UNIPROT:P10636 - FACTA Search

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Query: UNIPROT:P10636 (tau protein)
5,110 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ceramide has been recently proposed to be a signal mediator in several important physiological processes including apoptosis, cellular growth, and differentiation. Because the microtubule-associated protein tau plays an important role in the establishment and maintenance of neuronal morphology, the effects of ceramide on tau were examined. Treatment of differentiated PC12 cells with the cell-permeable ceramide derivative N-acetylsphingosine (C2) resulted in a significant reduction in tau levels. Significant decreases in tau levels were also observed when the cells were treated with another ceramide derivative, N-hexanoylsphingosine (C6). In addition, C2 treatment increased the levels of a calpain-derived spectrin breakdown product but did not alter the levels of two cytoskeletal proteins, alpha-actin and alpha-tubulin. Because both tau and spectrin are proteolyzed in vitro by the calcium-activated cysteine protease calpain, the effects of ceramide analogues on the activity of this protease were examined. Treatment of PC12 cells with C2 enhanced calcium-stimulated proteolytic activity significantly, as revealed by monitoring the hydrolysis of the membrane-permeable calpain-selective fluorescence probe N-succinyl-L-leucyl-L-leucyl-L-valyl-L-tyrosine-7-amido-4-methylcoumarin . This activity increase was not due to a direct effect of C2 on calpains, because C2 did not alter the activities of purified calpain I or II. In addition, C2 treatment of PC12 cells resulted in a significant increase in the levels of calpain I and, to a lesser extent, the levels of calpastatin (an endogenous calpain inhibitor protein), whereas the levels of calpain II were not changed. Moreover, treatment of the cells with the synthetic calpain-specific inhibitor N-carbobenzoxy-L-leucyl-L-leucyl-L-tyrosine diazomethyl ketone blocked the C2-induced decreases in tau levels. These results indicate that tau levels are regulated in response to a physiological factor and, thus, have implications for ceramide-mediated changes in normal and pathological neuronal processes.
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PMID:Ceramide selectively decreases tau levels in differentiated PC12 cells through modulation of calpain I. 928 24

Nitric oxide (NO.) can induce transient [Ca2+] changes in endothelial cells not different from receptor mediated signalling. Whether this Ca2+ signal may provide a link with IL-8 secretion induced by NO. donors was investigated in human endothelial cells. Sodium nitroprusside (SNP) and S-nitroso-N-acetyl-DL-penicillamine (SNAP) dose dependently increased IL-8 production in this cell type. Additive IL-8 secretion was found with TNFalpha. Buffering intracellular Ca2+ with MAPT/AM suppressed NO. induced [Ca2+]i changes and reduced subsequent IL-8 secretion. The additive effect of both NO. donors on TNFalpha induced IL-8 secretion was completely blocked in the presence of MAPT/AM. SKF 96365, which has been shown to block receptor mediated Ca2+ entry, and TMB-8, which blocks intracellular Ca2+ release, both inhibited IL-8 secretion, particularly when TNFalpha was used as a costimulator, indicating that [Ca2+]i changes are important components of IL-8 induction by NO..
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PMID:Intracellular Ca2+ dependence of nitric oxide mediated enhancement of interleukin-8 secretion in human endothelial cells. 935 Sep 89

