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Table of Contents

01 March 2012; volume 13, issue 3

Upfront

Editorial

  • Every cell is sacred
    1. Howy Jacobs

    As the US Presidential election campaign gets into gear, Howy peers into a grim future, if current trends should be taken to their (il)logical conclusion

    Howy Jacobs

Opinion

  • Simplicity
    1. Paul van Helden1
    1. 1 Department of Biomedical Science at Stellenbosch University, Faculty of Health Science, Tygerberg, Cape Town, South Africa

    Scientists should remember that some of the most successful theories have been the most simple; complex theories risk losing their usefulness in a thicket of detail and exceptions.

    Paul van Helden

Hot off the Press

  • Autophagy—alias self‐eating—appetite and ageing
    1. David C Rubinsztein1
    1. 1 Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, UK

    Two articles—one published online in January and in the March issue EMBO reports—implicate autophagy in the control of appetite by regulating neuropeptide production in hypothalamic neurons. Autophagy decline with age in POMC neurons induces obesity and metabolic syndrome.

    David C Rubinsztein

Meeting Point

  • Tales of the autophagy crusaders
    1. Eyal Kalie1 and
    2. Sharon A Tooze1
    1. 1 London Research Institute, Cancer Research UK, London, UK

    The EMBO workshop on Autophagy in Health and Disease brought together researchers to cover the biogenesis of the autophagosome, the regulation of autophagy, selective autophagy and the role of autophagy in disease and cell death.

    Eyal Kalie, Sharon A Tooze
  • Signalling through the grapevine
    1. Ivan Dikic1 and
    2. Roger J Daly2
    1. 1 Goethe University Medical School, Frankfurt, Germany
    2. 2 Cancer Research Program, Garvan Institute of Medical Research, Australia and St Vincent's Hospital Clinical School, Department of Medicine, University of New South Wales, Sydney, Australia

    The 5th Barossa Meeting on Cell Signalling and Molecular Medicine was held in November 2011 in the Barossa Valley, South Australia. The combination of an inspirational environment and outstanding science led to a superb meeting that highlighted the versatility of cellular signalling systems and how they can be targeted by novel therapeutic approaches.

    Ivan Dikic, Roger J Daly

Science & Society

Review

  • Protein phosphatases and their regulation in the control of mitosis
    1. Satoru Mochida*,1 and
    2. Tim Hunt2
    1. 1 Honjo‐Kyoyotou 206, Kumamoto University, 2‐2‐1 Honjo, Kumamoto City, Kumamoto, 860‐0811, Japan
    2. 2 Cancer Research UK, Clare Hall Laboratories, South Mimms, Hertfordshire, EN6 3LD, UK
    1. *Corresponding author. Tel: +81 373 6819; Fax: +81 373 6819; E-mail: mochida{at}kumamoto-u.ac.jp

    Our understanding of the role of kinases in cell cycle control is rather advanced, but we are only scratching the surface of the reciprocal control by protein phosphatases. This Review analyzes how phosphatases control mitosis and how to move this emerging field forward.

    • α‐endosulfine
    • CDK
    • Greatwall
    • mitosis
    • phosphatase
    • Received October 8, 2011.
    • Accepted December 22, 2011.
    Satoru Mochida, Tim Hunt
  • Merlin: a tumour suppressor with functions at the cell cortex and in the nucleus
    1. Wei Li*,1,,
    2. Jonathan Cooper1,,
    3. Matthias A Karajannis2 and
    4. Filippo G Giancotti*,1
    1. 1 Cell Biology Program, Sloan–Kettering Institute for Cancer Research, Memorial Sloan–Kettering Cancer Center, 1275 York Avenue, Box 216, New York, New York, 10065, USA
    2. 2 NYU Cancer Institute and Department of Pediatrics, NYU Langone Medical Center, New York, New York, 10016, USA
    1. *Corresponding authors. Tel: +1 212 639 7044; Fax: +1 212 794 6236; E-mail: liw{at}mskcc.org or Tel: +1 212 639 6998; Fax: +1 212 794 6236; E-mail: f-giancotti{at}ski.mskcc.org
    1. These authors contributed equally to this work

    Merlin, a crucial mediator of contact inhibition, is analysed here. It affects growth in several ways: activating the Hippo pathway, promoting the establishment of epithelial adhesion and polarity, and translocating to the nucleus to induce a growth‐suppressive programme of gene expression.

