Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have analyzed the modulation of amyloid beta-protein precursor (APP) gene expression in human umbilical vein endothelial cells (HUVEC). The level of the APP mRNA transcripts increased as HUVEC reached confluency. In confluent culture the half-life of the APP mRNA was 4 hr. Treatment of the cells with human-recombinant interleukin 1 (IL-1), phorbol 12-myristate 13-acetate, or heparin-binding growth factor 1 enhanced the expression of APP gene in these cells, but calcium ionophore A23187 and dexamethasone did not. The protein kinase C inhibitor 1-(isoquinolinsulfonyl)-2-methylpiperazine (H7) inhibited IL-1-mediated increase of the level of APP transcripts. To map IL-1-responsive elements of the APP promoter, truncated portions of the APP promoter were fused to the human growth hormone reporter gene. The recombinant plasmids were transfected into mouse neuroblastoma cells, and the cell medium was assayed for the human growth hormone. A 180-base-pair region of the APP promoter located between position -485 and -305 upstream from the transcription start site was necessary for IL-1-mediated induction of the reporter gene. This region contains the upstream transcription factor AP-1 binding site. These results suggest that IL-1 upregulates APP gene expression in HUVEC through a pathway mediated by protein kinase C, utilizing the upstream AP-1 binding site of the APP promoter.
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PMID:Interleukin 1 regulates synthesis of amyloid beta-protein precursor mRNA in human endothelial cells. 250 93

The promoter of the gene for the precursor of Alzheimer's Disease A4 amyloid protein (PAD gene) resembles promoters of housekeeping genes. A typical TATA box is missing, and transcription initiates at multiple sites. It shows a high GC content of 72% in a DNA region that confers promoter activity to a reporter gene in vivo. Upstream of the RNA start sites we found sequences homologous to the consensus binding sites of transcription factor AP-1 and the heat shock control element binding protein. Six copies of a 9bp long GC-rich element are located between positions -100 and -200 of the sequence. A protein-DNA interaction could be mapped to this element. The ratio of the dinucleotide CpG, the target for DNA methylation, versus GpC is about 1:1 around the RNA start site, in contrast to the normal ratio of 1:5 in eucaryotic DNA. These findings suggest that four mechanisms may participate in the regulation of the PAD gene: the stress-related heat shock; the AP-1/Fos binding; the GC-rich element, and the possible methylation of the CpG region. PAD gene regulation could be of relevance for the progression of amyloid deposition in Alzheimer's Disease.
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PMID:The promoter of Alzheimer's disease amyloid A4 precursor gene. 269 Jan 3

The promoter of the gene for the human precursor of Alzheimer's disease A4 amyloid protein (PAD gene) resembles promoters of housekeeping genes. It lacks a typical TATA box and shows a high GC content of 72% in a DNA region that confers promoter activity to a reporter gene in an in vivo assay. Transcription initiates at multiple sites. Sequences homologous to the consensus binding sites of transcription factor AP-1 and the heat shock control element binding protein were found upstream of the RNA start sites. Six copies of a 9-bp-long GC-rich element are located between positions -200 and -100. A protein--DNA interaction could be mapped to this element. The 3.8 kb of the 5' region of the PAD gene include two Alu-type repetitive sequences. These findings suggest that four mechanisms may participate in the regulation of the PAD gene and could be of relevance for the progression of amyloid deposition in Alzheimer's disease.
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PMID:The promoter of Alzheimer's disease amyloid A4 precursor gene. 305 67

Overexpression of the beta-amyloid precursor protein gene (beta-APP) may contribute to the abnormal generation of beta-amyloid protein in Alzheimer's disease. We demonstrate using a human glial cell line (1321N1) that activation of protein kinase C (PKC) with phorbol 12-myristate 13-acetate (PMA) increases beta-APP mRNA levels, induces known components of the transcription factor activator protein-1 (AP-1), and increases protein-DNA binding activity to AP-1 sequences within the beta-APP promoter. A beta-APP promoter-luciferase reporter gene is transcriptionally activated by PMA, as well as by expression of constitutively activated PKC or by expression of c-Jun. Further characterization suggests that the distal but not the proximal AP-1 recognition site binds nuclear proteins regulated by PKC, and that the AP-1 binding activity is likely to be composed of Jun-Jun homodimers rather than Jun-Fos heterodimers. Additional studies demonstrate that a single copy of the distal AP-1 site fused to a heterologous promoter is sufficient to confer a response to PMA. Mutagenesis of this site in the beta-APP promoter renders it unresponsive to c-Jun and attenuates transcriptional activation by PMA. We suggest that cellular mediators that activate PKC, particularly those that induce significant increases in c-Jun, may up-regulate expression of the beta-APP gene and consequently affect production and processing of this protein.
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PMID:A direct role for protein kinase C and the transcription factor Jun/AP-1 in the regulation of the Alzheimer's beta-amyloid precursor protein gene. 806 12

