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)

Microtubule-associated protein tau is abnormally hyperphosphorylated in the brain of patients with Alzheimer's disease, and is the major protein subunit of paired helical filaments. There is also a significant pool of non-paired helical filament abnormally phosphorylated tau in Alzheimer's disease brain. In the present study, the site-specific dephosphorylation of this Alzheimer's disease abnormally phosphorylated tau by protein phosphatase-2A was studied and compared with that by protein phosphatase-2B. The dephosphorylation was detected by its interaction with several phosphorylation-dependent antibodies to various abnormal phosphorylation sites. Protein phosphatase-2A was able to dephosphorylate the abnormally phosphorylated tau at Ser-46, Ser-199, Ser-202, Ser-396 and Ser-404, but not at Ser-235 (the amino acids are numbered according to the largest isoform of human tau, tau441). Two major types of protein phosphatase-2A, protein phosphatase-2A1 and -2A2, dephosphorylated the abnormally phosphorylated tau at approximately the same rate. After the abnormally phosphorylated tau was dephosphorylated by protein phosphatase-2A, its relative mobility on sodium dodecyl sulfate-polyacrylamide gel electrophoresis increased. The dephosphorylation of the abnormal tau by protein phosphatase-2A1 and -2A2 was markedly stimulated by Mn2+. These results suggest that tau dephosphorylation is catalysed by protein phosphatase-2A in addition to protein phosphatase-2B. A deficiency of either protein phosphatase-2A or -2B, or both, may be involved in abnormal phosphorylation of tau in Alzheimer's disease.
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PMID:Dephosphorylation of Alzheimer's disease abnormally phosphorylated tau by protein phosphatase-2A. 783 76

Abnormally hyperphosphorylated tau is the major protein subunit of paired helical filaments in Alzheimer brains. We have examined its site-specific dephosphorylation by different protein phosphatases. Dephosphorylation of tau was monitored by its interaction with several phosphorylation-dependent antibodies. Alzheimer tau was dephosphorylated by brain protein phosphatase-2B at the abnormally phosphorylated sites Ser46, Ser199, Ser202, Ser235, Ser396, and Ser404, and its relative mobility on sodium dodecyl sulfate-polyacrylamide gel electrophoresis shifted to that of normal tau. Protein phosphatases-1 and -2A could dephosphorylate only some of the above six phosphorylation sites. These results indicate that protein phosphatase-2B might be involved in hyperphosphorylation of tau in Alzheimer's disease.
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PMID:Alzheimer's disease abnormally phosphorylated tau is dephosphorylated by protein phosphatase-2B (calcineurin). 829 42

Mg-ATP-dependent protein phosphatase activating factor [kinase FA/glycogen synthase kinase 3 (GSK-3)] has been identified in highly purified clathrin-coated vesicles (CCVs) isolated from pig brain. Kinase FA was found to exist in an inactive state but can be activated by 1% Triton X-100 or 1 M Tris-HCl extraction in brain CCVs. Activation of kinase FA in CCVs is due to disassociation of the kinase from CCVs as demonstrated on sucrose density-gradient ultracentrifugation and Sepharose CL-4B gel filtration. Using purified brain CCVs as substrates, kinase FA enhanced the endogenous phosphorylation of assembly protein complexes in the molecular weight range of 100,000-130,000 severalfold, as demonstrated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by autoradiography. Comparisons with well-defined brain CCV-associated endogenous protein kinases such as pp50 kinase/AP50 and casein kinase 2 provide evidence that kinase FA/GSK-3 represents a third potent and unique CCV-associated protein kinase distinctly different from the previously described CCV protein kinases, suggesting the possible involvement of kinase FA in the regulation of CCV functions in the brain. The results also support the notion that protein kinase FA is involved in cell surface signal transduction in the CNS.
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PMID:Identification and characterization of protein kinase FA/glycogen synthase kinase 3 in clathrin-coated brain vesicles. 838 21

The trimeric form of protein phosphatase 2A consisting of 36-, 65-, and 72-kDa subunits (previously termed polycation-stimulated protein phosphatase M) was purified from rabbit skeletal muscle. Amino acid sequence data of the 72-kDa regulatory subunit (termed PR72) were used to isolate cDNAs from human heart and fetal brain libraries and libraries derived from WI-38 and MCF-7 cells. The clones isolated from the heart cDNA library revealed an open reading frame encoding a protein with a predicted molecular mass of 62 kDa. All the peptides sequenced from the protein matched with the sequence predicted from the cDNA. However, in vitro transcription and translation from this cDNA yielded a protein with an apparent molecular mass of 72 kDa on sodium dodecyl sulfate-polyacrylamide gels. From brain we isolated cDNA clones spanning an open reading frame encoding a 130-kDa protein (termed PR130). The apparent molecular mass of the protein produced by in vitro transcription and translation was 130 kDa. This protein has exactly the same deduced C-terminal protein sequence as the PR72 subunit from amino acids 45 to 527 but has an N-terminal extension of 665 amino acids. It is likely, therefore, that these two proteins arise from the same gene by alternative splicing. In human tissues several transcripts were detected by Northern analysis generated probably by the use of different polyadenylation signals and alternative splicing. High levels of the PR72 mRNAs were detected in heart and muscle, while lower levels of PR130 transcripts were found in heart, brain, placenta, lung, muscle, and kidney.
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PMID:Structure and expression of a 72-kDa regulatory subunit of protein phosphatase 2A. Evidence for different size forms produced by alternative splicing. 839 71