    • Merlin
    • type 2 neurofibromatosis
    • contact inhibition
    • tumour suppression
    • Hippo
    • Received October 23, 2011.
    • Accepted January 12, 2012.
    Wei Li, Jonathan Cooper, Matthias A Karajannis, Filippo G Giancotti

Scientific Reports

  • RWD domain: a recurring module in kinetochore architecture shown by a Ctf19–Mcm21 complex structure
    1. Florian Schmitzberger1 and
    2. Stephen C Harrison*,1,2
    1. 1 Department of Biological Chemistry and Molecular Pharmacology, and Harvard Medical School, 250 Longwood Avenue, Boston, Massachusetts, 02115, USA
    2. 2 Howard Hughes Medical Institute, Harvard Medical School, 250 Longwood Avenue, Boston, Massachusetts, 02115, USA
    1. *Corresponding author. Tel: +1 617 432 5607; Fax: +1 617 432 5600; E-mail: harrison{at}crystal.harvard.edu

    The crystal structure of kinetochore subcomplex Ctf19–Mcm21 reveals that both contain “double‐RWD” domains. Other kinetochore proteins also have related RWD domains, suggesting this building block is a recurring module of kinetochore architecture.

    • COMA
    • mitosis
    • X‐ray crystallography
    • yeast
    • Received September 15, 2011.
    • Revision received December 14, 2011.
    • Accepted December 20, 2011.
    Florian Schmitzberger, Stephen C Harrison
  • CryB from Rhodobacter sphaeroides: a unique class of cryptochromes with new cofactors
    1. Yann Geisselbrecht1,
    2. Sebastian Frühwirth2,
    3. Claudia Schroeder1,
    4. Antonio J Pierik3,
    5. Gabriele Klug2 and
    6. Lars‐Oliver Essen*,1
    1. 1 Department of Chemistry—Institute of Biochemistry, Philipps‐University, Marburg
    2. 2 Department of Biology and Chemistry—Institute of Microbiology and Molecular Biology, Justus‐Liebig‐University, Giessen
    3. 3 Department of Medicine—Core Facility for Protein Spectroscopy, Institute of Cytobiology and Cytopathology, Philipps‐University, Marburg, Germany
    1. *Corresponding author. Tel: +49 6421 28 22032; Fax: +49 6421 28 22191; E-mail: essen{at}chemie.uni-marburg.de

    The structure of RsCryB reveals two cofactors only conserved in the CryPro subfamily—6,7‐dimethyl‐8‐ribityl‐lumazine in the antenna‐binding domain and a [4Fe‐4S] cluster in the catalytic domain—suggesting an alternative method of electron transfer in this family.

    • CryPro
    • cryptochrome
    • iron–sulphur cluster
    • lumazine‐binding protein
    • Rhodobacter sphaeroides
    • Received August 16, 2011.
    • Revision received December 21, 2011.
    • Accepted December 22, 2011.
    Yann Geisselbrecht, Sebastian Frühwirth, Claudia Schroeder, Antonio J Pierik, Gabriele Klug, Lars‐Oliver Essen
  • The role of deimination in ATP5b mRNA transport in a transgenic mouse model of multiple sclerosis
    1. Di Ding1,2,
    2. Mabel Enriquez‐Algeciras1,
    3. Kunjan R Dave3,4,
    4. Miguel Perez‐Pinzon3,4 and
    5. Sanjoy K Bhattacharya*,1,2,3
    1. 1 Bascom Palmer Eye Institute, University of Miami, Miami, Florida, 33136, USA
    2. 2 Department of Biochemistry and Molecular Biology, University of Miami, Miami, Florida, 33136, USA
    3. 3 Neuroscience Program, University of Miami, Miami, Florida, 33136, USA
    4. 4 Department of Neurology, University of Miami, Miami, Florida, 33136, USA
    1. *Corresponding author. Tel: +1 305 482 4103 (Office) or +1 305 482 4109 (Lab); Fax: +1 305 326 6547; E-mail: sbhattacharya{at}med.miami.edu

    Bhattacharya and collaborators find that a mouse model for multiple sclerosis develops mitochondrial dysfunction through deimination of REF, an RNA‐binding protein involved in mRNA transport into mitochondria.

