EMBO Reports

NF-kappaB: no longer an island, but a piece of a continent.

Publication Date: 2010 Mar 5 PMID: 20203698
Authors: Natoli, G.
Journal: EMBO Rep

The Keystone meeting on NF-kappaB in Inflammation and Disease held in January covered several aspects of NF-kappaB regulation. Many new concepts emerged in signalling, transcriptional control and the involvement of NF-kappaB in disease, particularly cancer.

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Differences in the DNA replication of unicellular eukaryotes and metazoans: known unknowns.

Publication Date: 2010 Feb 26 PMID: 20203697
Authors: Errico, A. - Costanzo, V.
Journal: EMBO Rep

Although the basic mechanisms of DNA synthesis are conserved across species, there are differences between simple and complex organisms. In contrast to lower eukaryotes, replication origins in complex eukaryotes lack DNA sequence specificity, can be activated in response to stressful conditions and require poorly conserved factors for replication firing. The response to replication fork damage is monitored by conserved proteins, such as the TIPIN-TIM-CLASPIN complex. The absence of this complex induces severe effects on yeast replication, whereas in higher eukaryotes it is only crucial when the availability of replication origins is limiting. Finally, the dependence of DNA replication on homologous recombination proteins such as RAD51 and the MRE11-RAD50-NBS1 complex is also different; they are dispensable for yeast S-phase but essential for accurate DNA replication in metazoans under unchallenged conditions. The reasons for these differences are not yet understood. Here, we focus on some of these known unknowns of DNA replication.

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Tame affairs: domesticated transposase and domestic pigs.

Publication Date: 2010 Feb 26 PMID: 20203696
Authors: Volff, J. N.
Journal: EMBO Rep

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Women and telomeres.

Publication Date: 2010 Mar PMID: 20195279
Authors: Wolinsky, H.
Journal: EMBO Rep

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The basis of morality.

Publication Date: 2010 Mar PMID: 20195278
Authors: Hunter, P.
Journal: EMBO Rep

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Comment on 'Big science, little science'.

Publication Date: 2010 Mar PMID: 20195277
Authors: Valentine, A. J.
Journal: EMBO Rep

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Response by steven rose.

Publication Date: 2010 Mar PMID: 20195276
Authors: Rose, S.
Journal: EMBO Rep

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It takes two to tango.

Publication Date: 2010 Mar PMID: 20195275
Authors: Berlin, S.
Journal: EMBO Rep

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Comment on Steven Rose's opinion article, 'Academic freedom in Israel and Palestine'.

Publication Date: 2010 Mar PMID: 20195274
Authors: Elson, A.
Journal: EMBO Rep

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Pandemics: is hoping for the best enough?

Publication Date: 2010 Mar PMID: 20195273
Authors: Osterhaus, A. D.
Journal: EMBO Rep

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In defence of our realm.

Publication Date: 2010 Mar PMID: 20195272
Authors: Jacobs, H.
Journal: EMBO Rep

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Structural basis for the function of DEAH helicases.

Publication Date: 2010 Mar PMID: 20168331
Authors: He, Y. - Andersen, G. R. - Nielsen, K. H.
Journal: EMBO Rep

DEAH helicases participate in pre-messenger RNA splicing and ribosome biogenesis. The structure of yeast Prp43p-ADP reveals the homology of DEAH helicases to DNA helicases and the presence of an oligonucleotide-binding motif. A beta-hairpin from the second RecA domain is wedged between two carboxy-terminal domains and blocks access to the occluded RNA binding site formed by the RecA domains and a C-terminal domain. ATP binding and hydrolysis are likely to induce conformational changes in the hairpin that are important for RNA unwinding or ribonucleoprotein remodelling. The structure of Prp43p provides the framework for functional and genetic analysis of all DEAH helicases.

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Transcriptional targets of Drosophila JAK/STAT pathway signalling as effectors of haematopoietic tumour formation.

