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)

The phosphotyrosine interaction (PI) domains (also known as the PTB, or phosphotyrosine binding, domains) of Shc and IRS-1 are recently described domains that bind peptides phosphorylated on tyrosine residues. The PI/PTB domains differ from Src homology 2 (SH2) domains in that their binding specificity is determined by residues that lie amino terminal and not carboxy terminal to the phosphotyrosine. Recently, it has been appreciated that other cytoplasmic proteins also contain PI domains. We now show that the PI domain of X11 and one of the PI domains of FE65, two neuronal proteins, bind to the cytoplasmic domain of the amyloid precursor protein ((beta)APP). (beta)APP is an integral transmembrane glycoprotein whose cellular function is unknown. One of the processing pathways of (beta)APP leads to the secretion of A(beta), the major constituent of the amyloid deposited in the brain parenchyma and vessel walls of Alzheimer's disease patients. We have found that the X11 PI domain binds a YENPTY motif in the intracellular domain of (beta)APP that is strikingly similar to the NPXY motifs that bind the Shc and IRS-1 PI/PTB domains. However, unlike the case for binding of the Shc PI/PTB domain, tyrosine phosphorylation of the YENPTY motif is not required for the binding of (beta)APP to X11 or FE65. The binding site of the FE65 PI domain appears to be different from that of X11, as mutations within the YENPTY motif differentially affect the binding of X11 and FE65. Using site-directed mutagenesis, we have identified a crucial residue within the PI domain involved in X11 and FE65 binding to (beta)APP. The binding of X11 or FE65 PI domains to residues of the YENPTY motif of (beta)APP identifies PI domains as general protein interaction domains and may have important implications for the processing of (beta)APP.
Mol Cell Biol 1996 Nov
PMID:The phosphotyrosine interaction domains of X11 and FE65 bind to distinct sites on the YENPTY motif of amyloid precursor protein. 888 53

To examine intranuclear localization of metallothionein (MT) induced by administration of 4-aminopyrazolo [3,4-d] pyrimidine (4-APP), the present study of MT was performed by immuno-electron microscopy. One day after oral administration of 4-APP, the mouse pancreas removed and frozen with dry ice was cut at about 1 mm thickness. Pancreatic slices were reacted with anti-MT antibody, fixed with formaldehyde and glutaraldehyde, and embedded in hydrophilic Lowicryl K4M resin. Ultrathin sections were reacted with the secondary antibody labelled with colloidal gold, and stained both with uranyl acetate and with lead citrate. It was found that the MT site was shown simultaneously in the chromatin and in the rough endoplasmic reticulum of mouse pancreatic exocrine cells one day after administration of 4-APP. The structure of MT-binding chromatin was composed of supranucleosomal fibers, but not of nucleosomal fibers.
Cell Mol Biol (Noisy-le-grand) 1996 Dec
PMID:Bindings of metallothionein to supranucleosomal fibers in mouse pancreatic nuclei after induction by 4-aminopyrazolo [3,4-D] pyrimidine. 899 16

Abnormal deposition and accumulation of Alzheimer's amyloid beta-protein (A beta) and degeneration of forebrain cholinergic neurons are among the principal features of Alzheimer's disease. Studies in rat model systems have shown that forebrain cholinergic deficits are accompanied by induction of cortical beta-amyloid precursor protein (beta-APP) mRNAs and increased levels of secreted beta-APP in the CSF. The studies reported here determined whether the CSF levels of secreted beta-APP could be altered pharmacologically. In different experiments, rats with lesions of the forebrain cholinergic system received injections of vehicle, a muscarinic receptor antagonist scopolamine, or one of two cholinesterase inhibitors - diisopropyl phosphorofluoridate (DFP) or phenserine. Scopolamine was administered to determine whether the levels of beta-APP in the CSF could be increased by anticholinergic agents. The cholinesterase inhibitors were administered to determine whether the forebrain cholinergic system lesion-induced increases in CSF beta-APP could be reduced by cholinergic augmentation. Scopolamine administration led to a significant increase in the CSF levels of secreted beta-APP in sham-lesioned rats. Phenserine, a novel, reversible acetyl-selective cholinesterase inhibitor, significantly decreased the levels of secreted beta-APP in the CSF of forebrain cholinergic system-lesioned rats whereas DFP, a relatively non-specific cholinesterase inhibitor, failed to affect CSF levels of secreted beta-APP. These results suggest that the levels of secreted beta-APP in the CSF can be pharmacologically modulated but that this modulation is dependent upon the status of the forebrain cholinergic system and the pharmacological properties of the drugs used to influence it.
Brain Res Mol Brain Res 1997 Jun
PMID:Pharmacological modulation of Alzheimer's beta-amyloid precursor protein levels in the CSF of rats with forebrain cholinergic system lesions. 919 Oct 90

