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  • American Association for the Advancement of Science (AAAS)  (8)
  • Foley, John F.  (8)
  • English  (8)
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  • American Association for the Advancement of Science (AAAS)  (8)
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  • Foley, John F.  (8)
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  • English  (8)
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  • 1
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    American Association for the Advancement of Science (AAAS) ; 2011
    In:  Science Signaling Vol. 4, No. 158 ( 2011-02)
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    In: Science Signaling, American Association for the Advancement of Science (AAAS), Vol. 4, No. 158 ( 2011-02)
    Abstract: Circadian rhythms, which have a periodicity of ~24 hours, regulate many physiological and metabolic processes. From algae to humans, circadian rhythms are regulated by a transcription-translation feedback loop. The products of clock genes are transcriptional activators that drive the expression of repressor genes, whose products feed back to inhibit the activators (see Bass and Takahashi). O’Neill and Reddy investigated a role for nontranscriptional control of circadian rhythms in human red blood cells (RBCs), which lack nuclei and cannot support transcription. The authors monitored peroxiredoxins, proteins that protect RBCs from peroxides by becoming oxidized and forming dimers, which are then reduced to the monomeric form. The authors found that peroxiredoxins exhibited a circadian redox rhythm in RBCs kept in the dark at constant temperature. This cycle could be entrained by temperature and was not affected by inhibitors of transcription or translation. The equilibrium between dimeric hemoglobin (a source of peroxide) and tetrameric hemoglobin (which produces less peroxide) also exhibited a circadian rhythm, as did the reducing agents NADH and NADPH. The redox cycle of peroxiredoxins in mouse NIH 3T3 cells also exhibited a circadian rhythm, and this was altered in cells from mice deficient in clock genes. Conversely, knockdown of various peroxiredoxin-encoding genes in human cells had effects on circadian gene expression. In an accompanying study, O’Neill et al . examined circadian rhythms in the simple alga Ostreococcus tauri . When kept at constant temperature in the dark, circadian rhythms in the alga that are controlled by transcription-translation loops are suspended until it is reexposed to light. However, the cycles continue from the point at which darkness occurred, rather than becoming reset. The authors found that redox cycles of peroxiredoxins in the alga persisted in the dark in a transcription-independent manner and that inhibitors of clocks in mammalian cells had similar effects in the alga. Together, these studies suggest that nontranscriptional metabolic cycles couple with genetic oscillators to control rhythmic outputs. J. S. O’Neill, A. B. Reddy, Circadian clocks in human red blood cells. Nature 469 , 498–503 (2011). [Online Journal] J. S. O’Neill, G. van Ooijen, L. E. Dixon, C. Troein, F. Corellou, F.-Y. Bouget, A. B. Reddy, A. J. Millar, Circadian rhythms persist without transcription in a eukaryote. Nature 469 , 554–558 (2011). [Online Journal] J. Bass, J. S. Takahashi, Redox redux. Nature 469 , 476–478 (2011). [Online Journal]
    Type of Medium: Online Resource
    ISSN: 1945-0877 , 1937-9145
    URL: Article
    DOI: 10.1126/scisignal.4158ec29
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2011
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  • 2
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    The NADPH Survival Advantage
    American Association for the Advancement of Science (AAAS) ; 2012
    In:  Science Signaling Vol. 5, No. 227 ( 2012-06-05)
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    In: Science Signaling, American Association for the Advancement of Science (AAAS), Vol. 5, No. 227 ( 2012-06-05)
    Abstract: Under conditions of metabolic stress that lead to a decrease in the intracellular concentration of adenosine triphosphate (ATP), liver kinase B1 (LKB1) is activated, which in turn phosphorylates and activates adenosine monophosphate (AMP)–activated protein kinase (AMPK), which modulates glucose metabolism and autophagy in the cell to promote energy homeostasis. The LKB1-AMPK signaling pathway is also activated in tumor cells in response to certain oncogenes and as a result of the detachment of cells from the extracellular matrix. Noting that cells deficient in LKB1 or AMPK are resistant to oncogenic transformation, Jeon et al . investigated how AMPK modulated metabolism in tumor cells. A549 cells, a human epithelial cancer