Two myelin basic protein kinases designated MBPK-1 and MBPK-2 were purified to apparent homogeneity from extracts of bovine kidney cortex. The purified preparations exhibited an apparent M(r) approximately 40,000 by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and approximately 42,000 (MBPK-1) and 45,000 (MBPK-2) by gel permeation chromatography. Up to 0.4 and 1.8 mol of phosphoryl groups were incorporated per mol of MBPK-1 and MBPK-2, respectively, on threonines following incubation with ATP. Autophosphorylation, incubation with protein phosphatase 2A2 (PP2A2), CD45, or T-cell protein tyrosine phosphatase did not affect MBPK-1 activity. Autophosphorylation increased by about 3-fold MBPK-2 activity. This autophosphorylation and activation was reversed by PP2A2 but not by CD45 or T-cell protein tyrosine phosphatase. MBPK-1 and MBPK-2 displayed a positive reaction with an antibody to mitogen-activated protein kinase. Purified preparations of protamine kinase were activated by about 1.5-6-fold and, after inactivation with PP2A2, were reactivated by about 30% by MBPK-1 and MBPK-2. Activation and reactivation correlated with the incorporation, respectively, of 0.1-0.5 and 0.5 mol of phosphoryl groups/mol of the protamine kinase on serines. The results show that MBPK-1 and MBPK-2 are protamine kinase-activating kinases and suggest that MBPK-1 and MBPK-2 may be related to mitogen-activated protein kinase.
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PMID:Phosphorylation and activation of protamine kinase by two forms of a myelin basic protein kinase from extracts of bovine kidney cortex. 839 73

Hyperphosphorylated forms of the microtubule-associated protein tau are components of the paired helical filaments (PHFs) seen in patients with Alzheimer's disease. Slices of human lateral temporal cortex were obtained from tissues removed incidental to resections for intractable hippocampal epilepsy. Tau phosphorylation in temporal lobe slices was determined using mobility shifts after sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunodetection with the monoclonal antibodies Alz-50, 5E2, and Tau-1. The results indicate that tau phosphorylation was altered in a dose-dependent manner by the phosphatase inhibitor okadaic acid, but not by N-methyl-D-aspartate, quisqualate, or kainate. The slowest mobility forms of tau, termed "PHF-like tau," produced by okadaic acid treatment were dephosphorylated by purified protein phosphatase 2B (calcineurin). Formation of PHF-like tau peptides was blocked by KN-62, 1[N,O-bis(1,5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazi ne, an inhibitor of Ca2+/calmodulin-dependent protein kinase II. The protein kinase inhibitor staurosporine also prevented formation of PHF-like tau. These data suggest that phosphorylation of tau is regulated by Ca(2+)-dependent protein kinases and okadaic acid-sensitive protein phosphatases, alterations of which may be implicated in the pathogenesis of Alzheimer's disease.
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PMID:Okadaic acid induces hyperphosphorylated forms of tau protein in human brain slices. 849 35

Whether the anabolic effect of insulin-like growth factor-I (IGF-I) in osteoblastic MC3T3-E1 cells is modulated by zinc, an activator of bone formation, was investigated in vitro. After subculture for 3 days, the cells were cultured for 72 h with IGF-I (10(-8) M). The peptide produced a significant increase of protein concentration, deoxyribonucleic acid (DNA) content, and cell number in the cells. These increases were markedly enhanced by the presence of zinc sulfate (10(-5) M), but not zinc-chelating dipeptide (beta-alanyl-L-histidinato zinc; 10(-5) M). Also, the cellular alkaline phosphatase activity was synergistically increased by the presence of both IGF-I and zinc sulfate. Thus, effect was not seen in the presence of both insulin (10(-8) M) and zinc sulfate (10(-5) M). The effect of zinc sulfate to enhance the IGF-I-increased alkaline phosphatase activity and protein concentration in the cells was clearly prevented by the presence of cycloheximide (10(-6) M), staurosporin (10(-8) M), or okadaic acid (10(-7) M) with an effective concentration. However, staurosporin had a partial inhibiting effect on the IGF-I or the IGF-I plus zinc-induced increases in cellular protein, although okadaic acid entirely blocked the IGF-I or the IGF-I plus zinc effect. The present study demonstrates that the anabolic effect of IGF-I in osteoblastic cells is enhanced by zinc ion. The enhancement by zinc may be mediated through the signaling pathway of protein kinase C and protein phosphatase in the cells.
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PMID:Zinc modulation of insulin-like growth factor's effect in osteoblastic MC3T3-E1 cells. 853 89

