1,721,006 research outputs found
Role of peroxisome proliferator-activated receptor gamma and its ligands in the control of immune responses.
No full textExtracellular ATP activates transcription factor NF-κB through the P2Z purinoreceptor by selectively targeting NF-κB p65 (RelA)
No full textCells of the macrophage lineage express a peculiar surface receptor for extracellular ATP, designated P2Z/P2X7 purinergic receptor, that induces pore formation and collapse of the plasma membrane potential. Although the function of the P2Z receptor is largely unknown, accumulating evidence implicates its role in cell signaling and immune reactions. Here, we investigated the effect of P2Z receptor ligation on the activation of NF-kappaB, a transcription factor controlling cytokine expression and apoptosis. Exposure of microglial cells to ATP but not other nucleotides resulted in potent NF-kappaB activation. This effect was specifically mediated by the P2Z receptor, because selective receptor antagonists prevented NF-kappaB activation. NF-kappaB activation required reactive oxygen intermediates and proteases of the caspase family, because it was abolished by antioxidants and specific protease inhibitors. The subunit composition of the ATP-induced NF- kappaB-DNA complex was rather unusual. Whereas exposure to LPS-induced prototypical NF-kappaB p50 homo- and p65 (RelA)/p50 heterodimers, ATP stimulation resulted in the sole appearance of a p65 homodimer. This is the first demonstration that a certain stimulus activates a particular NF-kappaB subunit. Because different NF-kappaB complexes exhibit distinct transcriptional and DNA-binding activities, ATP may control the expression of a subset of NF-kappaB target genes distinct from those activated by classical proinflammatory mediators
P2Z purinoreceptor ligation induces activation of caspases with distinct roles in apoptotic and necrotic alterations of cell death
No full textMyeloic cells express a peculiar surface receptor for extracellular ATP, called the P2Z/P2X7 purinoreceptor, which is involved in cell death signalling. Here, we investigated the role of caspases, a family of proteases implicated in apoptosis and the cytokine secretion. We observed that extracellular ATP induced the activation of multiple caspases including caspase-1, -3 and -8, and subsequent cleavage of the caspase substrates PARP and lamin B. Using caspase inhibitors, it was found that caspases were specifically involved in ATP-induced apoptotic damage such as chromatin condensation and DNA fragmentation. In contrast, inhibition of caspases only marginally affected necrotic alterations and cell death proceeded normally whether or not nuclear damage was blocked. Our results therefore suggest that the activation of caspases by the P2Z receptor is required for apoptotic but not necrotic alterations of ATP-induced cell death
Activation of the death receptor apoptosis pathway by TRAIL overcomes anticancer drug resisitance in antiapoptotic bcl-2 family members expressing lymphoma cells
No full textPurinoceptor-mediated activation of transcription factors NFAT and NF-kB in microglial cells.
No full textNFAT and NF-kB are important transcriptional regulators that play a role in controlling the expression of several cytokines, cytokine receptors and adhesion molecules. The effect of extracellular ATP on the activation of NF-kB and NFAT was investigated in the mouse microglial cell lines N9 and N13. ATP potently activated NF-kB and NFAT with strikingly distinct kinetics. NFAT was induced as soon as 1 min after stimulation with the nucleotide, while NF-kB activation was quite delayed (3 h). Both NFAT-1 and NFAT-2 were activated by a calcineurin-dependent pathway that required influx of extracellular Ca2+. Inhibition of calcineurin and Ca2+ chelation prevented ATP-induced NFAT activation and nuclear translocation. Exposure to LPS induced the prototypical NF-kB p50 homo and p65/p50 heterodimers while ATP, only induced the peculiar p65 homodimer. NFAT and NF-kB activation involved a P2X-mediated pathway as oxidized ATP completely inhibited the activation of both factors and BzATP was a better agonist than ATP in inducing NFAT and NF-kB. Cells selected for the absence of P2X7 receptor but still expressing the P2Y subtype were refractory to ATP, suggesting that ATP-stimulated activation was a P2X7-mediated process. Furthermore, NF-kB activation required ROI production and involved proteasome activity, while secretion of soluble proteins was not required. Caspase-1 (ICE) was also activated during exposure to ATP
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Differential regulation and ATP requirement for caspase-8 and caspase-3 activation during CD95- and anticancer drug-induced apoptosis
No full textApoptosis is induced by different stimuli, among them triggering of the death receptor CD95, staurosporine, and chemotherapeutic drugs. In all cases, apoptosis is mediated by caspases, although it is unclear how these diverse apoptotic stimuli cause protease activation. Two regulatory pathways have been recently identified, but it remains unknown whether they are functionally independent or linked to each other. One is mediated by recruitment of the proximal regulator caspase-8 to the death receptor complex. The other pathway is controlled by the release of cytochrome c from mitochondria and the subsequent ATP-dependent activation of the death regulator apoptotic protease-activating factor 1 (Apaf-1). Here, we report that both pathways can be dissected by depletion of intracellular ATP. Prevention of ATP production completely inhibited caspase activation and apoptosis in response to chemotherapeutic drugs and staurosporine. Interestingly, caspase-8, whose function appeared to be restricted to death receptors, was also activated by these drugs under normal conditions, but not after ATP depletion. In contrast, inhibition of ATP production did not affect caspase activation after triggering of CD95. These results suggest that chemotherapeutic drug-induced caspase activation is entirely controlled by a receptor-independent mitochondrial pathway, whereas CD95-induced apoptosis can be regulated by a separate pathway not requiring Apaf-1 function
Regulation of NF-κB Activation by MAP Kinase Cascades
No full textTranscription factor NF-kappa B plays a crucial role in the regulation of numerous genes involved in the inflammatory response and control of cell death. Activation of NF-kappa B is mediated through the phosphorylation of its inhibitory subunit I kappa B, followed by the subsequent degradation of I kappa B at the proteasome. A second level of control involves phosphorylation events of NF-kappa B in the cell nucleus. The kinases that regulate these processes are rather undefined. NF-kappa B activation is induced by a great variety of predominantly pathogenic and noxious stimuli. A similar spectrum of conditions triggers the activation of two mitogen-activated protein (MAP) kinase cascades, designated as the JNK and p38 kinase pathways. Several points of evidence suggest that MAP kinases can participate in the regulation of NF-kappa B transcriptional activity. Here, we will review very recent data demonstrating that both the JNK and the p38 pathways are involved in the activation of NF-kappa B in the cytoplasm as well as in modulation of its transactivating potential in the nucleus
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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