Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10636 (tau protein)
 5,110 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of cAMP-dependent protein kinase (cAMP-PK) phosphorylation on the degradation of the microtubule-associated protein tau by calpain were studied. Purified bovine brain tau that had been phosphorylated by cAMP-PK had a slower migration pattern on sodium dodecyl sulfate-polyacrylamide gels and a more acidic, less heterogeneous pattern on two-dimensional, nonequilibrium pH gradient electrophoresis (NEPHGE) gels compared with untreated tau. Phosphorylation of tau by cAMP-PK significantly inhibited its proteolysis by calpain compared with untreated tau. To our knowledge this is the first demonstration that phosphorylation of tau by a specific kinase results in increased resistance to hydrolysis by calpain. Tau dephosphorylated by alkaline phosphatase migrated more rapidly on sodium dodecyl sulfate-polyacrylamide gels and also showed an altered two-dimensional NEPHGE pattern. Dephosphorylation of tau had no effect on its susceptibility to calpain proteolysis, indicating that regulation of the susceptibility to calpain hydrolysis is due to the phosphorylation of a specific site(s). These results suggest a role for phosphorylation in regulating the degradation of tau. Abnormal phosphorylation could result in a protease-resistant tau population which may contribute to the formation of paired helical filaments in Alzheimer's disease.
 ...
PMID:Phosphorylation by cAMP-dependent protein kinase inhibits the degradation of tau by calpain. 173 Jul 2

The cAMP-responsive element modulator (CREM) gene encodes a family of transcriptional regulators that bind to promoter sequences activated by increased intracellular cAMP levels. Both activators and repressors are generated by alternative splicing and alternative translational initiation. During the development of male germ cells, there is a switch in the transcripts generated by CREM. Specifically, from the prophase of meiosis, there is an increase in the CREM tau activator transcript. Here we present results showing that expression of the CREM activator protein is restricted to postmeiotic germ cells. We show that CREM tau is efficiently phosphorylated at a serine residue at position 117 by the protein kinase-A endogenous to germ cells, indicating that it constitutes a natural target of the adenylyl cyclase pathway during spermatogenesis. Phosphorylation of serine-117 turns CREM tau into a powerful activator. The rise in CREM tau protein coincides with the transcriptional activation of several genes. We show that CREM tau efficiently binds to CREs present in the promoters of these genes, suggesting that they could constitute down-stream targets of CREM. We have analyzed in more detail the regulation of one of these genes, the male germ cell-specific RT7. The RT7 promoter is cAMP inducible and activated by CREM tau in transfection assays. The RT7 promoter is efficiently transcribed in vitro with nuclear extracts from seminiferous tubules. CREM-specific antibodies block RT7 in vitro transcription, implicating a role for CREM tau in a cascade of transcriptional events during spermatogenesis.
 ...
PMID:Induction of CREM activator proteins in spermatids: down-stream targets and implications for haploid germ cell differentiation. 811 65

Phosphorylation of tau protein at Ser-262 has been shown to diminish its ability to bind to taxol-stabilized microtubules. The paired helical filaments (PHFs) found in Alzheimer's disease brain are composed of PHF-tau, which is hyperphosphorylated at multiple sites including Ser-262. However, protein kinase(s) able to phosphorylate this site are still under investigation. In this study, the ability of cyclic AMP-dependent protein kinase (cAMP-PK) and calcium/calmodulin-dependent protein kinase II (CaMKII) to phosphorylate tau at Ser-262, as well as Ser-356, is demonstrated by use of a monoclonal antibody (12E8) which has been shown to recognize tau when these sites are phosphorylated. Cleavage of cAMP-PK-phosphorylated tau at cysteine residues by 2-nitro-5-thiocyanobenzoic acid, which cuts the protein into essentially two fragments and separates Ser-262 from Ser-356, revealed that cAMP-PK phosphorylates both Ser-262 and Ser-356. In addition, phosphorylation with cAMP-PK or CaMKII of recombinant tau in which Ser-262, Ser-356 or both had been mutated to alanines, clearly demonstrated that cAMP-PK and CaMKII were able to phosphorylate both sites. Mitogen-activated protein kinase or protein kinase C did not phosphorylate tau at Ser-262 and/or Ser-356. Finally, evidence is presented that phosphorylation of both these sites occurs in cultured nerve cells under certain conditions, indicating their potential physiological relevance.
 ...
PMID:Tau protein is phosphorylated by cyclic AMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase II within its microtubule-binding domains at Ser-262 and Ser-356. 868 13

