EMBO Reports

Simplicity.

Publication Date: 2012 Feb 3 PMID: 22302031
Authors: van Helden, P.
Journal: EMBO Rep

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Autophagy-alias self-eating-appetite and ageing.

Publication Date: 2012 Feb 3 PMID: 22302030
Authors: Rubinsztein, D. C.
Journal: EMBO Rep

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Time, evolution and physical reductionism. The arrow of evolutionary time challenges an eventual physical theory of everything.

Publication Date: 2012 Feb 3 PMID: 22302015
Authors: Rull, V.
Journal: EMBO Rep

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All Chinese to me.

Publication Date: 2012 PMID: 22293865
Authors: Jacobs, H.
Journal: EMBO Rep

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CryB from Rhodobacter sphaeroides: a unique class of cryptochromes with new cofactors.

Publication Date: 2012 Jan 31 PMID: 22290493
Authors: Geisselbrecht, Y. - Fruhwirth, S. - Schroeder, C. - Pierik, A. J. - Klug, G. - Essen, L. O.
Journal: EMBO Rep

Cryptochromes and photolyases are structurally related but have different biological functions in signalling and DNA repair. Proteobacteria and cyanobacteria harbour a new class of cryptochromes, called CryPro. We have solved the 2.7 A structure of one of its members, cryptochrome B from Rhodobacter sphaeroides, which is a regulator of photosynthesis gene expression. The structure reveals that, in addition to the photolyase-like fold, CryB contains two cofactors only conserved in the CryPro subfamily: 6,7-dimethyl-8-ribityl-lumazine in the antenna-binding domain and a [4Fe-4S] cluster within the catalytic domain. The latter closely resembles the iron-sulphur cluster harbouring the large primase subunit PriL, indicating that PriL is evolutionarily related to the CryPro class of cryptochromes.

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'Positive biology' as a new paradigm for the medical sciences. Focusing on people who live long, happy, healthy lives might hold the key to improving human well-being.

Publication Date: 2012 Jan 27 PMID: 22281805
Authors: Farrelly, C.
Journal: EMBO Rep

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Large-scale mapping of human protein interactome using structural complexes.

Publication Date: 2012 Jan 20 PMID: 22261719
Authors: Tyagi, M. - Hashimoto, K. - Shoemaker, B. A. - Wuchty, S. - Panchenko, A. R.
Journal: EMBO Rep

Although the identification of protein interactions by high-throughput (HTP) methods progresses at a fast pace, 'interactome' data sets still suffer from high rates of false positives and low coverage. To map the human protein interactome, we describe a new framework that uses experimental evidence on structural complexes, the atomic details of binding interfaces and evolutionary conservation. The structurally inferred interaction network is highly modular and more functionally coherent compared with experimental interaction networks derived from multiple literature citations. Moreover, structurally inferred and high-confidence HTP networks complement each other well, allowing us to construct a merged network to generate testable hypotheses and provide valuable experimental leads.

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Protein phosphatases and their regulation in the control of mitosis.

Publication Date: 2012 Jan 20 PMID: 22261718
Authors: Mochida, S. - Hunt, T.
Journal: EMBO Rep

Cell cycle transitions depend on protein phosphorylation and dephosphorylation. The discovery of cyclin-dependent kinases (CDKs) and their mode of activation by their cyclin partners explained many important aspects of cell cycle control. As the cell cycle is basically a series of recurrences of a defined set of events, protein phosphatases must obviously be as important as kinases. However, our knowledge about phosphatases lags well behind that of kinases. We still do not know which phosphatase(s) is/are truly responsible for dephosphorylating CDK substrates, and we know very little about whether and how protein phosphatases are regulated. Here, we summarize our present understanding of the phosphatases that are important in the control of the cell cycle and pose the questions that need to be answered as regards the regulation of protein phosphatases.

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Nuclear IGF1R is a transcriptional co-activator of LEF1/TCF.

Publication Date: 2012 Jan 20 PMID: 22261717
Authors: Warsito, D. - Sjostrom, S. - Andersson, S. - Larsson, O. - Sehat, B.
Journal: EMBO Rep

Recent findings suggest that nuclear IGF1R binds to enhancer regions and functions as a transcriptional cofactor. However, the downstream transcriptional regulators of this pathway remain to be defined. Here, we show that nuclear IGF1R associates with the transcription factor LEF1 and increases promoter activity of LEF1 downstream target genes cyclin D1 and axin2. Furthermore, nuclear IGF1R augments protein levels of cyclin D1 and axin2. Our findings suggest a novel function for IGF1R, thus further emphasizing the important role of this receptor in cancer biology.

