Advertisement

  • Research Article
    VEGF dose regulates vascular stabilization through Semaphorin3A and the Neuropilin‐1+ monocyte/TGF‐β1 paracrine axis
    <div xmlns="http://www.w3.org/1999/xhtml">VEGF dose regulates vascular stabilization through Semaphorin3A and the Neuropilin‐1<sup>+</sup> monocyte/TGF‐β1 paracrine axis</div>
    1. Elena Groppa1,23,
    2. Sime Brkic1,2,
    3. Emmanuela Bovo1,2,
    4. Silvia Reginato1,2,
    5. Veronica Sacchi1,24,
    6. Nunzia Di Maggio1,2,
    7. Manuele G Muraro1,2,
    8. Diego Calabrese1,
    9. Michael Heberer1,2,
    10. Roberto Gianni‐Barrera1,2 and
    11. Andrea Banfi*,1,2
    1. 1Department of Biomedicine, University of Basel, Basel, Switzerland
    2. 2Department of Surgery, Basel University Hospital, Basel, Switzerland
    3. 3The Biomedical Research Centre, The University of British Columbia, Vancouver, BC, Canada
    4. 4 Heart Institute and Biology Department, San Diego State University, San Diego, CA, USA
    1. *Corresponding author. Tel: +41 61 265 3507; Fax: +41 61 265 3990; E‐mail: andrea.banfi{at}usb.ch

    VEGF impairs newly induced vessel stabilization by inhibiting endothelial Semaphorin3A (Sema3A) expression and recruitment of Neuropilin1‐expressing monocytes (NEM). Sema3A can accelerate vascular stabilization despite acute VEGF delivery.

    Synopsis

    VEGF impairs newly induced vessel stabilization by inhibiting endothelial Semaphorin3A (Sema3A) expression and recruitment of Neuropilin1‐expressing monocytes (NEM). Sema3A can accelerate vascular stabilization despite acute VEGF delivery.

    • The Neuropilin‐1 ligand Sema3A is required for recruitment of NEM, which promote the acquisition of VEGF‐independence by secreting TGF‐β1 and activating endothelial SMAD2/3 signaling.

    • The stabilizing signals are amplified and maintained by a novel positive feedback loop, whereby TGF‐β1, produced by Sema3A‐recruited NEM, stimulates further Sema3A secretion by the endothelium.

    • Sema3A production in vivo requires TGF‐β1, whereas VEGF directly and dose‐dependently inhibits Sema3A expression by activated endothelium.

    • Treatment with recombinant Sema3A rescues vascular stabilization impaired by high VEGF doses and prevents regression of newly induced angiogenesis after transient VEGF delivery by adenoviral vectors.

    • monocyte; TGF‐β1
    • semaphorin3A
    • vascular stabilization
    • VEGF
    • Received December 28, 2014.
    • Revision received July 15, 2015.
    • Accepted July 17, 2015.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Elena Groppa, Sime Brkic, Emmanuela Bovo, Silvia Reginato, Veronica Sacchi, Nunzia Di Maggio, Manuele G Muraro, Diego Calabrese, Michael Heberer, Roberto Gianni‐Barrera, Andrea Banfi
  • News & Views
    Bad vessels beware! Semaphorins will sort you out!
    Bad vessels beware! Semaphorins will sort you out!
    1. Guido Serini (guido.serini{at}ircc.it)1 and
    2. Luca Tamagnone (luca.tamagnone{at}ircc.it)1
    1. 1Department of Oncology, University of Torino and Candiolo Cancer Institute, FPO – IRCCS, Candiolo, Italy

    Secreted class 3 semaphorins (Sema3), which signal through plexin receptors and mostly use neuropilins (Nrps) as co‐receptors, were initially identified for their ability to steer navigating axons in the developing embryo. They were later found to control angiogenesis in physiological and pathological settings as well (Serini et al, 2013). Indeed, the development of a novel and aberrant vasculature is central to the pathogenesis of several human diseases, including cancer and vascular retinopathies (Goel et al, 2011). A large body of evidence demonstrates that in cancer, a massive regression of angiogenesis may trigger hypoxia‐driven genetic programs, which in turn can overcome drug inhibitory mechanisms and ultimately favour cancer cell invasion and dissemination. Thus, an emerging concept in molecular medicine is to devise therapeutic strategies that, rather than simply inhibiting angiogenesis, can foster the re‐establishment of a structural and functional normal network, a phenomenon often referred to as “vessel normalization” (Goel et al, 2011) (Fig 1). Of note, and in this context, Sema3A (Maione et al, 2009) and Sema3F (Wong et al, 2012) have been reported to favour the normalization of cancer vasculature and impair metastatic dissemination.