Since the PAD gene (also called promoter of Alzheimer's disease amyloid A4 precursor gene or amyloid beta-protein precursor promoter) has two AP-1 consensus sequences, and members of the Fos and Jun families are the major components of the transcription factor activator protein-1 (AP-1), we have investigated the localization of c-Fos and c-Jun immunoreactivity and its relationship to beta-amyloid deposition in the brains of patients with Alzheimer's disease and amyloid angiopathy. c-Jun, but not c-Fos, immunoreactivity is observed in the muscular layer of meningeal and cerebral blood vessels with amyloid angiopathy, and in the soma of glial cells and cellular processes of unknown origin surrounding beta-amyloid deposits in the brain. These results show that c-Jun may participate in the cascade of events leading to increased beta-APP (beta-amyloid precursor protein) production and beta-amyloid deposition in the brains of patients with Alzheimer's disease and amyloid angiopathy.
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PMID:Amyloid deposition is associated with c-Jun expression in Alzheimer's disease and amyloid angiopathy. 900 42

A unilateral hypoxic-ischemic (HI) episode in immature rat brain was used to investigate the role of the immediate early genes c-fos and c-jun in delayed neuronal death and survival. This HI paradigm results in an apoptotic cell death in selectively vulnerable areas, in particular the hippocampal CA1 pyramidal cell layer. In susceptible regions undergoing delayed neuronal death there was a prolonged induction of both c-Jun and c-Fos (mRNA and protein). This expression occurred in parallel with a pronounced increase in AP-1 DNA binding activity but was not associated with either increased levels of Jun NH2-terminal kinase or phosphorylation of c-Jun (ser-63). In addition to changes in immediate early gene expression, the CA1 neurons showed a delayed increase in the expression of amyloid precursor protein (APP751) mRNA, suggesting that APP, which contains an AP-1 site, might be a down-stream gene regulated by the Jun transcription factor in neurons dying by apoptosis. The surviving dentate granule cells also showed an increase in Fos, Jun, and APP751 although this expression occurred earlier than in the CA1 neurons and declined rapidly. These results are discussed with respect to the role of these proteins in neuronal death and survival.
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PMID:Do c-Jun, c-Fos, and amyloid precursor protein play a role in neuronal death or survival? 969 61

We have previously shown, by using the phosphate-dependent anti-tau antibodies Tau-1 and PHF-1, that heat shock induces rapid dephosphorylation of tau followed by hyperphosphorylation in female rats. In this study, we analyzed in forebrain homogenates from female Sprague-Dawley rats the activities of extracellular signal regulated kinase 1/2 (ERK1/2), c-Jun NH(2)-terminal kinase (JNK), glycogen synthase kinase-3beta (GSK-3beta), cyclin-dependent kinase 5 (Cdk5), cAMP-dependent protein kinase A (PKA), and Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) at 0 (n = 5), 3 (n = 4), 6 (n = 5), and 12 (n = 5) h after heat shock and in non-heat-shocked controls (n = 5). Immunoprecipitation kinase assays at 0 h showed suppression of the activities of all kinases except of GSK-3beta, which showed increased activity. At 3-6 h, the activities of ERK1/2, JNK, Cdk5, and GSK-3beta toward selective substrates were increased; however, only JNK, Cdk5, and GSK-3beta but not ERK1/2 were overactivated toward purified bovine tau. At 3-6 h, kinase assays specific for PKA and CaMKII showed no increased activity toward either tau or selective substrates. All of eight anti-tau antibodies tested showed dephosphorylation at 0 h and hyperphosphorylation at 3-6 h, except for 12E8, which showed hyperphosphorylation also at 0 h. Immunoblot analysis using activity-dependent antibodies against ERK1/2, JNK, and GSK-3beta confirmed the above data. Increased activation and inhibition of kinases after heat shock were statistically significant in comparison with controls. Because tau is hyperphosphorylated in Alzheimer disease these findings suggest that JNK, GSK-3beta, and Cdk5 may play a role in its pathogenesis.
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PMID:tau kinases in the rat heat shock model: possible implications for Alzheimer disease. 1112 Oct 21