Previous studies have demonstrated that the two cysteine residues in the calcium-binding protein S100B are required for its extracellular functions. In the present study, a recombinant S100B protein and mutant S100Bs containing one or no cysteine residue(s) have been used to determine the contribution of cysteine residues to S100B dimerization and interaction with the intracellular target proteins aldolase, phosphoglucomutase, and the microtubule associated tau protein. Mutation of C68 to a valine or C84 to a serine, C68 to valine and C84 to serine, or C68 to valine and C84 to alanine did not significantly alter S100B activation of aldolase. However, mutation of C84 to serine resulted in calcium-independent S100B activation of phosphoglucomutase and a loss of S100B inhibition of tau phosphorylation by Ca2+/calmodulin-dependent protein kinase II. The altered functionality of the C84S mutant with phosphoglucomutase and tau was not due to altered physical properties or dimerization state. All of the mutants exhibited heat stability and calcium dependent conformational changes which were identical to recombinant S100B. In addition, S100B proteins containing two, one or no cysteine residues behaved as dimers in size exclusion chromatography experiments in the presence or absence of calcium as well as in the presence or absence of reducing agent. Dynamic light scattering and analytical ultracentrifugation experiments confirmed that dimerization was not affected by calcium or reducing agent. Altogether these results demonstrate that S100B dimerization is not calcium- or sulfhydryl-dependent. In summary, cysteine residues are not necessary for the noncovalent dimerization of S100B, but are important in certain S100B target protein-interactions.
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PMID:The role of cysteine residues in S100B dimerization and regulation of target protein activity. 942 66

Previous studies have shown that treating rat cortical neurons in primary culture with apolipoprotein E (apoE) peptide increased cytoplasmic Ca2+ by 2 mechanisms: 1) an influx of extracellular Ca2+ resulting from the activation of a cell surface Ca2+ channel; and 2) release of Ca2+ from internal Ca2+ stores via a G-protein-coupled pathway (Wang and Gruenstein, 1997). These studies employed a biologically active apoE synthetic peptide (apoEdp) derived from the receptor binding domain of apoE. In the present study we examined whether activation of these 2 signal transduction pathways affects phosphorylation of microtubule-associated protein tau. The levels of tau phosphorylation at thr231, ser235, and ser396 were quantified by ELISA employing monoclonal antibodies PHF-6, SMI33, and PHF-1. ApoEdp treatment resulted in a concentration- and time-dependent dephosphorylation of tau at all 3 phosphorylation sites. The apoEdp-induced dephosphorylation of tau at thr231, and ser235 was dependent on the influx of extracellular Ca2+, while dephosphorylation at ser396 was mediated by a pertusis toxin-sensitive G-protein pathway. The involvement of protein phosphatases in mediating the apoEdp-induced dephosphorylation of tau was examined. Pretreatment with the protein phosphatase 2B inhibitor cyclosporin A blocked the apoEdp-induced dephosphorylation of tau at thr231 and ser235 but not at ser396. Pretreatment with the protein phosophatase 2A/1 inhibitor okadaic acid blocked the apoEdp-induced dephosphorylation of tau at all 3 sites, while pretreatment with the protein phosphates 1 inhibitor tautomycin was without effect. The present study suggests that apoE may affect several Ca2+-associated signal transduction pathways that increase the activity of protein phosphatases 2A and 2B, which in turn dephosphorylate tau.
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PMID:Apolipoprotein E (ApoE) peptide regulates tau phosphorylation via two different signaling pathways. 951 10

Epithelial cells play an important role in maintaining the intestinal mucosa barrier, a barrier that is impaired in several inflammatory conditions. The mechanisms behind this impairment are not known, but it can be presumed that structural alterations of the epithelial cells are involved. In support of this notion, we here show the inflammatory mediator leukotriene D4 (LTD4) triggered first a rapid (10 s) increase and immediately thereafter (30 s) a sustained decrease in the cellular filamentous actin (F-actin) level in intestinal epithelial cells. The initial LTD4-induced increase in F-actin content was effectively blocked by preincubating the cells with either pertussis toxin or the tyrosine kinase inhibitor genistein. A possible involvement of the tyrosine kinase-dependent phosphatidylinositol-3-kinase (PI-3-kinase) in the polymerisation of actin was supported by the observations that LTD4 induced a translocation to a membrane fraction of PI-3-kinase and by the findings that wortmannin, a PI-3-kinase inhibitor, totally abolished both this translocation of PI-3-kinase as well as the initial LTD4-induced polymerisation of actin. In addition, pertussis toxin and genistein, both known to interfere with the LTD4-induced calcium signal, completely or partially reversed the actin-depolymerising effect of LTD4. The calcium ionophore ionomycin (30s) induced actin depolymerisation to the same extent as LTD4 (30 s) did, but lacked the initial effect on actin polymerisation. In cells loaded with the calcium chelator MAPT, LTD4 induced a normal actin polymerisation response but the subsequent depolymerisation was completely inhibited. Similar results were obtained when the cells were preincubated with the protein kinase A inhibitor Rp-cAMPS, which has been shown to impair the LTD4-induced calcium signal in these epithelial cells. The present results show that the inflammatory mediator LTD4 triggers a reorganisation of the actin network in intestinal epithelial cells that is likely to contribute to the impairment of the intestinal barrier function.
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PMID:The inflammatory mediator leukotriene D4 triggers a rapid reorganisation of the actin cytoskeleton in human intestinal epithelial cells. 971 65