Salt tolerance of crops could be improved by genetic engineering if basic questions on mechanisms of salt toxicity and defense responses could be solved at the molecular level. Mutant plants accumulating proline and transgenic plants engineered to accumulate mannitol or fructans exhibit improved salt tolerance. A target of salt toxicity has been identified in Saccharomyces cerevisiae: it is a sodium-sensitive nucleotidase involved in sulfate activation and encoded by the HAL2 gene. The major sodium-extrusion system of S. cerevisiae is a P-ATPase encoded by the ENA1 gene. The regulatory system of ENA1 expression includes the protein phosphatase calcineurin and the product of the HAL3 gene. In Escherichia coli, the Na(+)-H+ antiporter encoded by the nhaA gene is essential for salt tolerance. No sodium transport system has been identified at the molecular level in plants. Ion transport at the vacuole is of crucial importance for salt accumulation in this compartment, a conspicuous feature of halophytic plants. The primary sensors of osmotic stress have been identified only in E. coli. In S. cerevisiae, a protein kinase cascade (the HOG pathway) mediates the osmotic induction of many, but not all, stress-responsive genes. In plants, the hormone abscisic acid mediates many stress responses and both a protein phosphatase and a transcription factor (encoded by the ABI1 and ABI3 genes, respectively) participate in its action.
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PMID:Salt tolerance in plants and microorganisms: toxicity targets and defense responses. 890 Sep 56

Whether deoxyribonucleic acid (DNA) synthesis in osteoblastic MC3T3-E1 cells is stimulated by zinc, an activator of bone formation, was investigated in vitro. After subculture for 3 days, the cells were cultured for up to 3 days (72 h) with zinc sulfate or zinc-chelated dipeptide (beta-alanyl-L-histidinato zinc; AHZ) in the range of 10(-7) to 10(-5) M. The culture with zinc compounds (10(-5) M) produced a significant increase of cell number, DNA content, and protein concentration in the cells, as reported previously. The culture with zinc compounds (10(-6) and 10(-5) M) clearly stimulated DNA synthesis in the homogenate, when it was estimated by the incorporation of [3H]deoxythymidine 5'-triphosphate into the DNA in the homogenate of cells. The AHZ effect was greater than that of zinc sulfate. The culture together with cycloheximide (19(-6) M) completely abolished the zinc compounds (10(-5) M)-induced increase of DNA synthesis in the cells, suggesting that the zinc compound effect is based on a newly synthesized protein component. Moreover, when zinc sulfate (10(-7) and 10(-6) M) or AHZ (10(-8) to 10(-5) M) was added into the reaction mixture with the homogenate of cells cultured without zinc compounds, the DNA synthesis was clearly increased. The effect of addition of zinc compounds (10(-6) M) on the DNA synthesis was completely inhibited by the presence of staurosporine (10(-8) M), an inhibitor of protein kinase C, or okadaic acid (10(-7) M), an inhibitor of protein phosphatase. The present study demonstrates that zinc compounds have a stimulatory effect on DNA synthesis in osteoblastic cells.
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PMID:Stimulatory effect of zinc-chelating dipeptide on deoxyribonucleic acid synthesis in osteoblastic MC3T3-E1 cells. 895 58

The anabolic effect of 17beta-estradiol in osteoblastic MC3T3-E1 cells was investigated. The cells were cultured for 3 days in the medium containing either vehicle or 17beta-estradiol (10(-11)-10(-9) M). 17beta-Estradiol significantly increased alkaline phosphatase activity and protein concentration in the cells. The steroid (10(-9) M) also significantly elevated the cell numbers and the cellular DNA content. The anabolic effect by 17beta-estradiol was blocked by the presence of dipicolinate (10(-3) M), a chelator of zinc ion, suggesting a role of cellular zinc in osteoblastic cell function. The presence of zinc sulfate (10(-5) M) or beta-alanyl-L-histidinato zinc (AHZ) (10(-5) M) significantly enhanced the 17beta-estradiol (10(-10) or 10(-9) M)-induced increase of alkaline phosphatase activity and protein concentration in the cells; the effect of AHZ was greater than that of zinc sulfate. The enhancement by zinc compounds was not based on the augmentation of osteoblastic cell numbers. The co-addition of cycloheximide (10(-6) M), an inhibitor of protein synthesis, completely blocked the zinc compound (10(-5) M)-induced enhancement of 17beta-estradiol's (10(-9) M) effect to increase alkaline phosphatase activity and protein concentration in the cells. Moreover, the anabolic effect of 17beta-estradiol together with or without zinc compounds was abolished by the presence of staurosporine (10(-8) M), an inhibitor of protein kinase C, or of okadaic acid (10(-7) M), an inhibitor of protein phosphatase. The present study demonstrates that the anabolic effect of 17beta-estradiol is enhanced by zinc-chelating dipeptide in osteoblastic MC3T3-E1 cells, and that the enhancing effect may involve protein synthesis and protein kinase activity.
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PMID:Zinc enhancement of 17beta-estradiol's anabolic effect in osteoblastic MC3T3-E1 cells. 916 27


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