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  • 1
    Electronic Resource
    Electronic Resource
    Enhanced Expression of Amyloid Precursor Protein in Response to Dibutyryl Cyclic AMP Is Not Mediated by the Transcription Factor AP-2 (1997)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 68 (1997), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: The gene for amyloid precursor protein (APP) is expressed almost ubiquitously, with high levels of mRNA being detected in brain. The basal expression level of the APP gene can be modulated by physiological stimuli, and in this report we demonstrate that the second messenger cyclic AMP can regulate APP mRNA through transcriptional mechanisms. Northern blot analysis showed a 1.8-fold increase in steady-state levels of APP mRNA when the neuroblastoma × glioma hybrid cell line NG108-15 was treated with dibutyryl cyclic AMP. Although the upstream sequences of the APP gene do not contain a canonical cyclic AMP response element, transient transfection assays in NG108-15 cells using different portions of the APP promoter showed an increase in reporter gene activity mediated by sequences located between −303 to −204 and −488 to −2991. Cotransfection assays carried out in HepG2 cells with AP-2, a cyclic AMP-regulated transcription factor, failed to activate the APP promoter through the AP-2 consensus sequence (GCCNNNCGG) located at position −205. Electrophoretic mobility shift analysis revealed that the AP-2 binding activity present in HeLa nuclear extracts fails to recognize the APP AP-2 consensus sequence. We conclude that increases in cyclic AMP levels can lead to an up-regulation of APP gene transcription through at least two different regions of the APP promoter. This increase does not involve the AP-2 consensus sequence present in the APP promoter located at position −205, and, moreover, this putative site is not recognized by the transcription factor AP-2.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1997.68030909.x
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  • 2
    Electronic Resource
    Electronic Resource
    p53 Induction by Tumor Necrosis Factor-α and Involvement of p53 in Cell Death of Human Oligodendrocytes (1999)
    Oxford UK : Blackwell Science Ltd.
    Journal of neurochemistry 73 (1999), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract : Oligodendrocytes (OLs) and their myelin membranes are the primary targets in the autoimmune disease multiple sclerosis (MS). The inflammatory cytokine tumor necrosis factor-α (TNF-α) has been implicated as a mediator of OL cell injury. TNF-α is detectable within MS lesions and induces apoptosis of mature human OLs in vitro. One possible mechanism by which TNF-α mediates cell death is through the activation of c-jun N-terminal kinase (JNK). We have previously shown that treatment of human OLs with TNF-α leads to activation of JNK. Here we provide evidence that p53, a regulator of the cell cycle and apoptosis, is a mediator of TNF-α-induced apoptosis of OLs. Although p53 was undetectable by western blot analysis in adult human OLs, its levels increased within 24 h after TNF-α treatment (100 ng/ml). The induced p53 was immunolocalized to the nucleus prior to the appearance of significant numbers of apoptotic cells. Overexpression of p53 by adenovirus-mediated gene transfer into human OLs in vitro resulted in marked apoptosis as revealed by in situ cleavage of DNA (TUNEL positive), decreased mitochondrial function, and release of lactate dehydrogenase into the culture medium. These in vitro studies demonstrate that increased p53 levels are associated with apoptosis of human OLs. The findings further implicate p53 as a target for the JNK pathway activated during TNF-α-mediated cell death of human adult OLs.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1999.0730605.x
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  • 3
    Electronic Resource
    Electronic Resource
    Transcriptional Regulation of Amyloid Precursor Protein During Dibutyryl Cyclic AMP-Induced Differentiation of NG108-15 Cells (1997)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 68 (1997), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Early expression of amyloid precursor protein (APP) during development of the nervous system suggests that this protein may play an important role first in axogenesis and later in synaptogenesis. To study regulation of APP mRNA expression in neuronal cells, NG108-15 neuroblastoma × glioma cells were induced to differentiate in the presence of dibutyryl cyclic AMP. Steady-state levels of APP mRNA and APP isoforms increased gradually, concomitantly with the appearance of differentiated phenotype. Northern blot analysis showed a three-fold increase in APP expression at day 6 of dibutyryl cyclic AMP treatment. Nuclear run-on assays and transient transfections performed using APP promoter/reporter constructs confirmed a twofold increase in the rate of APP gene transcription. The stability of the mRNA was unchanged, with differentiated and nondifferentiated cells having the same half-life of about 21 h. These results strongly suggest that APP mRNA induction in the differentiated NG108-15 cells is due to an increase in the rate of transcription of the gene.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1997.68030970.x
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  • 4
    Electronic Resource
    Electronic Resource