Excitatory amino acids may promote microtubular proteolysis observed in ischemic neuronal degeneration by calcium-mediated activation of calpain, a neutral protease. We tested this hypothesis in an animal model of focal cerebral ischemia without reperfusion. Spontaneously hypertensive rats were treated with 2, 3-dihydroxy-6-nitro-7-sulfamoyl-benzo-(F)quinoxaline (NBQX), a competitive antagonist of the neuronal receptor for alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), or cis-4-[phosphono-methyl]-2-piperidine carboxylic acid (CGS 19755), a competitive antagonist of the N-methyl-d-aspartate (NMDA) receptor. After treatment, all animals were subjected to permanent occlusion of the middle cerebral artery for 6 or 24 h. Infarct volumes measured in animals pretreated with CGS 19755 after 24 h of ischemia were significantly smaller than those quantified in ischemic controls. Rats pretreated with NBQX showed partial amelioration of cytoskeletal injury with preserved immunolabeling of microtubule-associated protein 2 (MAP 2) at 6 and 24 h and reduced accumulation of calpain-cleaved spectrin byproducts only at 6 h. Prevention of cytoskeletal damage was more effective after pretreatment with CGS 19755, as shown by retention of MAP 2 immunolabeling and significant restriction of calpain activity at both 6 and 24 h. Preserved immunolabeling of tau protein was observed at 6 and 24 h only in animals pretreated with CGS 19755. Western analysis performed on ischemic cortex taken from controls or rats pretreated with either NBQX or CGS 19755 suggested that loss of tau protein immunoreactivity was caused by dephosphorylation, rather than proteolysis. These results demonstrate a crucial link between excitotoxic neurotransmission, microtubular proteolysis, and neuronal degeneration in focal cerebral ischemia.
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PMID:Glutamate receptor antagonists inhibit calpain-mediated cytoskeletal proteolysis in focal cerebral ischemia. 981 16

The molecular mechanism of pathological aggregation of microtubule-associated protein tau during neurodegeneration is unclear. In the present study, the in vitro effect of various metal ions on the aggregation of tau was examined using paired helical filament tau (PHF-tau) obtained from corticobasal degeneration (CBD) and Alzheimer's disease (AD) brains as well as normal human tau proteins isolated from fetal and adult brains and a recombinant system. Among the metal ions tested, Ca2+ and Mg2+ effectively induced formation of approximately 340 kD aggregates of PHF-tau but not normal tau proteins as determined by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis and immunoblotting. Al3+ and Fe2+ precipitated both PHF-tau and normal tau protein as SDS-insoluble pellets. The other metal ions examined (Cu2+, Zn2+, and Li+) were inactive and caused neither aggregation nor precipitation of any tau protein. Intermixing experiments using PHF-tau and various normal tau preparations showed that the 340-kD aggregates induced by Ca2+ contained PHF-tau but not normal tau regardless whether unmodified (recombinant) or highly phosphorylated (fetal brain) tau proteins were used. The present results suggest that post-translational modifications other than the fetal-type phosphorylation are required for Ca2+- and Mg2+-dependent aggregation of PHF-tau and that the regional elevation of these ions may trigger pathological deposition of PHF-tau in certain neurodegenerative disorders.
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PMID:Ca2+ and Mg2+ selectively induce aggregates of PHF-tau but not normal human tau. 989 Apr 32