Presenilin 1 (PS1) plays a pivotal role in Notch signaling and the intracellular metabolism of the amyloid beta-protein. To understand intracellular signaling events downstream of PS1, we investigated in this study the action of PS1 on mitogen-activated protein kinase pathways. Overexpressed PS1 suppressed the stress-induced stimulation of stress-activated protein kinase (SAPK)/c-Jun NH(2)-terminal kinase (JNK) in human embryonic kidney 293 cells. Interestingly, two functionally inactive PS1 mutants, PS1(D257A) and PS1(D385A), failed to inhibit UV-stimulated SAPK/JNK. Furthermore, H(2)O(2-) or UV-stimulated SAPK activity was higher in mouse embryonic fibroblast (MEF) cells from PS1-null mice than in MEF cells from PS(+/+) mice. MEF(PS1(-/-)) cells were more sensitive to the H(2)O(2)-induced apoptosis than MEF(PS1(+/+)) cells. Ectopic expression of PS1 in MEF(PS1(-/-)) cells suppressed H(2)O(2)-stimulated SAPK/JNK activity and apoptotic cell death. Together, our data suggest that PS1 inhibits the stress-activated signaling by suppressing the SAPK/JNK pathway.
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PMID:Negative regulation of the SAPK/JNK signaling pathway by presenilin 1. 1133 Dec 98

We have recently shown that in utero treatment of guinea pigs with the DNA methylating substance methylazoxymethanol acetate (MAM) on gestation day (GD) 24 results in neocortical microencephalopathy, increased protein kinase C activity and altered processing of the amyloid precursor protein in neocortex of the offsprings. In order to identify the primary neuronal lesions produced by MAM-treatment, we mapped the 5-bromo-2'-deoxyuridine (BrdU)-incorporation in dividing neurons on GD 24 and we followed the effects of MAM-treatment on GD 24 on embryonic immediate early gene expression and on glial cell activation. BrdU injected on GD 24 labeled many neurons of the ventricular zone and of the intermediate zone but only scattered neurons of the cortical plate. When time-mated guinea pigs were injected intraperitoneally with MAM on GD 24, we observed the activation of microglial cells in the ventricular/intermediate zone and the appearence of astrocytes between the intermediate zone and the cortical plate, 48 h after intoxification. The activation of glial cells was accompanied by the neuronal expression of c-Fos but not of c-Jun in the ventricular/intermediate zone. Based on our observations on BrdU-incorporation and on the morphological outcome of MAM treatment in the juvenile guinea pig, our data presented here indicate that selective neurodegeneration during development induces the activation of both phagocytotic microglial cells and of astrocytes which might trophically support damaged neurons surviving this lesion procedure.
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PMID:Developmentally induced microencephalopathy in guinea pigs--embryonic glial cell activation marks selective neuronal death. 1133

We have isolated a novel protein based on its association with Drosophila APP-like protein (APPL), a homolog of the beta-amyloid precursor protein (APP) that is implicated in Alzheimer's disease. This novel APPL-interacting protein 1 (APLIP1) contains a Src homology 3 domain and a phosphotyrosine interaction domain and is expressed abundantly in neural tissues. The phosphotyrosine interaction domain of APLIP1 interacts with a sequence containing GYENPTY in the cytoplasmic domain of APPL. APLIP1 is highly homologous to the carboxyl-terminal halves of mammalian c-Jun NH(2)-terminal kinase (JNK)-interacting protein 1b (JIP1b) and 2 (JIP2), which also contain Src homology 3 and phosphotyrosine interaction domains. The similarity of APLIP1 to JIP1b and JIP2 includes interaction with component(s) of the JNK signaling pathway and with the motor protein kinesin and the formation of homo-oligomers. JIP1b interacts strongly with the cytoplasmic domain of APP (APPcyt), as APLIP1 does with APPL, but the interaction of JIP2 with APPcyt is weak. Overexpression of JIP1b slightly enhances the JNK-dependent threonine phosphorylation of APP in cultured cells, but that of JIP2 suppresses it. These observations suggest that the interactions of APP family proteins with APLIP1, JIP1b, and JIP2 are conserved and play important roles in the metabolism and/or the function of APPs including the regulation of APP phosphorylation by JNK. Analysis of APP family proteins and their associated proteins is expected to contribute to understanding the molecular process of neural degeneration in Alzheimer's disease.
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PMID:Interaction of Alzheimer's beta -amyloid precursor family proteins with scaffold proteins of the JNK signaling cascade. 1191 89


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