    USE OF TISSUE CULTURE MODELS TO STUDY ENVIRONMENTAL-GENETIC INTERACTIONS RELEVANT TO NEURODEGENERATIVE DISEASES (1995)
    Oxford, UK : Blackwell Publishing Ltd
    Clinical and experimental pharmacology and physiology 22 (1995), S. 0 
    Details
    ISSN: 1440-1681
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 1. Clonal cell lines, primary cultured neurones and transgenic animals expressing mutant genes linked to familial forms of neurodegenerative diseases provide models in which to examine the interaction between expression of a predisposing gene and exposure to neurotoxic chemicals. Methods of establishing these models are reviewed.2. Mutations in the gene encoding Cu/Zn-superoxide dismutase (SOD-1) have been identified in cases of familial amyotrophic lateral sclerosis linked to chromosome 21. We report that in clonal lines of PC12 cells, the cytotoxicity of a glutathione-depleting epoxide, styrene oxide, varied with SOD activity in a manner similar to that previously demonstrated for redox cycling chemicals. These preliminary data suggest that either low or high SOD-1 activities may be associated with greater toxicity of a variety of neurotoxic chemicals and their metabolites.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1440-1681.1995.tb02019.x
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  • 5
    Electronic Resource
    Electronic Resource
    Oligodendrocyte injury in multiple sclerosis: a role for p53 (2003)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 85 (2003), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Multiple sclerosis (MS) is a neurological disorder characterized by myelin destruction and a variable degree of oligodendrocyte death. We have previously shown that overexpression of the transcription factor p53 can induce oligodendrocyte apoptosis. We investigated the mechanism of p53-induced apoptosis using primary cultures of central nervous system-derived adult human oligodendrocytes. Adenovirus-mediated p53 overexpression resulted in up-regulation of the death receptors Fas, DR4 and DR5 with subsequent caspase-mediated apoptosis of the oligodendrocytes. The oligodendrocytes were protected from p53-induced cell death by blocking signaling through Fas and/or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors. Although lower levels of p53 did not induce apoptosis, the increase in death receptor expression was sufficient to render the oligodendrocytes susceptible to apoptosis in the presence of exogenous Fas ligand and TRAIL. These ligands are present in the inflammatory milieu of active MS lesions. In situ analysis of active MS lesions revealed increased p53 expression in oligodendrocytes in lesions that featured oligodendrocyte apoptosis and cell loss. Our data provide evidence for a novel role for p53 in the pathogenesis of MS.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2003.01674.x
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  • 6
    Electronic Resource
    Electronic Resource
    Interferons impair early transgene expression by adenovirus-mediated gene transfer in muscle cells (1998)
    Springer
    Journal of molecular medicine 76 (1998), S. 442-450 
    Details
    ISSN: 1432-1440
    Keywords: Key words Gene therapy ; Adenovirus ; Muscle ; Interferons
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Recombinant adenovirus (AVR) promises to be an efficient vector in gene therapy for neuromuscular diseases, but in preclinical experiments the expression of therapeutic genes is shorter lived in immunocompetent animals than in immunocompromised hosts. Interferons (IFN), which are known to have a role both in early antiviral activity and in late cytotoxic immunoreaction against the virus or transduced cells, may influence the efficiency of gene transfer. In this study we investigated the role of IFNs in determining the efficiency of gene transfer by AVR. AVRs expressing β-galactosidase (β-gal) from either a cytomegalovirus (CMV) or a troponin-I promoter were used. Muscle cells were infected by AVR after exposure to various IFNs. The αIFN treatment significantly reduced (up to fivefold) the CMV promoter-driven gene expression in muscle cells in vitro and in immature muscles in vivo, while the least effective inhibitor was βIFN. The decrease in gene expression by IFNs was more pronounced with the CMV-driven transgene than troponin-I promoter-driven one and was due to a decrease in transcript level. Intrinsic IFNs that are triggered by AVR administration can decrease the efficiency of gene transfer in muscle cells. Therefore the use of muscle specific promoters in AVR and/or IFN inhibitory agents will likely improve the prospects of effective gene therapy by AVR.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001090050236
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  • 7
    Electronic Resource
    Electronic Resource
    Neuronal progenitors—learning from the hippocampus (2000)
    [s.l.] : Nature America Inc.
    Nature medicine 6 (2000), S. 249-250 
    Details
    ISSN: 1546-170X
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Medicine
    Notes: [Auszug] Successful therapy OF the destructive and degenerative disorders that affect the adult human central nervous system (CNS) will require the ability both to reduce the rate and extent of tissue injury, and to restore or replace destroyed tissue. Most current therapeutic strategies focus on the ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/73076
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