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)

Nuclear factor of activated T cells (NFAT) regulates transcription of a number of cytokine genes, and NFAT DNA binding activity is stimulated following T cell activation. Several lines of evidence have suggested that NFAT is a substrate for calcineurin, a serine/threonine phosphatase. Using a polyclonal antibody to murine NFATp, Western blot analysis of various mouse tissues demonstrated that the 110-130-kDa NFATp protein was highly expressed in thymus and spleen. Treatment of immunoprecipitated NFATp from untreated HT-2 cells with calcineurin resulted in the dephosphorylation of NFATp, demonstrating that NFATp is an in vitro substrate for calcineurin. NFATp immunoprecipitated from 32P-labeled HT-2 cells migrated as an approximately 120-kDa protein that was localized to the cytosol of the cells. Treatment of the cells with ionomycin resulted in a decrease in the molecular weight of NFATp and a loss of 32P, consistent with NFATp dephosphorylation. The dephosphorylation of NFATp was accompanied by localization of the protein to the nuclear fraction. Both of these events were blocked by preincubation of the cells with FK506, a calcineurin inhibitor, consistent with the hypothesis that NFATp is a calcineurin substrate in cells.
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PMID:Direct demonstration of NFATp dephosphorylation and nuclear localization in activated HT-2 cells using a specific NFATp polyclonal antibody. 754 80

Calcineurin (CN), a Ca2+/calmodulin-regulated phosphatase 2B, plays an important role in many biological processes including T-cell signal transduction. In the present study, the distribution and activity of CN were investigated in rat tissues. CN has a wide tissue distribution, as measured by enzyme-linked immunosorbent assay. CN concentrations are 0.2-0.6 micrograms/mg protein in most tissues, while the brain contains 3-10-fold higher concentrations. Immunohistochemical analyses using a monoclonal antibody to CN B subunit reveals that CN is not evenly distributed but concentrated in specific cells, especially in the brain, kidneys and testis. The specific enzymic activity of CN in tissues is around 10 pmol.min.mg protein-1, except in brain and liver (60 pmol.min-1.mg protein-1 compared to 3.6 pmol.min-1.mg protein-1). The immunosuppressants cyclosporin A and tacrolimus, but not rapamycin, inhibit the phosphatase activity of CN derived from most tissues tested, while CN activity from liver was resistant to cyclosporin A. Furthermore, transcripts and protein of the common CN B subunit and of the testis-specific form of CN B subunit were analyzed. The common CN B subunit transcripts and protein are detected in all tissues. Transcripts for the 'testis-specific' CN B subunit are also found in brain, lung, thymus and heart, while the protein is only detected in testis. This indicates that the testis-specific CN B subunit gene expression is regulated at both transcriptional and posttranscriptional levels. The findings demonstrate that CN is a widely distributed protein phosphatase and that its activity is regulated in a tissue-specific manner.
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PMID:Distribution and activity of calcineurin in rat tissues. Evidence for post-transcriptional regulation of testis-specific calcineurin B. 760 17

The distribution of the mRNAs encoding the different isoforms of the catalytic subunit (A subunit) of calcineurin has been investigated in rat thymus and kidney using in situ hybridization histochemistry with specific antisense oligonucleotide probes. In the thymus, the mRNAs of the A beta isoforms were the predominant transcripts and showed very intense hybridization signals in the cortical areas. The A alpha mRNAs were expressed at low levels. A beta 2 mRNA was expressed at higher levels than A beta 3 mRNA, but no difference could be detected between the expression levels of A alpha 1 and A alpha 2. In the kidney, highest calcineurin A mRNA hybridization signals were found in the medulla. Signal intensities of A alpha mRNAs were comparable to those of A beta mRNAs. A alpha 1 mRNA level was extremely weak, and A beta 2 mRNA expression was slightly higher than A beta 3 mRNA expression. A tissue-specific distribution pattern of the alternatively spliced isoforms of calcineurin A, as suggested by these preliminary data from thymus and kidney, may be critical in understanding the toxic side-effects associated with the use of the immunosuppressive, calcineurin-inhibiting compounds cyclosporin A and FK506.
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PMID:Distribution of calcineurin A isoenzyme mRNAs in rat thymus and kidney. 763 61