cell line deficient in LKB1, were more sensitive than LKB1-sufficient cell lines to cell death induced by glucose deprivation. In addition, LKB1-deficient cells exhibited increased NADPH depletion and oxidative stress during glucose deprivation compared with LKB1-sufficient cells. NADPH is consumed by fatty acid synthesis (FAS) and generated through fatty acid oxidation (FAO). NAPDH reduces oxidative stress in cells by detoxifying hydrogen peroxide. AMPK phosphorylates and inhibits the enzymes acetyl-CoA carboxylase 1 (ACC1) and ACC2, thereby inhibiting FAS and increasing FAO. The authors found that knockdown of ACC1 or ACC2 substantially inhibited A549 cell death induced by glucose deprivation. Additionally, AMPK activation was required for the inhibition of the ACCs and for the maintenance of NAPDH abundance in cells during conditions of glucose deprivation or matrix detachment. Tumor growth in mice injected with oncogenic fibroblasts expressing mutant ACC isoforms that could not be phosphorylated by AMPK was reduced compared to that in mice injected with control tumor cells. Together, these data suggest that under conditions of metabolic stress, AMPK maintains NAPDH concentrations in tumor cells to reduce oxidative stress and promote survival. As Svensson and Shaw discuss in commentary, future work will determine how the timing and context of LKB1-AMPK signaling determine tumor cell survival. S.-M. Jeon, N. S. Chandel, N. Hay, AMPK regulates NAPDH homeostasis to promote tumour cell survival during energy stress. Nature 485 , 661–665 (2012). [Online Journal] R. U. Svensson, R. J. Shaw, Tumour friend or foe. Nature 485 , 590–591 (2012). [Online Journal]
    Type of Medium: Online Resource
    ISSN: 1945-0877 , 1937-9145
    URL: Article
    DOI: 10.1126/scisignal.2003284
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2012
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  • 3
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    Life and Death with Salicylic Acid
    American Association for the Advancement of Science (AAAS) ; 2012
    In:  Science Signaling Vol. 5, No. 229 ( 2012-06-19)
    Details
    In: Science Signaling, American Association for the Advancement of Science (AAAS), Vol. 5, No. 229 ( 2012-06-19)
    Abstract: When a plant is attacked by a pathogen, effector-triggered immunity is induced, which results in programmed cell death (PCD) at the site of infection and systemic acquired resistance (SAR) in other areas of the plant. SAR depends on the hormone salicylic acid (SA), which is produced at the site of infection and gradually decreases in concentration with increasing distance from the site of infection (see commentary by Gust and Nürnberger). SA controls the nuclear translocation of the transcriptional cofactor nonexpresser of PR genes 1 (NPR1), which is required for SAR. When NPR1 is degraded, cells undergo PCD, whereas when NPR1 accumulates in the nucleus, it induces the expression of genes required for SAR. Noting that degradation of NPR1 acts as a molecular switch to determine the response to infection, Fu et al . sought binding partners of NPR1 that might regulate its targeting by the CUL3 E3 ubiquitin ligase system in Arabidopsis thaliana . They found that loss of the NPR1 homologs NPR3 or NPR4, which contain domains typical of CUL3 adaptor proteins, prevented CUL3-dependent degradation of NPR1. Yeast two-hybrid studies and pull-down assays showed that NPR3 and NPR4 individually interacted with NPR1; however, NPR3 interacted with NPR1 only in the presence of SA and NPR4 interacted with NPR1 only in the absence of SA. Binding studies with [ 3 H]-SA showed that NPR3 was a low-affinity receptor for SA, whereas NPR4 was a high-affinity receptor. Studies of wild-type or NPR3- or NPR4-mutant Arabidopsis infected with a pathogen showed that loss of either NPR3 or NPR4 had differential effects on plant responses. These data led the authors to propose a model in which SA, which is at high concentration at the site of infection, binds to NPR3, enabling it to recruit CUL3 to NPR1, which leads to NPR1 degradation and PCD. In contrast, at more distant sites, SA is lower in concentration and binds only to the high-affinity receptor NPR4, which blocks its interaction with NPR1, causing NPR1 to accumulate, translocate to the nucleus, and induce SAR. Z. Q. Fu, S. Yan, A. Saleh, W. Wang, J. Ruble, N. Oka, R. Mohan, S. H. Spoel, Y. Tada, N. Zheng, X. Dong, NPR3 and NPR4 are receptors for the immune signal salicylic acid in plants. Nature 486 , 228–232 (2012). [Online Journal] A. D. Gust, T. Nürnberger, A life or death switch. Nature 486 , 198–199 (2012). [Online Journal]
    Type of Medium: Online Resource
    ISSN: 1945-0877 , 1937-9145
    URL: Article
    DOI: 10.1126/scisignal.2003315