Publication Date: 2010 Mar PMID: 20168330
Authors: Bina, S. - Wright, V. M. - Fisher, K. H. - Milo, M. - Zeidler, M. P.
Journal: EMBO Rep

Although many signal transduction pathways have been implicated in the development of human disease, the identification of pathway targets and the biological processes that mediate disease progression remains challenging. One such disease-related pathway is the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) cascade whose constitutive misactivation by the JAK2 V617F mutation underlies most human myeloproliferative disorders. Here, we use transcript profiling of Drosophila haemocyte-like cells to identify JAK/STAT target genes, combined with an in vivo model for JAK-induced blood cell overproliferation, to identify the main effectors required for haematopoietic tumour development. The identified human homologues of the Drosophila effectors were tested for potential V617F-mediated transcriptional regulation in human HeLa cells and compared with small interfering RNA-derived data, quantify their role in regulating the proliferation of cancer-derived cell lines. Such an inter-species approach is an effective way to identify factors with conserved functions that might be central to human disease.

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From discovering to understanding.

Publication Date: 2010 Mar PMID: 20168329
Authors: Dahm, R.
Journal: EMBO Rep

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Induced pluripotent stem cells: paths to new medicines.

Publication Date: 2010 Mar PMID: 20168328
Authors: Deng, W.
Journal: EMBO Rep

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TBCCD1, a new centrosomal protein, is required for centrosome and Golgi apparatus positioning.

Publication Date: 2010 Mar PMID: 20168327
Authors: Goncalves, J. - Nolasco, S. - Nascimento, R. - Fanarraga, M. L. - Zabala, J. C. - Soares, H.
Journal: EMBO Rep

In animal cells the centrosome is positioned at the cell centre in close association with the nucleus. The mechanisms responsible for this are not completely understood. Here, we report the first characterization of human TBCC-domain containing 1 (TBCCD1), a protein related to tubulin cofactor C. TBCCD1 localizes at the centrosome and at the spindle midzone, midbody and basal bodies of primary and motile cilia. Knockdown of TBCCD1 in RPE-1 cells caused the dissociation of the centrosome from the nucleus and disorganization of the Golgi apparatus. TBCCD1-depleted cells are larger, less efficient in primary cilia assembly and their migration is slower in wound-healing assays. However, the major microtubule-nucleating activity of the centrosome is not affected by TBCCD1 silencing. We propose that TBCCD1 is a key regulator of centrosome positioning and consequently of internal cell organization.

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Evolution and regulation of cellular periodic processes: a role for paralogues.

Publication Date: 2010 Mar PMID: 20168326
Authors: Trachana, K. - Jensen, L. J. - Bork, P.
Journal: EMBO Rep

Several cyclic processes take place within a single organism. For example, the cell cycle is coordinated with the 24 h diurnal rhythm in animals and plants, and with the 40 min ultradian rhythm in budding yeast. To examine the evolution of periodic gene expression during these processes, we performed the first systematic comparison in three organisms (Homo sapiens, Arabidopsis thaliana and Saccharomyces cerevisiae) by using public microarray data. We observed that although diurnal-regulated and ultradian-regulated genes are not generally cell-cycle-regulated, they tend to have cell-cycle-regulated paralogues. Thus, diverged temporal expression of paralogues seems to facilitate cellular orchestration under different periodic stimuli. Lineage-specific functional repertoires of periodic-associated paralogues imply that this mode of regulation might have evolved independently in several organisms.

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Silencing in trans: position matters in fission yeast.

Publication Date: 2010 Mar PMID: 20154645
Authors: Gullerova, M. - Proudfoot, N. J.
Journal: EMBO Rep

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Protein synthesis meets ABC ATPases: new roles for Rli1/ABCE1.

Publication Date: 2010 Mar PMID: 20154644
Authors: Rodnina, M. V.
Journal: EMBO Rep

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The spectacular landscape of chromatin and ncRNAs under the Tico sunlight.