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The role of deimination in ATP5b mRNA transport in a transgenic mouse model of multiple sclerosis.

Publication Date: 2012 Jan 20 PMID: 22261716
Authors: Ding, D. - Enriquez-Algeciras, M. - Dave, K. R. - Perez-Pinzon, M. - Bhattacharya, S. K.
Journal: EMBO Rep

Deimination refers to conversion of protein-bound arginine into citrulline. An mRNA carrier, RNA binding export factor (REF), present on mitochondria undergoes loss of deimination with impaired ATP5b mRNA transport in ND4 mice (model of multiple sclerosis) compared with the controls. We present evidence of (1) reduced ATP5b mRNA binding strength of non-deiminated REF compared with deiminated REF, (2) impaired ATP5b mRNA transport in ND4 mice and (3) reduced mitochondrial ATP synthase activity on inhibition of deimination in PC12 cells. Impaired deimination of REF and defect in mitochondrial mRNA transport are critical factors in mitochondrial dysfunction in ND4 mice.

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Suppression of Rac1 activity at the apical membrane of MDCK cells is essential for cyst structure maintenance.

Publication Date: 2012 Jan 20 PMID: 22261715
Authors: Yagi, S. - Matsuda, M. - Kiyokawa, E.
Journal: EMBO Rep

Using MDCK cells that constitutively express a Forster resonance energy transfer biosensor, we found that Rac1 activity is homogenous at the entire plasma membrane in early stages of cystogenesis, whereas in later stages Rac1 activity is higher at the lateral membrane than at the apical plasma membrane. If Rac1 is activated at the apical membrane in later stages, however, the monolayer cells move into the luminal space. In these cells, tight junctions are disrupted, accompanied by mislocalization of polarization markers and disorientation of cell division. These observations indicate that Rac1 suppression at the apical membrane is essential for the maintenance of cyst structure.

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Loss of autophagy in hypothalamic POMC neurons impairs lipolysis.

Publication Date: 2012 Jan 17 PMID: 22249165
Authors: Kaushik, S. - Arias, E. - Kwon, H. - Lopez, N. M. - Athonvarangkul, D. - Sahu, S. - Schwartz, G. J. - Pessin, J. E. - Singh, R.
Journal: EMBO Rep

Autophagy degrades cytoplasmic contents to achieve cellular homeostasis. We show that selective loss of autophagy in hypothalamic proopiomelanocortin (POMC) neurons decreases alpha-melanocyte-stimulating hormone (MSH) levels, promoting adiposity, impairing lipolysis and altering glucose homeostasis. Ageing reduces hypothalamic autophagy and alpha-MSH levels, and aged-mice phenocopy, the adiposity and lipolytic defect observed in POMC neuron autophagy-null mice. Intraperitoneal isoproterenol restores lipolysis in both models, demonstrating normal adipocyte catecholamine responsiveness. We propose that an unconventional, autophagosome-mediated form of secretion in POMC neurons controls energy balance by regulating alpha-MSH production. Modulating hypothalamic autophagy might have implications for preventing obesity and metabolic syndrome of ageing.

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Strong association between mRNA folding strength and protein abundance in S. cerevisiae.

Publication Date: 2012 Jan 17 PMID: 22249164
Authors: Zur, H. - Tuller, T.
Journal: EMBO Rep

One of the open questions in regulatory genomics is how the efficiency of gene translation is encoded in the coding sequence. Here we analyse recently generated measurements of folding energy in Saccharomyces cerevisiae, showing that genes with high protein abundance tend to have strong mRNA folding (mF; R=0.68). mF strength also strongly correlates with ribosomal density and mRNA levels, suggesting that this relation at least partially pertains to the efficiency of translation elongation, presumably by preventing aggregation of mRNA molecules.

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Emerging journals. The benefits of and challenges for publishing scientific journals in and by emerging countries.

Publication Date: 2012 PMID: 22240975
Authors: Meneghini, R.
Journal: EMBO Rep

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The anglerfish deception. The light of proposed reform in the regulation of GM crops hides underlying problems in EU science and governance.

Publication Date: 2012 PMID: 22240974
Authors: Wickson, F. - Wynne, B.
Journal: EMBO Rep

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Research and practice coming together. The advent of personalized medicine is bringing clinical research and practice closer together.