The amounts of four isoforms of the catalytic subunit of type-1 protein phosphatase, PP1 alpha, PP1 gamma 1, PP1 gamma 2, and PP1 delta have been determined in extracts of various mouse tissues including brain, liver, skeletal muscle, kidney, small intestine, heart, lung, spleen, thymus, and testis by Western blot analysis. Immunoreactive bands for PP1 isoforms were detected at 39.5, 38.5, and 40 kDa for PP1 alpha, PP1 gamma 1, and PP1 gamma 2, respectively, and at 39 and 37 kDa for PP1 delta. The amount of PP1 alpha was at comparable levels in all tissues examined except skeletal and heart muscles, in which it was detected slightly or not detectable, respectively. The amount of PP1 gamma 1 was at higher levels in brain, small intestine, and lung, being 2 to 3 times those in other tissues except heart and spleen, in which PP1 gamma 1 was not detectable. The amount of PP1 gamma 2 was extremely large in testis, small in brain, lung, spleen, and thymus, but it was not detectable in the other tissues. The amount of PP1 delta was at comparable levels in all the tissues except skeletal muscle, in which it was at a low but detectable level. Then, the amounts of the four PP1 isoforms were determined in non-obese diabetic (NOD) mice. The amounts of PP1 alpha were progressively decreased in livers of NOD mice as a function of increasing concentrations of blood glucose, whereas the amounts of PP1 gamma 1 and PP1 delta were unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Tissue distribution of isoforms of type-1 protein phosphatase PP1 in mouse tissues and its diabetic alterations. 782 62

Entry of thymus-migrated precursor cells into the CD4/CD8 developmental pathway was analyzed by using the short-term organ cultures of day 14 fetal mouse thymus lobes. Organ cultures of CD4-CD8- day 14 fetal thymocytes for 1-2 days resulted in the generation of CD4-CD8+ cells, which were mostly immediate precursor cells for CD4+CD8+ thymocytes. This differentiation of CD4-CD8- thymocytes into CD4-CD8+ cells was strongly enhanced by anti-CD3 antibodies. The anti-CD3- induced generation of CD4-CD8+ cells was even found in the immunodeficient scid fetal thymus cultures, and the cell surface CD3 expression on the scid fetal thymocytes could be directly visualized, indicating that functional CD3 could be expressed on CD4-CD8- immature thymocytes without being associated with rearranged TCR components. The anti-CD3-induced generation of CD4-CD8+ cells from scid and normal fetal thymus cultures was inhibited by tyrosine kinase inhibitors Herbimycin A and Tyrphostin. The generation of CD4-CD8+ cells in unstimulated normal fetal thymus cultures was also markedly inhibited by the tyrosine kinase inhibitors but not by Cyclosporin A, suggesting that tyrosine kinase-dependent but calcineurin-independent signals were essential for the differentiation of CD4-CD8- thymocytes. Interestingly, the generation of CD4-CD8+ cells from the normal fetal thymus cultures was modestly but consistently enhanced by anti-TCR beta antibody, suggesting that functional TCR beta in addition to CD3 was expressed on normal CD4-CD8- immature thymocytes. On the other hand, anti-TCR delta antibody did not affect this differentiation in the normal fetal thymus cultures and the generation of CD4-CD8+ cells from the fetal thymus cultures of TCR delta-deficient mice was still enhanced by anti-TCR beta or anti-CD3 antibodies, indicating that either TCR delta chains or TCR delta+ cells were not involved in the control of the differentiation into CD4-CD8+ cells. These results indicate that the entry of CD4-CD8- immature thymocytes into the CD4/CD8 developmental pathway is controlled by tyrosine kinase signals and that these signals can be provided through the engagement of TCR-CD3 complexes with or without TCR beta chains expressed on the CD4-CD8- immature thymocytes.
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PMID:Entry of CD4-CD8- immature thymocytes into the CD4/CD8 developmental pathway is controlled by tyrosine kinase signals that can be provided through TCR components. 782 42

The repetitive C-terminal domain (CTD) of RNA polymerase (RNAP) II is extensively phosphorylated concomitant with the initiation of transcription and must be dephosphorylated before RNAP II can begin another round of transcription. A CTD phosphatase was purified more than 7,500-fold from a HeLa cell extract. SDS-polyacrylamide gel electrophoresis shows a predominant protein of 205 kDa and a less abundant protein of 150 kDa co-eluting with the CTD phosphatase activity. Sedimentation and gel filtration analysis suggest that CTD phosphatase has an elongated structure with a M(r) of 200,000. This enzyme is a type 2C phosphatase in that it requires Mg2+ for activity and is resistant to okadaic acid. CTD phosphatase appears to processively dephosphorylate the CTD and is specific in that it does not dephosphorylate phosphorylase a, the alpha or beta subunits of phosphorylase kinase or RNAP II phosphorylated with casein kinase II. CTD phosphatase dephosphorylates RNAP IIO purified from calf thymus or generated in vitro by two previously described CTD kinases. These results suggest that CTD phosphatase has the properties expected for a protein phosphatase that catalyzes the conversion of RNAP IIO to RNAP IIA and may play a key role in the transcription cycle of RNAP II.
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PMID:Purification and characterization of a phosphatase from HeLa cells which dephosphorylates the C-terminal domain of RNA polymerase II. 792 41