Publication Date: 2010 Mar PMID: 20154643
Authors: Timmers, H. T. - Tora, L.
Journal: EMBO Rep

The biannual Abcam meeting on Chromatin: Structure & Function held last November covered many aspects of chromatin regulation in health and disease. Important discussion points were the dynamic aspects of chromatin and the ever-increasing involvement of non-coding RNAs in chromatin and epigenetic mechanisms.

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A functional role for the p62-ERK1 axis in the control of energy homeostasis and adipogenesis.

Publication Date: 2010 Mar PMID: 20154642
Authors: Lee, S. J. - Pfluger, P. T. - Kim, J. Y. - Nogueiras, R. - Duran, A. - Pages, G. - Pouyssegur, J. - Tschop, M. H. - Diaz-Meco, M. T. - Moscat, J.
Journal: EMBO Rep

In vivo genetic inactivation of the signalling adapter p62 leads to mature-onset obesity and insulin resistance, which correlate with reduced energy expenditure (EE) and increased adipogenesis, without alterations in feeding or locomotor functions. Enhanced extracellular signal-regulated kinase (ERK) activity in adipose tissue from p62-knockout (p62(-/-)) mice, and differentiating fibroblasts, suggested an important role for this kinase in the metabolic alterations of p62(-/-) mice. Here, we show that genetic inactivation of ERK1 in p62(-/-) mice reverses their increased adiposity and adipogenesis, lower EE and insulin resistance. These results establish genetically that p62 is a crucial regulator of ERK1 in metabolism.

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Skp2B attenuates p53 function by inhibiting prohibitin.

Publication Date: 2010 Mar PMID: 20134482
Authors: Chander, H. - Halpern, M. - Resnick-Silverman, L. - Manfredi, J. J. - Germain, D.
Journal: EMBO Rep

The F-box protein Skp2 and its isoform Skp2B are both overexpressed in breast cancers. Skp2 alters the activity of p53 by inhibiting its interaction with p300 and by promoting p300 degradation. Here, we report that Skp2B also attenuates the activity of p53; however, this effect is independent of p300, suggesting that another mechanism might be involved. Prohibitin, a protein reported to activate p53, was isolated in a two-hybrid screen with the carboxy-terminal domain unique to Skp2B. We observed that prohibitin is a new substrate of Skp2B and that the degradation of prohibitin is responsible for the attenuated activity of p53 in cells overexpressing Skp2B. Furthermore, we show that the activity of p53 is reduced in the mammary glands of Skp2B transgenic mice. This study indicates that both Skp2 and Skp2B attenuate p53 activity through different pathways, suggesting that amplification of the Skp2 locus represents a powerful mechanism to attenuate p53 function in cancer.

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Transcriptional activation of DNA-dependent protein kinase catalytic subunit gene expression by oestrogen receptor-alpha.

Publication Date: 2010 Mar PMID: 20111054
Authors: Medunjanin, S. - Weinert, S. - Poitz, D. - Schmeisser, A. - Strasser, R. H. - Braun-Dullaeus, R. C.
Journal: EMBO Rep

The cellular response to DNA double-strand break (DSB) occurs through an integrated sensing and signalling network that maintains genomic stability. Oestrogen (E2), among its many functions, is known to have a positive effect on global genomic DNA repair; however, the mechanism by which it functions is unclear. A central enzyme involved in DNA DSB repair in mammalian cells is the DNA-dependent protein kinase (DNA-PK). Here, we show that E2 enhances DNA-PK catalytic subunit (DNA-PKcs) promoter activity with subsequent transcriptional and translational upregulation of DNA-PKcs in a breast cancer cell line. We identify two potential E2 receptor-alpha (ERalpha)-binding sites in a region upstream from the DNA-PKcs initiation site. By using small interfering RNA and the specific E2 receptor antagonist ICI 182,780, we demonstrate that ERalpha knockdown reduces E2-induced upregulation of DNA-PKcs expression and activity in breast carcinoma cells. E2-induced DNA-PK transactivation results in an increased ability of the cells to repair DNA DSB. This previously unknown mechanism of DNA-PK regulation sheds new light on tumour biology and reveals new possibilities for the prevention and therapy of E2-sensitive proliferative diseases.