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.
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PMID:Reduction of calcineurin activity in brain by antisense oligonucleotides leads to persistent phosphorylation of tau protein at Thr181 and Thr231. 1010 Oct 20

Glutamate receptor induced changes in the activity of different phosphorylation systems were measured in hippocampal slices from 12- and 56-day-old rats, by determining the endogenous phosphorylation of 2.5% perchloric acid (PCA) soluble proteins. We identified among these proteins an 85, 80 kDa and the tau protein as specific substrates for protein kinase A (PKA), MARCKS, and neurogranin as specific substrates for protein kinase C (PKC), and prostaglandin-D-synthase as substrate for casein kinase II (CKII). In addition, a 35 kDa protein was phosphorylated by calcium/calmodulin dependent kinase II and protein kinase C and a 21 kDa protein was a substrate for all investigated kinases. The basal endogenous phosphorylation of 2.5% PCA soluble proteins changed during development qualitatively and quantitatively. Thus, the phosphorylation degree of nearly all proteins declines during maturation. Activation of mGluR induced an increased phosphorylation of PKA, PKC, and CKII substrates in hippocampal slices from 12-day-old rats, but in slices of 56-day-old rats only PKA and to a lower extent PKC substrates were affected. In contrast, stimulation of NMDA receptors led to an enhancement of CKII and PKA dependent phosphorylation only in slices of young animals, whereas the endogenous phosphorylation of some proteins in adult slices was actually decreased. These data showing developmental changes in the coupling of metabotropic and ionotropic glutamate receptors to different phosphorylation systems are discussed in the light of altered physiological properties of the mature hippocampus.
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PMID:Age-dependent differences in glutamate-induced phosphorylation systems in rat hippocampal slices. 1022 77

Diisopropyl phosphorofluoridate (DFP) produces organophosphorus ester-induced delayed neurotoxicity (OPIDN) in hen, human, and other sensitive species. This is characterized by mild ataxia, which progresses to severe ataxia or paralysis in a few days. Ultrastructurally, OPIDN is associated with the degeneration of axons in central and peripheral nervous systems. Bacterially expressed longest human tau protein (htau40) phosphorylated by DFP-treated hen brain supernatant showed a decrease in microtubule binding in a shorter time than that phosphorylated by control hen brain supernatant. The decrease in htau40-microtubule binding observed on htau40 phosphorylation by the recombinant Ca2+/calmodulin (CaM)-dependent protein kinase II (CaM kinase II) alpha-subunit showed that CaM kinase II present in brain supernatant could participate in tau phosphorylation even in the absence of Ca2+/CaM and decrease tau-microtubule binding. In addition, use of htau40 mutants, htau40m1 (Ala416) and htau40m6 (Asp416), suggested that replacement of Ser416 by neutral or acidic amino acid produced some change in htau40 conformation that caused diminished binding with microtubules phosphorylated by brain supernatant in the presence of ethylene glycol bis(beta-aminoethyl ether) N, N'tetraacetic acid (EGTA). The change in conformation produced by Ser416 phosphorylation, however, was different from that produced by mutants since only nonmutated htau40 showed a significant decrease in binding with microtubules on phosphorylation by recombinant CaM kinase II in the presence of Ca2+/CaM compared to that obtained by phosphorylation in the presence of EGTA. This study showed that enhanced Ca2+/CaM-dependent protein kinase activity in DFP-treated hen brain supernatant may cause decreased tau-microtubule binding and destabilization of microtubules and may be involved in axonal degeneration in OPIDN.
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PMID:Tau phosphorylation by diisopropyl phosphorofluoridate (DFP)-treated hen brain supernatant inhibits its binding with microtubules: role of Ca2+/Calmodulin-dependent protein kinase II in tau phosphorylation. 1032 22

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