Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phosphorylation of tau protein promotes stability of the axonal cytoskeleton; aberrant tau phosphorylation is implicated in the biogenesis of paired helical filaments (PHF) seen in Alzheimer's disease. Protein kinases and phosphatases that modulate tau phosphorylation have been identified using in vitro techniques; however, the role of these enzymes in vivo has not been determined. We used intraventricular infusions of antisense oligodeoxynucleotides (ODNs) directed against the major brain isoforms of the Ca2+/calmodulin-dependent phosphatase calcineurin to determine how reduced activity of this enzyme would affect tau dephosphorylation. Five-day infusions of antisense ODNs (5 and 10 nmol/day) in rats decreased immunoreactive levels and activity of calcineurin throughout the brain; sense ODNs, scrambled ODNs, and infusion vehicle alone had no effect. When neocortical slices were prepared from antisense ODN-treated rats and incubated for 1 to 2 h in vitro, tau protein remained phosphorylated as determined by using the phosphorylation-sensitive monoclonal antibodies AT-180 (Thr231) and AT-270 (Thr181). In contrast, AT-180 and AT-270 sites were completely dephosphorylated during incubation of neocortical slices from vehicle-infused controls and sense ODN-treated rats. Neocortical slices from antisense-treated rats were incubated with the phosphatase inhibitors okadaic acid (100 nM; 10 microM) and FK-520 (5 microM); these preparations showed enhanced tau phosphorylation, consistent with a significant loss of calcineurin activity. Thus, we conclude that phosphorylation of at least two sites on tau protein, namely, Thr181 and Thr231, is regulated by calcineurin.
Mol Pharmacol 1999 Apr
PMID:Reduction of calcineurin activity in brain by antisense oligonucleotides leads to persistent phosphorylation of tau protein at Thr181 and Thr231. 1010 Oct 20

The target of the immunosuppressants cyclosporin A(CsA) and FK506 is calcineurin, a highly conserved protein phosphatase that is required for T-cell activation and the regulation of ion homeostasis in yeast. Here we identify two genes, PMR2B and LIC4 which, when overexpressed, suppress the cation-sensitive phenotype of yeast cells lacking calcineurin. PMR2B encodes a Na+/Li+-specific plasma membrane pump and is similar to PMR2A, whose expression is known to be regulated by calcineurin. LIC4 (lithium comvertas) encodes a novel 33-kDa protein with no identity to known proteins. LIC4 overexpression suppresses the Li+-sensitive phenotype of calcineurin mutants but not the defect in recovery from pheromone arrest or viability of calcineurin dependent mutants, indicating a specific role in cation homeostasis. Similarly, lic4 mutations increase the Li+ sensitivity of both wild-type and calcineurin mutant strains, and reduce expression of pmr2A in calcineurin mutant strains, indicating that calcineurin and Lic4 may regulate parallel cation homeostatic pathways. lic4 mutations also exacerbate the Li+-sensitive phenotype of hal3 mutant strains, and overexpression of either Lic4 or Hal3 suppresses the salt sensitivity of mutant strains lacking calcineurin, Hal3, or Lic4, either singly or in combination. Taken together, these observations suggest that calcineurin, Hal3, and Lic4 cooperatively regulate the response of yeast cells to cation stress. Lic4 is phosphoprotein in vivo and a calcineurin substrate in vitro. By indirect and direct immunofluorescence detection of HA- and GFP-tagged proteins, Lic4 is localized in the nucleus in wild-type cells but predominantly cytoplasmic in cells lacking calcineurin. Taken together, our findings support a model in which calcineurin and Lic4 are components of signalling cascades that regulate cation stress responses in yeast.
Mol Gen Genet 1999 Mar
PMID:Lic4, a nuclear phosphoprotein that cooperates with calcineurin to regulate cation homeostasis in Saccharomyces cerevisiae. 1010 75

Glucose induces an increase in the intracellular Ca2+ concentration in pancreatic beta-cells to secrete insulin. CD38 occurs in beta-cells and has both ADP-ribosyl cyclase, which catalyzes the formation of cyclic ADP-ribose (cADPR) from NAD+, and cADPR hydrolase, which converts cADPR to ADP-ribose. ATP, produced by glucose metabolism, competes with cADPR for the binding site, Lys-129, of CD38, resulting in the inhibition of the hydrolysis of cADPR and thereby causing cADPR accumulation in beta-cells. Cyclic ADP-ribose then binds to FK506-binding protein 12.6 in the ryanodine receptor Ca2+ channel (RyR), dissociating the binding protein from RyR to induce the release of Ca2+ from the endoplasmic reticulum. Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) phosphorylates RyR to sensitize and activate the Ca2+ channel. Ca2+, released from the RyR, further activates CaM kinase II and amplifies the process. Thus, cADPR acts as a second messenger for Ca2+ mobilization to secrete insulin. The novel mechanism of insulin secretion described above is different from the conventional hypothesis in which Ca2+ influx from extracellular sources plays a role in insulin secretion by glucose.
Mol Cell Biochem 1999 Mar
PMID:The CD38-cyclic ADP-ribose signaling system in insulin secretion. 1033 47