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2012
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  • 4
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    Getting Choosy
    American Association for the Advancement of Science (AAAS) ; 2011
    In:  Science Signaling Vol. 4, No. 193 ( 2011-10-04)
    Details
    In: Science Signaling, American Association for the Advancement of Science (AAAS), Vol. 4, No. 193 ( 2011-10-04)
    Abstract: Members of the NOD-like receptor (NLR) family of cytosolic proteins respond to microbial components in the cytoplasm of infected cells by forming multiprotein complexes called inflammasomes, which stimulate the processing and activation of caspase 1. This protease then processes precursor forms of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18, which induce cell death. NLRC4-containing inflammasomes are formed in response to the bacterial proteins flagellin and PrgJ, a conserved component of the type-III secretion system (TTSS); however, how NLRC4 responds to specific stimuli is unclear (see commentary by Monack). Two groups now implicate NLR family members called NAIPs (NLR family, apoptosis inhibitory proteins) in determining the ligand specificity of NLRC4 inflammasome activation. Kofoed and Vance showed that mouse macrophages lacking NAIP2 failed to activate caspase 1 or undergo cell death in response to PrgJ; however, loss of NAIP2 had no effect on cell death induced by flagellin. In contrast, NAIP5 was required for flagellin-induced caspase 1 activation but was not necessary for cell death induced by PrgJ. Experiments in a reconstituted in vitro system showed that stimulation of NLRC4 inflammasome formation by flagellin required NAIP5, and NAIP5 and flagellin were also present in the complex. In contrast, PrgJ did not induce NAIP5-NLRC4 inflammasome formation but did stimulate complex formation between NAIP2 and NLRC4. Zhao et al . also demonstrated the ability of NAIP2 and NAIP5 to activate NLRC4 inflammasome formation in mouse cells in response to distinct ligands from various bacteria. In addition, they showed that CprI (a TTSS component from Chromobacterium violaceum ), but not flagellin, activated NLRC4 inflammasome formation in a human macrophage cell line and that CprI bound to NAIP, the sole human NAIP protein. Together, these data suggest that NAIP proteins bind directly to distinct microbial products and confer ligand specificity to NLRC4 inflammasomes. E. M. Kofoed, R. E. Vance, Innate immune recognition of bacterial ligands by NAIPs determines inflammasome specificity. Nature 477 , 592–595 (2011). [PubMed] Y. Zhao, J. Yang, J. Shi, Y.-N. Gong, Q. Lu, H. Xu, L. Liu, F. Shao, The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus. Nature 477 , 596–600 (2011). [PubMed] D. M. Monack, Recognition of a unique partner. Nature 477 , 543–544 (2011). [Online Journal]
    Type of Medium: Online Resource
    ISSN: 1945-0877 , 1937-9145
    URL: Article
    DOI: 10.1126/scisignal.4193ec274
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2011
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  • 5
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    Exciting Structures
    American Association for the Advancement of Science (AAAS) ; 2009
    In:  Science Signaling Vol. 2, No. 101 ( 2009-12-15)
    Details
    In: Science Signaling, American Association for the Advancement of Science (AAAS), Vol. 2, No. 101 ( 2009-12-15)
    Abstract: Glutamate is an excitatory neurotransmitter, which when released into the synapse activates metabotropic and ionotropic glutamate receptors in postsynaptic cells. Ionotropic glutamate receptors (iGluRs), such as AMPA, NMDA, and kainate receptors, are ligand-gated ion channels consisting of tetramers of receptor subunits containing amino-terminal domains (ATDs), ligand-binding domains (LBDs), and transmembrane domains (TMDS), which form the ion channel (see Wollmuth and Traynelis). Whereas previous studies have focused on individual domains of various iGluRs, Sobolevsky et al . solved the x-ray crystal structure of the full-length rat AMPA receptor, a homotetramer of GluA2 subunits, bound to an antagonist. The structure resembled a “Y,” with the ATDs at the prongs, the TMDs at the base, and the LBDs between the two. Whereas the extracellular ATDs and LBDs consisted of pairs of dimers arranged around two-fold axes of symmetry, the TMDs exhibited a four-fold, rotational axis of symmetry. Substantial crossover of the subunits (A to D) resulted in domain-swapping in the extracellular regions. Thus, the dimer pairs at the level of the ATDs were A-B and C-D, whereas at the lower level of the LBDs, the pairs were A-D and B-C. The authors found similar structural features in NMDA receptors made up of GluN1 and GluN2 subunits. Analysis of the structure of the TMDs and the ion channel of the AMPA receptor, which was closed because of the antagonist, revealed similarities with the pores of K + channels. Based on the structure as a whole, the authors proposed mechanisms for the action, desensitization, and inhibition of the AMPA receptor, which they suggest can be applied to iGluRs in general. A. I. Sobolevsky, M. P. Rosconi, E. Gouaux, X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor. Nature 462 , 745–756 (2009). [PubMed] L. P. Wollmuth, S. F. Traynelis, Excitatory view of a receptor. Nature 462 , 729–731 (2009). [Online Journal]