Publication Date: 2012 PMID: 22240973
Authors: Hunter, P.
Journal: EMBO Rep

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Neutrophils-the unexpected helpers of B-cell activation.

Publication Date: 2012 PMID: 22240972
Authors: Harwood, N. E. - Barral, P. - Batista, F. D.
Journal: EMBO Rep

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Inside an unquiet mind. Music and science join forces to explore mental ill health.

Publication Date: 2012 PMID: 22240971
Authors: Critchlow, H. M. - Herrington, P. - Gunton, S.
Journal: EMBO Rep

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Regulation of TOR by small GTPases.

Publication Date: 2012 PMID: 22240970
Authors: Duran, R. V. - Hall, M. N.
Journal: EMBO Rep

TOR is a conserved serine/threonine kinase that responds to nutrients, growth factors, the bioenergetic status of the cell and cellular stress to control growth, metabolism and ageing. A diverse group of small GTPases including Rheb, Rag, Rac1, RalA and Ryh1 play a variety of roles in the regulation of TOR. For example, while Rheb binds to and activates TOR directly, Rag and Rac1 regulate its localization and RalA activates it indirectly through the production of phosphatidic acid. Here, we review recent findings on the regulation of TOR by small GTPases.

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Assurance of mitochondrial integrity and mammalian longevity by the p62-Keap1-Nrf2-Nqo1 cascade.

Publication Date: 2012 PMID: 22222206
Authors: Kwon, J. - Han, E. - Bui, C. B. - Shin, W. - Lee, J. - Lee, S. - Choi, Y. B. - Lee, A. H. - Lee, K. H. - Park, C. - Obin, M. S. - Park, S. K. - Seo, Y. J. - Oh, G. T. - Lee, H. W. - Shin, J.
Journal: EMBO Rep

Sqstm1/p62 functions in the non-canonical activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). However, its physiological relevance is not certain. Here, we show that p62(-/-) mice exhibited an accelerated presentation of ageing phenotypes, and tissues from these mice created a pro-oxidative environment owing to compromised mitochondrial electron transport. Accordingly, mitochondrial function rapidly declined with age in p62(-/-) mice. In addition, p62 enhanced basal Nrf2 activity, conferring a higher steady-state expression of NAD(P)H dehydrogenase, quinone 1 (Nqo1) to maintain mitochondrial membrane potential and, thereby, restrict excess oxidant generation. Together, the p62-Nrf2-Nqo1 cascade functions to assure mammalian longevity by stabilizing mitochondrial integrity.

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Histone deacetylase 1 enhances microRNA processing via deacetylation of DGCR8.

Publication Date: 2012 PMID: 22222205
Authors: Wada, T. - Kikuchi, J. - Furukawa, Y.
Journal: EMBO Rep

Relatively little is known about the regulatory mechanisms of the Drosha/DGCR8 complex, which processes miRNAs at the initial step of biogenesis. We found that histone deacetylase 1 (HDAC1) increases the expression levels of mature miRNAs despite repressing the transcription of host genes. HDAC1 is an integral component of the Drosha/DGCR8 complex and enhances miRNA processing by increasing the affinity of DGCR8 to primary miRNA transcripts via deacetylation of critical lysine residues in the RNA-binding domains of DGCR8. This finding suggests that HDACs have two arms for gene silencing: transcriptional repression by promoter histone deacetylation and post-transcriptional inhibition by increasing miRNA abundance.

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Synthetic biology's flywheel.

Publication Date: 2012 PMID: 22222204
Authors: Danchin, A.
Journal: EMBO Rep

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Regulation and function of innate and adaptive interleukin-17-producing cells.

Publication Date: 2012 PMID: 22193778
Authors: Hirota, K. - Ahlfors, H. - Duarte, J. H. - Stockinger, B.
Journal: EMBO Rep

Interleukin-17 (IL-17)-mediated immune responses play a crucial role in the mucosal host defence against microbial and fungal pathogens. However, the chronic activation of IL-17-producing T helper cells can cause autoimmune disease. In addition, recent studies have highlighted key roles of innate cell-mediated IL-17 responses in various inflammatory settings. Besides inflammation, there have also been intriguing findings regarding the involvement of IL-17 responses in the pathogenesis of cardiovascular diseases and tumour formation. Here, we discuss the latest discoveries in regulation and function of innate and adaptive IL-17-producing cells.