Two major protein phosphatase (PP) activities were purified from cytosolic extracts of the erythrocytic stage of the malaria parasite, Plasmodium falciparum. Both enzymes were specific for phosphoserine and phosphothreonine residues with very little activity against phosphotyrosine residues. The biochemical properties of the enzymes suggested their strong similarity with eukaryotic PP2A and PP2B protein phosphatases. Both enzymes preferentially dephosphorylated the alpha subunit of phosphorylase kinase, and were resistant to inhibitor-1. The PP2A-like enzyme required Mn2+ for activity and was inhibited by nanomolar concentrations of okadaic acid (OA). The cDNA sequence of the PP2A-like enzyme was identified through a match of its predicted amino acid sequence with the N-terminal sequence of the catalytic subunit. The PP2B-like (calcineurin) enzyme was stimulated by calmodulin and Ca2+ or Ni2+, but was resistant to OA. Malarial calcineurin was strongly and specifically inhibited by cyclosporin A (CsA) only in the presence of wild type P. falciparum cyclophilin but not a mutant cyclophilin. The inhibition was noncompetitive, and provides a potential explanation for the cyclosporin-sensitivity of the parasite. There was no significant quantitative difference in the total protein Ser/Thr phosphatase activity among the ring, trophozoite, and schizont stages.
Mol Biochem Parasitol 1999 Apr 30
PMID:Characterization of protein Ser/Thr phosphatases of the malaria parasite, Plasmodium falciparum: inhibition of the parasitic calcineurin by cyclophilin-cyclosporin complex. 1034 Apr 82

Prolactin (PRL) is produced in human thymocytes, T-cells and endometrium. In these extrapituitary tissues, PRL gene transcription is directed by an alternative upstream promoter, and it is thought to act as a locally produced cytokine, with relevance for immune regulation and modulation of T-cell function. We have studied PRL transcriptional regulation in the human T-lymphoblastoid Jurkat cell line transfected with a fragment of the upstream promoter linked to luciferase. A cAMP analogue (cptAMP) increased promoter activity rapidly and dose dependently. This increase was resistant to inhibition by cyclosporin A and thus independent of calcineurin phosphatase (CN). T-cell activation by phorbol myristate acetate (PMA) failed to enhance promoter activity but phytohaemagglutinin (PHA) alone or PHA+PMA increased it, and cptAMP acted in synergy with PMA or PHA to increase it further. H-89, a cAMP-dependent protein kinase A (PKA) inhibitor, inhibited the effect of cptAMP as did transfection with protein kinase inhibitor PKI, an expression vector of the specific inhibitor of PKA. A single point mutation in the CRE (cAMP response element) located at -25 bp in the PRL upstream promoter (TGACGT to TGCCGT) failed to reduce the response to cptAMP, while mutations or deletion of four nucleotides in the CRE to TACTCT diminished the response to cAMP by more than half. We conclude that activity of the human PRL upstream extrapituitary promoter can be induced by activators of T-cells, as well as by a cAMP analogue. The signal is transmitted by PKA and the effect of cAMP is independent of CN. It is partly dependent on an intact proximal CRE motif but a more upstream enhancer may contribute to promoter regulation.
J Mol Endocrinol 1999 Jun
PMID:The human prolactin gene upstream promoter is regulated in lymphoid cells by activators of T-cells and by cAMP. 1034 87

The immunosuppressants cyclosporin A and FK506 (tacrolimus) can block the phosphatase calcineurin, thereby inhibiting gene transcription directed by the cyclic AMP (cAMP)- and calcium-responsive transcription factor, cAMP response element (CRE)-binding protein, and its binding site, CRE, in various cell lines. This action is a novel molecular mechanism of cyclosporin A and FK506 action. Because inhibition of CREB/CRE-directed transcription by cyclosporin A and FK506 has previously been observed by using synthetic minienhancers, reporter fusion genes were constructed to examine the effect of cyclosporin A and FK506 on the transcriptional activity of CRE-containing natural promoters. In transient transfection experiments, cyclosporin A and FK506 inhibited the transcriptional activation by cAMP and the membrane depolarization of three CRE-containing promoters. However, cyclosporin A and FK506 failed to inhibit the activation by cAMP of another promoter, the rat insulin I gene promoter. The lack of cyclosporin A/FK506 sensitivity is not intrinsic to the insulin CRE because cyclosporin A and FK506 inhibited the activation by cAMP of the insulin CRE when isolated and used as a synthetic minienhancer. Rather, cyclosporin A/FK506 resistance may be conferred by specific promoter interactions because a mutational analysis of the insulin promoter revealed that inside this promoter, CRE activity depends on an adjacent control element. These data show that cyclosporin A and FK506 can inhibit CRE activity when the CRE resides in its natural promoter. However, the cyclosporin A/FK506 sensitivity depends on the specific promoter context. The results suggest that cyclosporin A and FK506 may alter target tissue function through the regulation of a subset of CRE-containing genes.
Mol Pharmacol 1999 Jun
PMID:Inhibition of cyclic AMP response element-binding protein/cyclic AMP response element-mediated transcription by the immunosuppressive drugs cyclosporin A and FK506 depends on the promoter context. 1034 53