    Type of Medium: Online Resource
    ISSN: 1945-0877 , 1937-9145
    URL: Article
    DOI: 10.1126/scisignal.2101ec398
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2009
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    Sweet Signals
    American Association for the Advancement of Science (AAAS) ; 2012
    In:  Science Signaling Vol. 5, No. 212 ( 2012-02-21)
    Details
    In: Science Signaling, American Association for the Advancement of Science (AAAS), Vol. 5, No. 212 ( 2012-02-21)
    Abstract: When the bacterium Salmonella enterica serovar Typhimurium infects a cell, it enters a vesicle called the Salmonella -containing vacuole (SCV), from which it secretes effector proteins into the host cytosol to modulate the immune response. Such activity damages the SCV, which enables some bacteria to escape and replicate in the cytosol (see commentary by Huang and Brumell). Damage to the SCV stimulates components of the autophagy machinery, such as p62 and NDP52, to target the exposed bacteria, resulting in formation of an autophagosome around the SCV and destruction of the bacteria. Thurston et al . investigated a role for galectins, lectins that are best known to bind to glycans extracellularly, in stimulating autophagy in Salmonella -infected HeLa cells. About 10% of S . Typhyimurium were coated with various galectins within 1 hour of infection and were associated with lysosomes. Knockdown of galectin 8, but not other galectins, resulted in increased proliferation of bacteria compared with that in control cells. Galectin 8 physically associated with NDP52 in vitro, and many SCVs in infected HeLa cells contained both galectin 8 and NDP52. Recruitment of galectin 8 to damaged SCVs did not depend on Salmonella components, but on the exposure of host glycans within the vesicle membrane. Indeed, osmotic damage of endosomes or lysosomes in uninfected cells also resulted in the recruitment of galectin 8, which was dependent on its N-terminal carbohydrate-recognition domain. Galectins 3, 8, and 9 also accumulated on other types of bacteria in infected cells. Whereas binding of NDP52 to galectin 8–coated bacteria occurred early in infection, binding of NDP52 to ubiquitinated bacteria, a previously characterized mechanism that triggers an autophagic response, occurred at later time points. Together, these data suggest that galectin 8 provides an early alternative response to infection of cells by bacteria by sensing damage of vesicular membranes and stimulating the autophagic response. T. L. M. Thurston, M. P. Wandel, N. von Muhlinen, Á. Foeglein, F. Randow, Galectin 8 targets damaged vesicles for autophagy to defend cells against bacterial invasion. Nature 482 , 414–418 (2012). [PubMed] J. Huang, J. H. Brumell, A sweet way of sensing danger. Nature 482 , 316–317 (2012). [Online Journal]
    Type of Medium: Online Resource
    ISSN: 1945-0877 , 1937-9145
    URL: Article
    DOI: 10.1126/scisignal.2002973
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2012
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    Tryptophan Fix
    American Association for the Advancement of Science (AAAS) ; 2011
    In:  Science Signaling Vol. 4, No. 195 ( 2011-10-18)
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    In: Science Signaling, American Association for the Advancement of Science (AAAS), Vol. 4, No. 195 ( 2011-10-18)
    Abstract: Breakdown of tryptophan to kynurenine by the enzyme indoleamine-2,3-dioxygenase (IDO) inhibits T cell responses and promotes immune tolerance. Tryptophan degradation by IDO in tumor cells is associated with immune evasion and increased tumor growth (see commentary by Prendergast). Thus, better understanding of how tryptophan catabolism affects immune responses might help to develop anticancer therapies. Opitz et al . found that cultured human glioma cell lines and glioma-initiating cells degraded tryptophan and produced large quantities of kynurenine. Knockdown of IDO isoforms in these cells had no effect on tryptophan metabolism; rather, knockdown of another tryptophan-degrading enzyme, TDO, blocked production of kynurenine. Immunohistochemical analysis showed that the abundance of TDO