptional factor NF(P). 803 12

The simian virus 40 small tumor antigen (small t) specifically interacts with protein phosphatase type 2A (PP2A) in vivo and alters its catalytic activity in vitro. Among the substrates for PP2A in vitro are the activated forms of MEK and ERK kinases. Dephosphorylation of the activating phosphorylation sites on MEK and ERKs by PP2A in vitro results in a decrease in their respective kinase activities. Recently, it has been shown that overexpression of small t in CV-1 cells results in an inhibition of PP2A activity toward MEK and ERK2 and a constitutive upregulation of MEK and ERK2 activity. Previously, we have observed that overexpression of either ERK1, MEK1, or a constitutively active truncated form of c-Raf-1 (BXB) is insufficient to activate AP-1 in REF52 fibroblasts. We therefore examined whether overexpression of small t either alone or in conjunction with ERK1, MEK1, or BXB could activate AP-1. We found that coexpression of small t and either ERK1, MEK1, or BXB resulted in an increase in AP-1 activity, whereas expression of either small t or any of the kinases alone did not have any effect. Similarly, coexpression of small t and ERK1 activated serum response element-regulated promoters. Coexpression of kinase-deficient mutants of ERK1 and ERK2 inhibited the activation of AP-1 caused by expression of small t and either MEK1 or BXB. Coexpression of an interfering MEK, which inhibited AP-1 activation by small t and BXB, did not inhibit the activation of AP-1 caused by small t and ERK1. In contrast to REF52 cells, we observed that overexpression of either small or ERK1 alone in CV-1 cells was sufficient to stimulate AP-1 activity and that this stimulation was not enhanced by expression of small t and ERK1 together. These results show that the effects of small t on immediate-early gene expression depend on the cell type examined and suggest that the mitogen-activated protein kinase activation pathway is distinctly regulated in different cell types.
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PMID:Simian virus 40 small t antigen cooperates with mitogen-activated kinases to stimulate AP-1 activity. 806 56

The serine/threonine protein phosphatase inhibitor okadaic acid (OA) was found to enhance mRNA transcripts of c-fos and of the jun family of proto-oncogenes including c-jun, jun B and jun D in cultured pheochromocytoma PC12 cells. This expression remained elevated for more than 8 hr. An increase in the binding of the transcription factor activator protein 1 (AP1) to its DNA consensus sequence that occurred prior to early gene transcription was observed. Enhanced AP1 activity was still observed when OA was added to the cells together with the transcription inhibitor actinomycin D, or with the protein synthesis inhibitor cycloheximide, indicating that it is actually AP1 activation due to posttranslational modifications that triggers transcription of the fos and jun genes. AP1 was activated through serine/threonine phosphorylation since its activation was abolished when nuclear extracts of OA-treated cells were incubated with protein phosphatase-1 or, to a lesser extent, with protein phosphatase-2A. C-Jun and Jun D proteins are likely candidates for being phosphorylated, since they were shown to constitute the AP1 complex at the time when it was activated (2 hr after OA addition).
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PMID:Okadaic acid induces activator protein 1 activity and immediate early gene transcription in rat pheochromocytoma cells. Mechanism of action. 808 Apr 55

Human hepatitis B virus (HBV) X protein, HBx, transactivates virus and host genes through a wide variety of cis-elements. Expression of HBx is controlled by HBV enhancer 1 (Enh1). Both Enh1 and the core sequence of Enh1, which consists of an AP-1 related site (cFAP1) and a C stretch, respond to HBx and a phorbol ester (TPA). Biochemical pathways of the responses to HBx and TPA are still controversial. We therefore asked whether HBx and TPA stimulate Enh1 core activity through a common process. Protein kinase C (PKC) inhibitors, H-7 and staurosporin, did not inhibit HBx transactivation at concentrations sufficient to abolish the TPA effects in HepG2 cells. Although HBx transactivation synergized independently with TPA or a phosphoprotein phosphatase inhibitor, okadaic acid (OA), the PKC inhibitors eliminated only the TPA contribution. HBx transactivation required both the cFAP1 and the C stretch of the Enh1 core region; however, mutations in either or both of the two cis-elements demonstrated that TPA augmentation required only cFAP1. These results imply that HBx transactivation operates through a mechanism distinct from the PKC and OA activation pathways.
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PMID:Transactivation of human hepatitis B virus X protein, HBx, operates through a mechanism distinct from protein kinase C and okadaic acid activation pathways. 811 51