Previous work has provided conclusive support for a role of various protein kinases in processes underlying learning and memory formation. While these processes are not yet established in full detail, it is interesting to entertain the idea of protein phosphatases being involved in such mechanisms as well. Recent advances in this respect have provided preliminary support of this view. From the pharmacological as well as the transgenic analysis, it appears that especially the calcineurin/inhibitor-1 cascade plays an important role in the transition of intermediate-term into long-term memory formation.
Cell Mol Life Sci 1999 Apr
PMID:If phosphatases go up, memory goes down. 1035 25

Signal transduction mediated by the single yeast isozyme of protein kinase C (Pkc1p) is essential for the maintenance of cellular integrity in this model eukaryote. The past few years have seen a dramatic increase in our knowledge of the upstream regulatory factors that modulate Pkc1p activity (e.g. Tor2p, Rom1p, Rom2p, Rho1p, Slg1p, Mid2p) and of the downstream targets of the MAP kinase cascade triggered by it (e.g. Rlm1p, SBF complex). The picture that has emerged connects this pathway to a variety of other cellular processes, such as cell cycle progression (Cdc28p, Swi4p), mating (Ste20p), nutrient sensing (Ira1p), calcium homeostasis (calcineurin, Mid2p, Fks2p) and the structural dynamics of the cytoskeleton (Spa1p, Bni1p).
Mol Microbiol 1999 May
PMID:The protein kinase C-mediated MAP kinase pathway involved in the maintenance of cellular integrity in Saccharomyces cerevisiae. 1036 Dec 72

Treatment of C2-C12 mouse myoblasts with the immunosuppressant drug cyclosporin A (CsA) enhances the increase in acetylcholinesterase (AChE) expression observed during skeletal muscle differentiation. The enhanced AChE expression is due primarily to increased mRNA stability because CsA treatment increases the half-life of AChE mRNA, but not the apparent transcriptional rate of the gene. Neither tacrolimus (FK506), an immunosuppressive agent with a distinct structure, nor cyclosporine H, an inactive congener of CsA, alters AChE expression. The enhanced AChE expression is associated with the muscle differentiation process, but cannot be triggered by CsA exposure before differentiation. Myoblasts and myotubes of C2-C12 cells express similar amounts of cyclophilin A and FKBP12, immunophilins known to be intracellular-binding targets for CsA and tacrolimus, respectively. However, cellular levels of calcineurin, a calcium/calmodulin-dependent phosphatase known to be the cellular target of ligand-immunophilin complexes, increase 3-fold during myogenesis. Overexpression of constitutively active calcineurin in differentiating cells reduces AChE mRNA levels and CsA antagonizes such an inhibition. Conversely, overexpression of a dominant negative calcineurin construct increases AChE mRNA levels, which are further enhanced by CsA. Thus, a CsA sensitive, calcineurin mediated pathway appears linked to differentiation-induced stabilization of AChE mRNA during myogenesis.
Mol Pharmacol 1999 Nov
PMID:Calcineurin enhances acetylcholinesterase mRNA stability during C2-C12 muscle cell differentiation. 1053 91

In several moth species sex pheromone production in the pheromone gland is regulated by a neurohormone, pheromone biosynthesis activating neuropeptide (PBAN). In Bombyx mori it is suggested that PBAN, after binding to the cell-surface receptor, primarily activates a plasma membrane receptor-activated Ca2+ channel to increase cytosolic levels of Ca2+, and Ca2+/calmodulin complex directly or indirectly activates a phosphoprotein phosphatase, which in turn elicits activation of acyl CoA reductase (the key enzyme under PBAN control) through dephosphorylation, resulting in pheromone (bombykol) production. The effect of cyclosporin A (CsA) and FK 506, specific inhibitors of calcineurin (phosphoprotein phosphatase 2B) was studied on the sex pheromone production, in B. mori. The in vitro experiments showed that both chemicals exerted a dose-dependent inhibitory action when they were co-incubated with TKYFSPRL amide (Hez-PBAN fragment peptide). Practically, no difference was detected between the two chemicals in the tested doses (0.025-1250 microM). When effects of CsA or FK 506 were studied on cell-free production of bombykol by using microsomal fraction no inhibition was detected. Since microsomal fraction contains the acyl CoA synthetase, the rate-limiting acyl CoA reductase and the precursor, bombykol is produced if supplied with CoA, ATP and NADPH. Thus, the inhibitory action of CsA and FK506 under in vitro conditions should occur before the step of acyl group reduction and the effect is likely to be attributable to the inhibition of calcineurin in the signal transduction cascade mechanism of PBAN, in B. mori. The existence of calcineurin in the pheromone gland by using Western blot analysis is also demonstrated.
Comp Biochem Physiol B Biochem Mol Biol 1999 Sep
PMID:Involvement of calcineurin in the signal transduction of PBAN in the silkworm, Bombyx mori (Lepidoptera). 1058 20


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