Bovine thymus nuclei contain a species of protein phosphatase-1 (PP-1N alpha) that can be partially activated by phosphorylation of an associated inhibitory polypeptide, NIPP-1, with protein kinase A [Beullens, Van Eynde, Bollen and Stalmans (1993) J. Biol. Chem. 268, 13172-13177]. Here it is shown that PP-1N alpha can also be activated 4-fold by phosphorylation of NIPP-1 with casein kinase-2. The effects of protein kinase A and casein kinase-2 were additive, yielding an enzyme with an activity close to that of the free catalytic subunit. Casein kinase-2 introduced up to 1.2 phosphate groups into purified NIPP-1 on serine and threonine residues. This phosphorylation was associated with a 14-fold increase in the concentration of NIPP-1 required for 50% inhibition of the type-1 catalytic subunit. The kinase-mediated inactivation of NIPP-1 could be reversed by incubation with the catalytic subunit of protein phosphatase-2A.
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PMID:Full activation of a nuclear species of protein phosphatase-1 by phosphorylation with protein kinase A and casein kinase-2. 811 Jan 79

We have recently purified two potent and specific inhibitory polypeptides of protein phosphatase-1 from the particulate fraction of bovine thymus nuclei (Beullens, M., Van Eynde, A., Stalmans, W., and Bollen, M. (1992) J. Biol. Chem. 267, 16538-16544). Here it is reported that these inhibitors, termed NIPP-1a (18 kDa) and NIPP-1b (16 kDa), are excellent substrates (Km = 0.1 microM) for phosphorylation by protein kinase A on both Ser and Thr residues. Phosphorylation was temporally closely related with an activation of NIPP-1. Maximal phosphorylation by protein kinase A (1.5 mol of phosphate/mol of NIPP-1) caused an 8-fold increase in the concentration of NIPP-1 required for half-complete inhibition of the catalytic subunit of protein phosphatase-1, irrespective of the concentration of the phosphatase. Phosphorylation decreased the binding of NIPP-1 to immobilized protein phosphatase-1. NIPP-1 could be efficiently and completely reactivated by incubation with the catalytic subunit of protein phosphatase-2A. The type-1 catalytic subunit was much less effective, however, even when present in a molar excess to NIPP-1. Chromatography of a salt extract of the particulate nuclear fraction of Mono Q revealed three species of PP-1. One of these species, termed PP-1N alpha, contained NIPP-1 as a subunit and could be activated 6-fold by incubation with protein kinase A under phosphorylating conditions. This activation of PP-1N alpha is opposite to the known inhibition of cytoplasmic species of protein phosphatase-1 by protein kinase A.
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PMID:Inactivation of nuclear inhibitory polypeptides of protein phosphatase-1 (NIPP-1) by protein kinase A. 839 Apr 58

Stimulation of the cAMP-dependent signaling pathway exerts an inhibitory effect on the proliferation and effector functions of T cells. The ability of T cells to form high intracellular levels of cAMP is acquired during development in the human thymus and is retained by the majority of mature peripheral T lymphocytes. Here we show that elevated cAMP levels in T cells correlate with the expression of the potent transcriptional repressor ICER (inducible cAMP early repressor) previously described in the hypothalamic-pituitary-gonadal axis. Further, in transcriptional assays in vivo, ICER inhibits calcineurin-mediated expression of the interleukin 2 promoter as well as Tax-mediated transactivation of the human T-lymphotropic virus type I (HTLV-I) promoter. Thus, the induction of ICER in T cells may play an important role in the cAMP-induced quiescence and the persistent latency of HTLV-I.
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PMID:cAMP inducibility of transcriptional repressor ICER in developing and mature human T lymphocytes. 862 71

We have applied an in vitro system that mimics thymic negative selection to investigate signaling pathways that may be important for the removal of autoreactive cells from the thymus. We sought to more precisely determine the contribution of calcium-dependent pathways to CD4+CD8+ thymocyte deletion that is mediated by either an antigenic peptide or a peptide analogue. We show that the requirement for external calcium influx is dependent upon the strength of the deleting ligand. Furthermore, these results correlate well with a requirement, under certain circumstances, for signaling through the calcium/calmodulin-dependent phosphatase calcineurin. The use of suboptimal stimuli may, therefore, be useful in revealing biochemical pathways important for CD4+CD8+ thymocyte negative selection.
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PMID:A role for calcium influx in setting the threshold for CD4+CD8+ thymocyte negative selection. 864 1


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