    • deimination
    • mitochondria
    • ATP synthase
    • multiple sclerosis
    • RNA binding export factor
    • Received August 3, 2011.
    • Revision received December 20, 2011.
    • Accepted December 21, 2011.
    Di Ding, Mabel Enriquez‐Algeciras, Kunjan R Dave, Miguel Perez‐Pinzon, Sanjoy K Bhattacharya
  • Suppression of Rac1 activity at the apical membrane of MDCK cells is essential for cyst structure maintenance
    1. Shunsuke Yagi1,
    2. Michiyuki Matsuda1,2 and
    3. Etsuko Kiyokawa*,2,
    1. 1 Laboratory of Bioimaging and Cell Signaling, Graduate School of Biostudies, Kyoto University, Yoshida Konoe‐cho, Kyoto, 606‐8501, Japan
    2. 2 Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Yoshida Konoe‐cho, Kyoto, 606‐8501, Japan
    1. *Corresponding author. Tel: +81 76 286 8116; Fax: +81 76 286 6926; E-mail: kiyokawa{at}kanazawa-med.ac.jp
    • Present address: Department of Oncologic Pathology, Kanazawa Medical University, 1‐1 Daigaku, Ishikawa 920‐0293, Japan

    Kiyokawa and colleagues use FRET biosensors in 3D MDCK cell cultures to find that Rac1 activity is suppressed in the apical membrane of polarized cells. Ectopic activation of Rac1 in this domain severely disorders epithelial structure by disrupting intercellular tight junctions and reorienting cell division axes.

    • cell division axis
    • FRET
    • polarity
    • Rho family GTPases
    • tight junction
    • Received June 17, 2011.
    • Revision received November 30, 2011.
    • Accepted December 1, 2011.
    Shunsuke Yagi, Michiyuki Matsuda, Etsuko Kiyokawa
  • Nuclear IGF1R is a transcriptional co‐activator of LEF1/TCF
    1. Dudi Warsito1,
    2. Sylvia Sjöström1,
    3. Sandra Andersson1,
    4. Olle Larsson1 and
    5. Bita Sehat*,1
    1. 1 Department of Oncology and Pathology, Karolinska Institutet, Cancer Center Karolinska, R8:04, Karolinska University Hospital, SE‐171 76, Stockholm, Sweden
    1. *Corresponding author. Tel: +46 (8) 517 752 49; Fax: +46 (8) 32 10 47; E-mail: bita.sehat{at}ki.se

    Insulin growth factor 1 receptor is known to translocate to the nucleus upon IGF1 signalling. Sehat and collaborators show in this report that nuclear IGFR1 is a transcriptional co‐factor of LEF1/TCF required for cyclin D and axin2 activation independently of β‐catenin.

    • gene activation
    • LEF1
    • nuclear IGF1R
    • Received June 8, 2011.
    • Revision received December 1, 2011.
    • Accepted December 1, 2011.
    Dudi Warsito, Sylvia Sjöström, Sandra Andersson, Olle Larsson, Bita Sehat
  • The FIH hydroxylase is a cellular peroxide sensor that modulates HIF transcriptional activity
    1. Norma Masson*,1,
    2. Rachelle S Singleton1,
    3. Rok Sekirnik2,
    4. David C Trudgian1,
    5. Lucy J Ambrose1,
    6. Melroy X Miranda1,
    7. Ya‐Min Tian1,
    8. Benedikt M Kessler1,
    9. Christopher J Schofield2 and
    10. Peter J Ratcliffe1
    1. 1 Henry Wellcome Building for Molecular Physiology, and University of Oxford, Oxford, OX3 7BN, UK
    2. 2 Chemistry Research Laboratory, University of Oxford, Oxford, OX3 7BN, UK
    1. *Corresponding author. Tel: +44 (0)1865 287781; Fax: +44 (0)1865 287787; E-mail: nmasson{at}well.ox.ac.uk

    HIF asparaginyl hydroxylase (FIH) is shown to be strikingly more sensitive to peroxide than the HIF prolyl hydroxylases, indicating that hypoxia and oxidative stress are distinct regulators of the HIF response.

    • FIH
    • HIF
    • hydroxylation
    • peroxide
    • Received September 16, 2011.
    • Revision received December 28, 2011.
    • Accepted January 9, 2012.

    This is an open‐access article distributed under the terms of the Creative Commons Attribution License, which permits distribution, and reproduction in any medium, provided the original author and source are credited. This license does not permit commercial exploitation without specific permission.