We report a novel mutation in the amyloid precursor protein gene (APP I716V) which probably leads to familial early onset Alzheimer's disease with an onset age in the mid 50s. Cells transfected with cDNAs bearing this mutation produce more A beta 1-42(43) than those transfected with wild-type APP and this effect is additive with that of the previously reported APP V717I mutation thus providing a novel approach for further increasing A beta 1-42(43) in model systems.
Hum Mol Genet 1997 Nov
PMID:A new pathogenic mutation in the APP gene (I716V) increases the relative proportion of A beta 42(43). 932 72

Human beta-secretase candidates, MP78 (h-MP78, EC 3.4.24.15) and cathepsin D (Cat D, EC 3.4.23.5), were evaluated for their ability to enhance amyloid-beta-protein (A beta) secretion when overexpressed in beta APP-containing cells. HEK-293 cells stably co-expressing h-MP78 or Cat D and h-beta APP695 were metabolically labeled with [35S]methionine and A beta secretion was quantified in the conditioned media by immunoprecipitation and ELISA without showing any significant increase in A beta production. Because Cat D is known to have a higher affinity for APP-substrate containing the Swedish familial Alzheimer's disease double mutation (SFAD, K595N and M596L substitutions in beta APP695) than for the wild type substrate [Dreyer et al., Eur. J. Biochem., 224 (1994) 265-271], the effect of Cat D overexpression was tested in a HEK293/beta APPSFAD stable cell line. ELISA analysis of the conditioned media from these cells did also not reveal any increase in A beta generation. In addition, recombinant h-MP78 purified from E. coli cleaved an APP-derived substrate spanning the beta-secretase site (ISEVKMD1AEFRHDS) at multiple sites, but the beta-site cleavage was only a minor one; cleavage occurred predominantly at K-M and E-F bonds. Human liver Cat D also cleaved the same substrate at multiple sites, yet the major cleavage at pH 4.0 occurred at the amyloidogenic D1 site. These findings indicate that h-MP78 does not have the cleavage specificity required for a beta-secretase protease and although Cat D fulfilled the amyloidogenic cleavage specificity, the results of the co-expression experiments make both enzymes less likely candidates as relevant beta-secretases.
Brain Res Mol Brain Res 1997 Sep
PMID:Expression and characterization of human beta-secretase candidates metalloendopeptidase MP78 and cathepsin D in beta APP-overexpressing cells. 933 17

Two closely related genes, the presenilins ( PS ), located at chromosomes 14q24.3 and 1q42.1, have been identified for autosomal dominant Alzheimer disease (AD) with onset age below 65 years (presenile AD). We performed a systematic mutation analysis of all coding and 5'-non-coding exons of PS -1 and PS -2 in a population-based epidemiological series of 101 unrelated familial and sporadic presenile AD cases. The familial cases included 10 patients of autosomal dominant AD families sampled for linkage analysis studies. In all patients mutations in the amyloid precursor protein gene ( APP ) had previously been excluded. Four different PS -1 missense mutations were identified in six familial cases, two of which where autosomal dominant cases. Three mutations resulted in onset ages above 55 years, with one segregating in an autosomal dominant family with mean onset age 64 years (range 50-78 years). One PS -2 mutation was identified in a sporadic case with onset age 62 years. Our mutation data provided estimates for PS -1 and PS -2 mutation frequencies in presenile AD of 6 and 1% respectively. When family history was accounted for mutation frequencies for PS -1 were 9% in familial cases and 18% in autosomal dominant cases. Further, polymorphisms were detected in the promoter and the 5'-non-coding region of PS -1 and in intronic and exonic sequences of PS -2 that will be useful in genetic association studies.
Hum Mol Genet 1998 Jan
PMID:Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease. 938 2

We investigated a potential role for the soluble interleukin-6 receptor (sIL-6R) in modulating interleukin-6 (IL-6) function in the central nervous system by assessing IL-6 and sIL-6R effects on beta-amyloid precursor protein (beta-APP) transcription and expression in cells of human neuronal origin. Cells transfected with a luciferase reporter plasmid containing a 3.8 kb DNA fragment of the beta-APP promoter were shown to have inducible promoter activity when treated with phorbol ester or basic fibroblast growth factor, but not when treated with lipopolysaccharide or Il-6. PCR amplification analysis revealed the presence of mRNA encoding the signaling subunit of the Il-6 receptor complex, the gp130 subunit, at levels approximating that found in human cortical tissue. The mRNA encoding the IL-6 receptor, however, was poorly expressed and was detectable only at high amplification cycles. When purified sIL-6R protein was added together with IL-6, there was a rapid induction of promoter activity within 2 h of stimulation followed by elevations in protein levels of both cell-associated and secreted beta-APP. Analysis of mRNA transcripts from human cortical brain tissue and cell cultures derived from fetal human brain demonstrated the presence of an alternatively spliced secreted form of the IL-6 receptor mRNA, suggesting that cells of the central nervous system may themselves be a source of sIL-6R protein. The capacity for sIL-6R to enhance IL-6 function and broaden the IL-6 target cell population in the brain has implications for the regulation of beta-APP expression in disease states such as Alzheimer's disease where elevations in brain IL-6 levels have been reported.
Brain Res Mol Brain Res 1998 Mar 30
PMID:Enhancement of beta-amyloid precursor protein transcription and expression by the soluble interleukin-6 receptor/interleukin-6 complex. 964 58