Two cis-acting elements GM-kappa B/GC-box and CLE0, of the granulocyte-macrophage colony-stimulating factor (GM-CSF) gene are required for maximal induction in Jurkat T cells by costimulation with phorbol-12-myristate acetate (PMA) and Ca2+ ionophore (A23187). The GM-kappa B sequence is recognized by NF-kappa B, which is mainly induced by PMA. The CLE0 sequence interacts with factors, related to a PMA-induced AP-1 and a PMA/A23187-induced NF-AT. We examined whether signal transducing components in T cells can activate transcription of the GM-CSF gene. Cotransfection of NF-kappa B (p50/p65)- or AP-1 (c-Jun/c-Fos)-expression vectors into Jurkat cells with a luciferase reporter containing the GM-CSF promoter did not stimulate transcription from the GM-CSF promoter. In contrast, cotransfection with a combination of NF-kappa B and AP-1 significantly augmented transcription from the GM-CSF promoter containing the GM-kappa B/GC-box and the CLE0 (AP-1/NF-AT). Expression of a constitutively active calcineurin (CN), a Ca2+/calmodulin-dependent protein phosphatase, potentiated by two fold the transcriptional activation by NF-kappa B/AP-1. Both constitutively active forms of CN and protein kinase C (PKC) synergistically activated transcription from the GM-CSF promoter. These results suggest that cooperation among NF-kappa B-, AP-1- and NF-AT-binding sequences is required for induction of the GM-CSF gene through PKC- and Ca2+-signaling pathways downstream of T cell activation.
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PMID:Calcineurin activates transcription from the GM-CSF promoter in synergy with either protein kinase C or NF-kappa B/AP-1 in T cells. 813 80

Interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have previously been reported to induce rapid phosphorylation of the mitogen-activated protein (MAP) kinase. However, little is known about signaling events initiated by both hematopoietins that occur downstream of the MAP kinase. MAP kinase has been shown to phosphorylate the AP-1 transcription factor and also to activate two kinases designated insulin-stimulated protein kinase-1 and MAP kinase-activated protein (MAP-KAP) kinase 2. We show here that IL-3 and GM-CSF induce MAPKAP kinase 2 activity in the human megakaryoblastic leukemia cell line MO7 and phosphorylate the human small heat shock protein Hsp 27 on serine residues in vitro. GM-CSF also induced Hsp 27 phosphorylation in neutrophils in a range similar to that observed in MO7 cells, suggesting that MAPKAP kinase 2-mediated Hsp 27 activation occurs independently of proliferation. Hsp 27 phosphorylation was dose-dependent, occurred as early as 5 minutes after factor exposure, and was inhibited by the tyrosine kinase inhibitors genistein and herbimycin A. Furthermore, the protein phosphatase A2 abolished IL-3- and GM-CSF-induced serine phosphorylation of Hsp 27. Taken together, our findings indicate that tyrosine phosphorylation of MAP kinase is a prerequisite for serine phosphorylation of Hsp 27, which is mediated by MAPKAP kinase 2. Hsp 27 has shown activation-dependent translocation from the cytosolic to the nuclear region and has been linked to the cellular stress response. However, its precise function is largely unknown. Our data identify Hsp 27 as a target of the IL-3/GM-CSF stimulation pathway that involves MAP kinase and MAPKAP kinase 2. In addition, our results indicate that Hsp 27 may be target of phosphorylation events not only in the stress response but also in unstressed cells responding to cytokine stimulation.
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PMID:Interleukin-3 and granulocyte-macrophage colony-stimulating factor induce activation of the MAPKAP kinase 2 resulting in in vitro serine phosphorylation of the small heat shock protein (Hsp 27). 1101 49

Protein phosphatases 1 and 2A are important in regulating cellular functions by controlling the phosphorylation state of their substrates. In human monocytes, the inhibitors of these phosphatases, okadaic acid and calyculin A, were found to increase the mRNA accumulation and cytokine production of interleukin-1 beta and interleukin-1 alpha. The increased mRNA accumulation was found to be primarily because of the increase in the transcription rate of the interleukin-1 genes. Stimulation of interleukin-1 gene transcription may be caused by the stimulation of transcription factor activities, including those of AP-1, by these protein phosphatase inhibitors. Okadaic acid increased the synthesis of the interleukin-1 beta precursor and mature forms and their secretion. This increased processing and secretion correlated with the stimulation of IL-1 beta convertase mRNA accumulation. The stimulation of interleukin-1 alpha production by okadaic acid was more modest than that of interleukin-1 beta. However, the phosphorylation of the precursor interleukin-1 alpha cytokine was increased. These results show that protein phosphatase 1 and 2A inhibitors exert multiple effects on cytokine production in human monocytes and suggest that these two phosphatases play important roles in regulating interleukin-1 production.
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PMID:Stimulation of interleukin-1 alpha and interleukin-1 beta production in human monocytes by protein phosphatase 1 and 2A inhibitors. 838 77