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ChAM, a novel motif that mediates PALB2 intrinsic chromatin binding and facilitates DNA repair.

Publication Date: 2012 PMID: 22193777
Authors: Bleuyard, J. Y. - Buisson, R. - Masson, J. Y. - Esashi, F.
Journal: EMBO Rep

The partner and localizer of breast cancer 2 susceptibility protein (PALB2) is crucial for the repair of DNA damage by homologous recombination. Here, we report that chromatin-association motif (ChAM), an evolutionarily conserved motif in PALB2, is necessary and sufficient to mediate its chromatin association in both unperturbed and damaged cells. ChAM is distinct from the previously described PALB2 DNA-binding regions. Deletion of ChAM decreases PALB2 and Rad51 accumulation at DNA damage sites and confers cellular hypersensitivity to the genotoxic drug mitomycin C. These results suggest that PALB2 chromatin association via ChAM facilitates PALB2 function in the cellular resistance to DNA damage.

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Xenopus paraxial protocadherin inhibits Wnt/beta-catenin signalling via casein kinase 2beta.

Publication Date: 2012 PMID: 22193776
Authors: Kietzmann, A. - Wang, Y. - Weber, D. - Steinbeisser, H.
Journal: EMBO Rep

Xenopus paraxial protocadherin (PAPC) regulates cadherin-mediated cell adhesion and promotes the planar cell polarity (PCP) pathway. Here we report that PAPC functions in the Xenopus gastrula as an inhibitor of the Wnt/beta-catenin pathway. The intracellular domain of PAPC interacts with casein kinase 2 beta (CK2beta), which is part of the CK2 holoenzyme. The CK2alpha/beta complex stimulates Wnt/beta-catenin signalling, and the physical interaction of CK2beta with PAPC antagonizes this activity. By this mechanism, PAPC restricts the expression of Wnt target genes during gastrulation. These experiments identify a novel function of protocadherins as regulators of the Wnt pathway.

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Synergism between altered cortical polarity and the PI3K/TOR pathway in the suppression of tumour growth.

Publication Date: 2012 PMID: 22173033
Authors: Rossi, F. - Gonzalez, C.
Journal: EMBO Rep

Loss of function of pins (partner of inscuteable) partially disrupts neuroblast (NB) polarity and asymmetric division, results in fewer and smaller NBs and inhibits Drosophila larval brain growth. Food deprivation also inhibits growth. However, we find that the combination of loss of function of pins and dietary restriction results in loss of NB asymmetry, overproliferation of Miranda-expressing cells, brain overgrowth and increased frequency of tumour growth on allograft transplantation. The same effects are observed in well-fed pins larvae that are mutant for pi3k (phosphatidylinositol 3-kinase) or exposed to the TOR inhibitor rapamycin. Thus, pathways that are sensitive to food deprivation and dependent on PI3K and TOR are essential to suppress tumour growth in Drosophila larval brains with compromised pins function. These results highlight an unexpected crosstalk whereby the normally growth-promoting, nutrient-sensing PI3K/TOR pathway suppresses tumour formation in neural stem cells with compromised cell polarity.

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Mdm2 associates with Ras effector NORE1 to induce the degradation of oncoprotein HIPK1.

Publication Date: 2012 PMID: 22173032
Authors: Lee, D. - Park, S. J. - Sung, K. S. - Park, J. - Lee, S. B. - Park, S. Y. - Lee, H. J. - Ahn, J. W. - Choi, S. J. - Lee, S. G. - Kim, S. H. - Kim, D. H. - Kim, J. - Kim, Y. - Choi, C. Y.
Journal: EMBO Rep

The Ras effector NORE1 is frequently silenced in primary adenocarcinomas, although the significance of this silencing for tumorigenesis is unclear. Here we show that NORE1 induces polyubiquitination and proteasomal degradation of oncoprotein HIPK1 by facilitating its interaction with the Mdm2 E3 ubiquitin ligase. Endogenous HIPK1 is stabilized in Nore1-deficient mouse embryonic fibroblasts, and depletion of HIPK1 in NORE1-silenced lung adenocarcinoma cells inhibits anchorage-independent cell growth and tumour formation in nude mice. These findings indicate that the control of HIPK1 stability by Mdm2-NORE1 has a major effect on cell behaviour, and epigenetic inactivation of NORE1 enables adenocarcinoma formation in vivo through HIPK1 stabilization.

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