    Norma Masson, Rachelle S Singleton, Rok Sekirnik, David C Trudgian, Lucy J Ambrose, Melroy X Miranda, Ya‐Min Tian, Benedikt M Kessler, Christopher J Schofield, Peter J Ratcliffe
  • Loss of autophagy in hypothalamic POMC neurons impairs lipolysis
    1. Susmita Kaushik1,2,,
    2. Esperanza Arias1,2,,
    3. Hyokjoon Kwon1,3,4,
    4. Nuria Martinez Lopez1,3,4,
    5. Diana Athonvarangkul1,3,4,
    6. Srabani Sahu1,3,4,
    7. Gary J Schwartz1,2,4,5,
    8. Jeffrey E Pessin1,2,3,4 and
    9. Rajat Singh*,1,2,3,4
    1. 1 Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, 10461, USA
    2. 2 Institute for Aging Research, Albert Einstein College of Medicine, Bronx, New York, 10461, USA
    3. 3 Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, 10461, USA
    4. 4 Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York, 10461, USA
    5. 5 Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, 10461, USA
    1. *Corresponding author. Tel: +1 718 430 4118; Fax: +1 718 430 8557; E-mail: rajat.singh{at}einstein.yu.edu
    1. These authors contributed equally to this work

    Both selective loss of autophagy in POMC neurons and ageing decrease ?‐melanocyte stimulating hormone levels, promoting adiposity, impairing lipolysis and altering glucose homeostasis. These effects can be pharmacologically alleviated, suggesting prevention strategies for obesity and metabolic syndrome.

    • autophagy
    • ageing
    • hypothalamus
    • obesity
    • POMC
    • Received September 20, 2011.
    • Revision received December 16, 2011.
    • Accepted December 16, 2011.
    Susmita Kaushik, Esperanza Arias, Hyokjoon Kwon, Nuria Martinez Lopez, Diana Athonvarangkul, Srabani Sahu, Gary J Schwartz, Jeffrey E Pessin, Rajat Singh
  • Large‐scale mapping of human protein interactome using structural complexes
    1. Manoj Tyagi1,,
    2. Kosuke Hashimoto1,,
    3. Benjamin A Shoemaker1,
    4. Stefan Wuchty1 and
    5. Anna R Panchenko*,1
    1. 1 National Center for Biotechnology Information, US National Library of Medicine, National Institutes of Health, 8600 Rockville Pike, Bethesda, Maryland, 20894, USA
    1. *Corresponding author. Tel: +1 301 435 5891; Fax: +1 301 435 7794; E-mail: panch{at}ncbi.nlm.nih.gov
    1. These authors contributed equally to this work

    This study describes a new framework that utilizes experimental evidence on structural complexes, the atomic details of binding interfaces and evolutionary conservation to map the human protein interactome.

    • protein interactions
    • protein structures
    • protein complexes
    • IBIS
    • Received September 8, 2011.
    • Revision received November 23, 2011.
    • Accepted December 9, 2011.

    This is an open‐access article distributed under the terms of the Creative Commons Attribution License, which permits distribution, and reproduction in any medium, provided the original author and source are credited. This license does not permit commercial exploitation without specific permission.

    Manoj Tyagi, Kosuke Hashimoto, Benjamin A Shoemaker, Stefan Wuchty, Anna R Panchenko
  • Strong association between mRNA folding strength and protein abundance in S. cerevisiae
    1. Hadas Zur1 and
    2. Tamir Tuller*,2
    1. 1 School of Computer Science, and Faculty of Engineering, Department of Biomedical Engineering, Tel Aviv University, Ramat Aviv, 69978, Israel
    2. 2 Faculty of Engineering, Department of Biomedical Engineering, Tel Aviv University, Ramat Aviv, 69978, Israel
    1. *Corresponding author. Tel: +972 3 6405836; Fax: +972 3 6407939; E-mail: tamirtul{at}post.tau.ac.il

    On the basis of large‐scale analyses of genomic data, this study identifies a strong correlation between the strength of mRNA folding and protein expression levels in S. cerevisiae and discusses potential explanations for this correlation.

    • gene translation
    • mRNA folding
    • mRNA aggregation
    • translation elongation
    • protein abundance
    • Received September 17, 2011.
    • Revision received December 14, 2011.
    • Accepted December 16, 2011.
    Hadas Zur, Tamir Tuller