The involvement of serine/threonine protein phosphatases in signaling pathways which modulate the activity of the transcription factor AP-1 was examined. Purified protein phosphatase types 1 (PP1) and 2A (PP2A) were microinjected into cell lines containing stably transfected lacZ marker genes under the control of an enhancer recognized by AP-1. Microinjection of PP2A potentiated serum-stimulated beta-galactosidase expression from the AP-1-regulated promoter. Similarly, transient expression of the PP2A catalytic subunit with c-Jun resulted in a synergistic transactivation of an AP-1-regulated reporter gene. PP2A, but not PP1, potentiated serum-induced c-Jun expression, which has been previously shown to be autoregulated by AP-1 itself. Consistent with these results, PP2A dephosphorylated c-Jun on negative regulatory sites in vitro, suggesting one possible direct mechanism for the effects of PP2A on AP-1 activity. Microinjection of PP2A had no effect on cyclic AMP (cAMP)-induced expression of a reporter gene containing a cAMP-regulated promoter, while PP1 injection abolished cAMP-induced gene expression. Taken together, these results suggest a specific role for PP2A in signal transduction pathways that regulate AP-1 activity and c-Jun expression.
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PMID:Protein phosphatase 2A potentiates activity of promoters containing AP-1-binding elements. 838 5

Treatment of U937 human leukemic cells with the phorbol ester PMA, activates both mitogen-activated protein kinase (MAPK) and stress-activated protein kinase (SAPK), stimulates c-Jun phosphorylation and transcriptional activity, and induces a macrophage-like differentiation of U937 cells. The involvement of the MAPK pathway in mediating both the early phosphorylation and transcriptional activation events and the chronic differentiation of U937 cells was examined utilizing constitutively active MAPK kinase (MEK1) mutants. Transient expression of an activated MEK1 construct in U937 cells was found to stimulate MAPK and SAPK activity, as well as enhancing AP1-, SRE- and c-Jun-mediated transcriptional activity. Transient transfection of MAPK phosphatase-1 (MKP-1), a protein phosphatase which preferentially dephosphorylates and inactivates MAPK, inhibited the functional effects of both PMA and the constitutively active MEK1 mutants. To determine whether specific activation of the MEK/MAPK pathway was sufficient to induce hematopoietic differentiation, U937 cell lines were established that conditionally expressed the activated MEK1 mutant under the control of the human IIa metallothionein promoter. The induction of constitutively active MEK1 protein expression resulted in an increase in MEK1 activity, c-Jun and AP-1 transcriptional activity and an inhibition of U937 cell growth. However, this growth inhibition was not accompanied by U937 cell differentiation. These results suggest that a cross-talk mechanism exists between the MAPK and SAPK signal transduction pathways in U937 cells and that PMA-mediated SAPK activation may involve the MAPK pathway. Furthermore, selective activation of the MEK/MAPK pathway utilizing a constitutively active MEK1 mutant, while growth inhibitory, was not sufficient to induce the macrophage-like differentiation of U937 cells.
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PMID:Constitutively active MAP kinase kinase (MEK1) stimulates SAP kinase and c-Jun transcriptional activity in U937 human leukemic cells. 857 Jan 88

The transcription factor, Nuclear Factor of Activated T cells (NFAT) is a major target for p21ras and calcium signalling pathways in the IL-2 gene and is induced by p21ras signals acting in synergy with calcium/calcineurin signals. One p21ras effector pathway involves the MAP kinase ERK-2, and we have examined its role in NFAT regulation. Expression of dominant negative MAPKK-1 prevents NFAT induction. Constitutively active MAPKK-1 fully activates ERK-2 and the transcription factor Elk-1, but does not substitute for activated p21ras and synergize with calcium/calcineurin signals to induce NFAT. Expression of dominant negative N17Rac also prevents TCR and p21ras activation of NFAT, but without interfering with the ERK-2 pathway. The transcriptional activity of the NFAT binding site is mediated by a complex comprising a member of the NFAT group and AP-1 family proteins. The induction of AP-1 by p21ras also requires Rac-1 function. Activated Rac-1 could mimic activated p21ras to induce AP-1 but not to induce NFAT. Moreover, the combination of activated MAPKK-1 and Rac-1 could not substitute for activated p21ras and synergize with calcium signals to induce NFAT. Thus, p21ras regulation of NFAT in T cells requires the activity of multiple effector pathways including those regulated by MAPKK-1/ERK-2 and Rac-1.
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PMID:Multiple p21ras effector pathways regulate nuclear factor of activated T cells. 867 Aug 97


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