A sequential activation of L-selectin and beta 2-integrins on neutrophils is crucial for the rolling, adherence and subsequent migration of these cells on the endothelium. However, little is known about a possible interplay between these adhesion receptors in the final regulation of cell motility. The results presented here show that sulfatides themselves (here used as tools to activate L-selectins), have no major effect on the cellular content of filamentous actin (F-actin), but cause a time-related decrease in the beta 2-integrin-induced formation of F-actin. This effect of sulfatides was abolished in cells lacking L-selectin as a result of pretreatment with chymotrypsin. A similar sulfatide-induced activation of L-selectin also caused a pronounced and time-related decrease of a subsequent chemotactic peptide-induced F-actin response. The effect of sulfatides on both beta 2-integrin- and chemotactic peptide-induced F-actin were abolished if L-selectin were blocked by preincubating the cells with specific antibodies to L-selectin. These effects of L-selectin engagement on cellular F-actin content were neither abolished by blocking the cytosolic free Ca2+ signal with bis-(2-amino-5-methylphenoxy)ethane-N,N,N',N'-tetraaceticacid tetraacetoxymethyly ester (MAPT/AM) nor by blocking a cAMP-induced activation of protein kinase A by pretreating the cells with adenosine-3',5'-cyclic monophos-phorothioate (Rp-cAMPS). Instead we found that L-selectin engagement impaired an early beta 2-integrin-induced tyrosine kinase activation, an event shown to be necessary for a normal beta 2-integrin-mediated F-actin response. The present demonstration of a negative feed-back function of L-selectin on beta 2-integrin-induced modulations of the actin cytoskeleton, suggests that the relative distribution and/or density of the respective L-selectin and beta 2-integrin ligands on endothelial cells might be important factors in determining the final site of firm adhesion and extravasation of neutrophils.
 ...
PMID:Engagement of L-selectin impairs the actin polymerizing capacity of beta 2-integrins on neutrophils. 888 85

Axonal microtubules have two essential roles: providing the track for organelle transport and forming the cytoskeletal framework to maintain axonal morphology. Microtubule-associated proteins (MAPs) are essential for the formation of cytoskeletal architecture. However, they may have additional roles on the regulation of organelle transport by their interaction with motor proteins on the microtubules. We first examined the effects of axonal MAPs on the organelle movement along microtubules in a heterologous system using COS fibroblasts, which express no axonal MAPs, such as tau or MAP2C. Transfection of tau or MAP2C gene suppressed organelle movement almost completely in this cell type, hence interaction of axonal MAPs with microtubules interferes with organelle transports. It is known that the phosphorylation of MAPs reduces their interaction with microtubules. In this sense, phosphorylation of MAPs can be a good candidate for the molecular switch to regulate the organelle transport. As a second set of experiments, we investigated the effects of modulating cAMP dependent protein kinase pathway on organelle transports in primary sensory neurons, where high-molecular-weight tau protein is the major MAP. We found that the application of dibutyryl cAMP enhanced transports of large organelles in the axon. Furthermore, this drug treatment phosphorylated endogenous tau protein and thus reduced the affinity of tau to microtubules. These results indicate that axonal MAPs can work as a phosphorylation-dependent regulator of organelle transport. Local activation of protein kinase pathways in the axon might play an important role on the segregation of microtubules serving for either organelle transport or cytoskeletal architecture.
 ...
PMID:Microtubule-associated proteins regulate microtubule function as the track for intracellular membrane organelle transports. 911 34

We studied the expression of the NO synthase isoforms in an in vitro model of neural development using RT-PCR, Western blot and immunohistochemistry. Murine PCC7-Mz1 cells (Jostock et al., Eur. J. Cell Biol. 76, 63-76, 1998) differentiate in the presence of all-trans retinoic acid and dibutyryl cAMP along the neural pathway into neuron-like, fibroblast-like and astroglia-like cells. Undifferentiated cells showed immunofluorescent staining for neuronal-type NOS I and endothelial-type NOS III. This expression pattern was retained in those cells differentiating into neurofilament- and tau protein-positive neuronal cells. Thymocyte alloantigen (Thy1.2/CD 90.2)-positive fibroblasts, appearing around day 3, and glial fibrillary acidic protein (GFAP)-positive astroglial cells, appearing after day 6 of differentiation, stained negative for any NOS isoform. Starting at day 6 of differentiation, expression of inducible-type NOS II could be stimulated with cytokines in a subset of cells, which may represent activated astrocytes. NOS II was always undetectable in non-induced cultures. These data indicate that the ability of stem cells to express NOS I and NOS III is only retained when the cells differentiate along the neuronal lineage, while a small subpopulation of cells acquires the ability to express NOS II in response to cytokines.
 ...
PMID:Analysis of NO synthase expression in neuronal, astroglial and fibroblast-like derivatives differentiating from PCC7-Mz1 embryonic carcinoma cells. 1009 36