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Mdm10 as a dynamic constituent of the TOB/SAM complex directs coordinated assembly of Tom40.

Publication Date: 2010 Mar PMID: 20111053
Authors: Yamano, K. - Tanaka-Yamano, S. - Endo, T.
Journal: EMBO Rep

The mitochondrial outer membrane contains two protein translocators: the TOM40 and TOB/SAM complexes. Mdm10 is distributed in the TOB complex for beta-barrel protein assembly and in the MMM1 complex for tethering of the endoplasmic reticulum and mitochondria. Here, we establish a system in which the Mdm10 level in the TOB complex-but not in the MMM1 complex-is altered to analyse its part in beta-barrel protein assembly. A decrease in the Mdm10 level results in accumulation of in vitro imported Tom40, which is a beta-barrel protein, at the level of the TOB complex. An increase in the Mdm10 level inhibits association not only of Tom40 but also of other beta-barrel proteins with the TOB complex. These results show that Mdm10 regulates the timing of release of unassembled Tom40 from the TOB complex, to facilitate its coordinated assembly into the TOM40 complex.

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Ionotropic and metabotropic mechanisms in chemoreception: 'chance or design'?

Publication Date: 2010 Mar PMID: 20111052
Authors: Silbering, A. F. - Benton, R.
Journal: EMBO Rep

Chemosensory receptors convert an enormous diversity of chemical signals from the external world into a common language of electrical activity in the brain. Mammals and insects use several families of transmembrane receptor proteins to recognize distinct classes of volatile and non-volatile chemicals that are produced by conspecifics or other environmental sources. A comparison of the signalling mechanisms of mammalian and insect receptors has revealed an unexpected functional distinction: mammals rely almost exclusively on metabotropic ligand-binding receptors, which use second messenger signalling cascades to indirectly activate ion channels, whereas insects use ionotropic receptors, which are gated directly by chemical stimuli, thereby leading to neuronal depolarization. In this review, we consider possible reasons for this dichotomy, taking into account biophysical, cell biological, ecological and evolutionary influences on how information is extracted from chemosensory cues by these animal classes.

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The iron-sulphur protein RNase L inhibitor functions in translation termination.

Publication Date: 2010 Mar PMID: 20062004
Authors: Khoshnevis, S. - Gross, T. - Rotte, C. - Baierlein, C. - Ficner, R. - Krebber, H.
Journal: EMBO Rep

The iron-sulphur (Fe-S)-containing RNase L inhibitor (Rli1) is involved in ribosomal subunit maturation, transport of both ribosomal subunits to the cytoplasm, and translation initiation through interaction with the eukaryotic initiation factor 3 (eIF3) complex. Here, we present a new function for Rli1 in translation termination. Through co-immunoprecipitation experiments, we show that Rli1 interacts physically with the translation termination factors eukaryotic release factor 1 (eRF1)/Sup45 and eRF3/Sup35 in Saccharomyces cerevisiae. Genetic interactions were uncovered between a strain depleted for Rli1 and sup35-21 or sup45-2. Furthermore, we show that downregulation of RLI1 expression leads to defects in the recognition of a stop codon, as seen in mutants of other termination factors. By contrast, RLI1 overexpression partly suppresses the read-through defects in sup45-2. Interestingly, we find that although the Fe-S cluster is not required for the interaction of Rli1 with eRF1 or its other interacting partner, Hcr1, from the initiation complex eIF3, it is required for its activity in translation termination; an Fe-S cluster mutant of RLI1 cannot suppress the read-through defects of sup45-2.

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