correlated with malignancy in human brain tumors. The amount of kynurenine produced by glioma cells correlated with inhibition of the proliferation of cocultured T cells. Knockdown of TDO in glioma cells restored T cell proliferation, whereas T cell proliferation was inhibited by the addition of exogenous kynurenine. The growth of TDO knockdown tumors implanted in the brains of nude mice was impeded compared to that of tumors proficient in TDO . Microarray analysis of kynurenine-treated glioma cells revealed the enhanced expression of many aryl hydrocarbon receptor (AHR)–responsive genes. The AHR is a transcription factor that responds to xenobiotic compounds, such as dioxin, to suppress immune responses and stimulate tumorigenesis. AHR-responsive gene expression in glioma cells was decreased when TDO was knocked down, suggestive of autocrine AHR signaling. However, when injected into Ahr -deficient mice, Tdo -expressing tumor cells exhibited attenuated growth, suggesting that paracrine AHR signaling was also required for tumor progression. Microarray analysis showed that expression of TDO correlated with that of AHR-responsive genes in many different cancer types, and high expression of TDO , AHR , or the AHR-responsive gene CYP1B1 correlated with poor survival of glioma patients. Together, these data suggest that TDO-derived kynurenine acts in an autocrine and paracrine fashion through the AHR to promote tumor growth. C. A. Opitz, U. M. Litzenburger, F. Sahm, M. Ott, I. Tritschler, S. Trump, T. Schumacher, L. Jestaedt, D. Schrenk, M. Weller, M. Jugold, G. J. Guillemin, C. L. Miller, C. Lutz, B. Radlwimmer, I. Lehmann, A. von Deimling, W. Wick, M. Platten, An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478 , 197–203 (2011). [PubMed] G. C. Prendergast, Why tumours eat tryptophan. Nature 478 , 192–194 (2011). [Online Journal]
    Type of Medium: Online Resource
    ISSN: 1945-0877 , 1937-9145
    URL: Article
    DOI: 10.1126/scisignal.4195ec289
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2011
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    Evading a Block on Translation
    American Association for the Advancement of Science (AAAS) ; 2012
    In:  Science Signaling Vol. 5, No. 228 ( 2012-06-12)
    Details
    In: Science Signaling, American Association for the Advancement of Science (AAAS), Vol. 5, No. 228 ( 2012-06-12)
    Abstract: Under conditions of normal oxygen tension (normoxia), translation of messenger RNAs (mRNAs) into proteins depends on the binding of eukaryotic translation initiation factor 4E (eIF4E) to the 7-methylguanosine (m 7 -GpppG) 5′ cap of the mRNA. When oxygen tension is low (hypoxia), mammalian target of rapamycin (mTOR)–dependent signaling results in the sequestration of eIF4E, thus inhibiting cap-dependent translation. Uniacke et al . studied expression of the gene encoding the epidermal growth factor receptor (EGFR) and found that EGFR mRNA was translated under hypoxic conditions through a process that was dependent on hypoxia-inducible factor 2α (HIF-2α) but was not affected by the addition of transcription inhibitors to block the expression of HIF-2α target genes. EGFR mRNA was associated with polysomes in hypoxic cells, and knockdown of HIF-2α blocked its translation. HIF-2α was physically associated with polysomes containing EGFR mRNA, and RNA immunoprecipitation assays showed that the HIF-2α was associated with a region in the 3′-untranslated region (UTR) of EGFR mRNA. This association was indirect and depended on RNA-binding motif protein 4 (RBM4), which interacted with the N-terminal region of HIF-2α during hypoxia to recruit HIF-2α to EGFR mRNA. The RBM4–HIF-2α complex was captured by m 7 -GpppG–conjugated beads, and immunoprecipitation studies showed that the RBM4–HIF-2α complex bound to eIF4E2, a homolog of eIF4E. Silencing of eIF4E2, but not eIF4E, blocked the translation of EGFR mRNA, among others, during hypoxia. Under normoxic conditions, eIF4E was associated with polysomes, whereas under hypoxic conditions, eIF4E was replaced with eIF4E2. Inhibition of mTOR with rapamycin blocked mRNA translation under normoxic, but not hypoxic, conditions. Together, these data suggest that a reduction in oxygen tension causes a switch from eIF4E- to eIF4E2-dependent translation through a process that depends on HIF-2α. J. Uniacke, C. E. Holterman, G. Lachance, A. Franovic, M. D. Jacob, M. R. Fabian, J. Payette, M. Holcik, A. Pause, S. Lee, An oxygen-regulated switch in the protein synthesis machinery. Nature 486 , 126–129 (2012). [Online Journal]
    Type of Medium: Online Resource
    ISSN: 1945-0877 , 1937-9145
    URL: Article
    DOI: 10.1126/scisignal.2003303
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2012
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