Since increasing evidence suggests that upregulation of the cAMP-second messenger system may be implicated in Alzheimer's disease neurodegeneration, we have compared the cAMP and cGMP levels in cerebrospinal fluid (CSF) from patients with dementia of the Alzheimer type (DAT, n=10) with those from nondemented age-matched controls (n=10). Our results show that cAMP levels, but not cGMP, are significantly (p<0.01) elevated in CSF from patients with DAT compared to those from nondemented controls. Moreover, a linear regression analysis demonstrated a significant correlation (r=0.62; p<0.01) between cAMP and tau protein levels in CSF when controls and patients with DAT were studied together. These results suggest that upregulation of cAMP-signaling pathway is implicated in Alzheimer's disease physiopathology.
 ...
PMID:Increased cerebrospinal fluid cAMP levels in Alzheimer's disease. 1055 45

Neuronal cells display different subsets of dynamic microtubules. In axons and extending neurites, this intrinsic dynamics is modulated by the microtubule-associated protein tau. Moreover, posttranslational modifications of tubulin, namely acetylation, tyrosination or glutamylation are directly involved in determining the stability of neuronal microtubules. Studies were carried out to analyze the interaction patterns of tau with subsets of microtubules in N2A neuroblastoma cells, which can differentiate in the presence of dibutyryl cAMP. Double labeling studies showed a differential pattern of tau association with microtubules containing acetylated and tyrosinated tubulin. Furthermore, studies using depolymerizing drugs revealed a selectivity in the association of tau with microtubular polymers and microfilaments, within the organization of the neuronal cytoskeleton. In order to study the association of specific tau isoforms with microtubules containing modified tubulin variants, immunoprecipitation studies were carried out. The coimmunoprecipitation data indicated a selective binding of specific tau isoforms to either modified tubulin variant. To assess the hypothesis on the roles of tau isoforms in the stabilization of microtubules containing modified tubulins, the association of those variants with tau isoforms was analyzed in overlay experiments. A preferential binding of acetylated tubulin from undifferentiated N2A cell extracts, to at least one slow-migrating tau isoform was revealed. However, acetylated tubulin from N2A cells containing long neurites displayed a preferential association with two isoforms of tau. On the other hand, tyrosinated tubulin from N2A extracts bound to the entire set of neuronal tau isoforms. These studies, along with the tau association with microtubules with different stability, indicate that tau segregates into subsets of microtubules in the axonal processes. The studies also suggest that these interactions may respond to a functional versatility of these polymers in differentiating neurons.
 ...
PMID:Differential association of tau with subsets of microtubules containing posttranslationally-modified tubulin variants in neuroblastoma cells. 1068 5

PKA phosphorylations of tau may be an early event in the development of neurofibrillary pathology in Alzheimer's disease. Serines 214 and 409 of tau are highly phosphorylated in PHF-tau, but are not phosphorylated to any significant extent in normal adult human brain; both of these sites are phosphorylated in human fetal tissue. To further study this phenomenon, a developmental characterization of these phosphorylation sites relative to PKA, cAMP-dependent response binding element (CREB) and phosphorylated CREB was performed using samples from mouse brain. Immunoblot analysis using antibodies specific for phospho-serine 214 (CP-3) and phospho-serine 409 (PG-5) revealed a marked decrease in phosphorylation occurring at each of these sites between postnatal day 11 (P11) and P20. Immunoblots with TG-5, a pan-tau antibody, revealed uniform expression of tau during postnatal development, as well as a switch in isoform composition that is evident between P7 and P11. This switch in isoform composition just precedes the change in the extent of phosphorylation at serines 214 and 409, and occurs at a time when PKA phosphorylation of CREB is increasing.
 ...
PMID:PKA phosphorylations on tau: developmental studies in the mouse. 1096 52

In humans, the apolipoprotein E gene (APOE) is polymorphic with the alleles APOE epsilon 2, 3 and 4 coding for apolipoproteins (Apo) E2, 3 and 4. Apart from age, the APOE epsilon 4 allele represents the most important risk factor in sporadic Alzheimer's disease (AD). Compared to APOE epsilon 3 homozygotes, the histopathological onset of tau pathology is found 1-2 decades earlier but progresses with the same speed. ApoE dose-dependently and specifically increases free intraneuronal calcium levels in the order ApoE4 > ApoE3 > ApoE2. This effect is amplified in the presence of beta A4-peptide. The ApoE effects on calcium are not affected by the blockade of action potentials with tetrodotoxin, or by inhibition of common ApoE binding sites. The calcium channel involved has been identified as a P/Q-type-like channel. Brain tissue ApoE levels differ with respect to APOE alleles and Braak-stage for Alzheimer-histopathology. The production of ApoE in astrocytes is controlled by several receptor/effector systems such as adrenoceptors and cAMP. In the presence of beta A4-peptide fragments, astrocytes stop their synthesis of ApoE resulting in a massive reduction in the bioavailability of ApoE. In the periphery, ApoE directs cholesterol transport and thereby influences its cellular concentrations. In neurons, changes in the concentration of cholesterol influence the phosphorylation status of the microtubule-associated protein tau at sites known to be altered in AD.
 ...
PMID:Apolipoprotein E and beta A4-amyloid: signals and effects. 1144 28


1 2 3 Next >>