The APP gene promoter has multiple regulatory sequences, some of which may contribute to the neuropathology of Alzheimer's disease (AD). In this study, we investigated the effects of phorbol ester (PMA), IL-1, retinoic acid and reactive oxygen species on APP promoter activity in primary hippocampal neurons. We transfected neurons with either of two APP promoter constructs, a -2.8 kb and a shorter -488 bp upstream fragment fused to the chloramphenicol transferase (CAT) reporter gene. We demonstrated that phorbol 12-myristate-13 acetate (PMA), retinoic acid and IL-1 all stimulated both APP promoter constructs in hippocampal neurons after 24 h treatment. PMA and IL-1 treatments led to 2-fold increases of APP promoter activity. Retinoic acid induced a 3-fold increase. In addition, the magnitude of APP promoter responses to PMA and IL-1 treatment was similar between APP -2.8 kb and -488 bp plasmid transfected neurons. This suggests that the AP-1 sequence at -350 to -344 in the APP promoter may mediate the stimulatory effects of PMA and IL-1, as previously observed in endothelial and HeLa cells. In contrast, hydrogen peroxide, which was shown to activate NF-kappaB in primary neurons, failed to stimulate APP promoter activity, suggesting that the regulatory elements in the APP promoter may not respond to reactive oxygen species. Overall, these data indicate that APP expression in primary neurons can be modulated by PMA, IL-1 and retinoic acid. However, the contribution of reactive oxygen to Alzheimer's disease may not be directly related to the activation of the APP gene promoter but instead to neuronal damage associated with oxidative stress. Since elevated levels of IL-1 have been observed in AD brain, IL-1 could contribute to development of Alzheimer's disease by stimulating APP synthesis in primary neurons.
Brain Res Mol Brain Res 1998 Sep 18
PMID:Upregulation of amyloid precursor protein gene promoter in rat primary hippocampal neurons by phorbol ester, IL-1 and retinoic acid, but not by reactive oxygen species. 974 93

Epidemiologic and laboratory results consistently implicate the APOE gene in the pathogenesis of late-onset Alzheimer's disease (AD): the epsilon 4 allele increases risk in a dose-dependent fashion, while epsilon 2 confers protection. Individuals are susceptible for AD in varying degrees depending on which combination of APOE alleles has been inherited, APOE promoter polymorphism and other factors. Deposition of both senile plaques and neurofibrillary tangles, the pathologic hallmarks of AD, are enhanced by epsilon 4 from the earliest lesions onward--diffuse plaques consisting of A beta 1-42 and neurofibrillary tangles in the entorhinal cortex. Transgenic APOE mice carrying an APP mutation and 0, 1 or 2 copies of APOE showed dose-related increases in plaque deposition in the hippocampus and cortex, a clear indication that APOEp promotes A beta deposition. The presence of each additional APOE epsilon 4 allele leads to an earlier onset of the histopathological process of about 1 decade, on average. The association of both types of AD-related changes with the occurrence of epsilon 4 suggests that the APOE polymorphism causally contributes to the pathogenesis of AD.
Cell Mol Life Sci 1998 Sep
PMID:The role of APOE polymorphisms in late-onset dementias. 979 36

The beta-amyloid (A beta) peptide is present both in serum and in platelets, however it is unclear whether A beta plays a role in platelet function. We have now investigated the effects of soluble A beta on platelet function and have found that low levels (0.1-1 nM) of soluble A beta augment ADP-dependent platelet aggregation and translocation of focal adhesion kinase to the platelet cytoskeleton. Addition of A beta to gel-filtered platelets along with concentrations of adenosine diphosphate (ADP) producing submaximal aggregation responses increased the aggregation response by over 2-fold depending on the ADP:A beta ratios. The structure activity requirements for A beta activity showed intriguing constraints. Only full length A beta has significant activity. Truncated A beta peptides, such as A beta(1-16) or A beta(25-35), or reverse A beta(40-1) all show little or no activity. We also examined the activity of mutant A beta peptides, corresponding with the APP(692A-G) and APP(693E-Q) (at A beta21 and A beta22, respectively) which are found in familial Alzheimer's disease and hereditary cerebral hemorrhagic amyloidosis, Dutch type (HCHWA-D), and found that these peptides showed little or no activity. These results suggest that A beta interacts with platelets in a highly specific manner and may play a role in regulating platelet function.
Mol Psychiatry 1998 Nov
PMID:Beta-amyloid augments platelet aggregation: reduced activity of familial angiopathy-associated mutants. 985 75


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