    See also: W‐J Yang et al

    Serini and Tamagnone comment on the report by Fischer and colleagues in this issue describing Semaphorin 3C as an inhibitor of pathological retinal angiogenesis and provide a general overview of this burgeoning field.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Guido Serini, Luca Tamagnone
  • News & Views
    Mutant Cullin causes cardiovascular compromise
    Mutant Cullin causes cardiovascular compromise
    1. Friedrich C Luft (friedrich.luft{at}charite.de)1
    1. 1Experimental and Clinical Research Center, a cooperation between the Max‐Delbrück Center for Molecular Medicine and the Charité Medical Faculty, Berlin, Germany

    Mendelian hypertension is rare; however, Mendelian syndromes have taught us an amazing amount about mechanisms of distal sodium and chloride reabsorption, as well as how systemic hypertension might come about. In this issue of EMBO Molecular Medicine, Schumacher et al (2015) present a mouse model of the Cullin‐3 (CUL3Δ403–459) mutation, which causes a form of pseudohypoaldosteronism type‐2 (PHA‐2). CUL3 is involved in ubiquitination. Surprising is the severity of the hypertension, which may be explained in part on the basis of CUL3 actions in vascular cells. The findings underscore the role of “cleanup” in the maintenance of normal physiology.

    See also: FR Schumacher et al

    Friedrich C Luft discusses the clinical relevance of a novel mouse model of the Cullin‐3 (CUL3Δ403–459) mutation causing a form of pseudohypoaldosteronism type‐2 (PHA‐2) and highlights the importance of better understanding CUL3 function in the vascular hypertension.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Friedrich C Luft
  • Research Article
    PHD1 regulates p53‐mediated colorectal cancer chemoresistance
    PHD1 regulates p53‐mediated colorectal cancer chemoresistance
    1. Sofie Deschoemaeker1,2,
    2. Giusy Di Conza1,2,
    3. Sergio Lilla3,
    4. Rosa Martín‐Pérez1,2,
    5. Daniela Mennerich4,
    6. Lise Boon1,2,
    7. Stefanie Hendrikx1,2,
    8. Oliver DK Maddocks3,
    9. Christian Marx3,5,
    10. Praveen Radhakrishnan6,
    11. Hans Prenen7,
    12. Martin Schneider6,
    13. Johanna Myllyharju8,
    14. Thomas Kietzmann4,
    15. Karen H Vousden3,
    16. Sara Zanivan3 and
    17. Massimiliano Mazzone*,1,2
    1. 1Lab of Molecular Oncology and Angiogenesis, Department of Oncology, KU Leuven, Leuven, Belgium
    2. 2Lab of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven, Belgium
    3. 3Cancer Research UK Beatson Institute, Glasgow, UK
    4. 4Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Oulu, Finland
    5. 5Department of Biochemistry, Center for Molecular Biomedicine, Institute for Biochemistry and Biophysics, Friedrich Schiller University of Jena, Jena, Germany
    6. 6Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
    7. 7Digestive Oncology Department, University Hospitals Leuven, Leuven, Belgium
    8. 8Oulu Center for Cell‐Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
    1. *Corresponding author. Tel: +32 16 37 32 13; E‐mail: massimiliano.mazzone{at}vib-kuleuven.be

    Resistance to the commonly used chemotherapeutic drugs 5‐FU, irinotecan and oxaliplatin in colorectal cancer remains a major clinical problem. Here, it is shown that PHD1 (EGLN2) can cause resistance to chemotherapy through the regulation of p53‐mediated DNA repair.

    Synopsis

    Resistance to the commonly used chemotherapeutic drugs 5‐FU, irinotecan and oxaliplatin in colorectal cancer remains a major clinical problem. Here, it is shown that PHD1 (EGLN2) can cause resistance to chemotherapy through the regulation of p53‐mediated DNA repair.

    • Chemotherapy (5‐FU) effectiveness was improved upon silencing of PHD1 in a xenograft colorectal cancer model.

    • p38α‐mediated p53 phosphorylation upon chemotherapy was facilitated by PHD1 prolyl hydroxylase function and interaction with p53.

    • The interaction of p53 with the nucleotide excision repair component XPB and thus DNA repair upon chemotherapy‐induced damage was blocked by the reduction of p53 phosphorylation at Ser15.

    • DNA contact mutant p53 (R248) can still be modulated by PHD1 and regulate DNA repair.

    • chemotherapy resistance
    • colorectal cancer
    • DNA repair
    • prolyl hydroxylase domain proteins
    • tumor suppressor p53
    • Received June 1, 2015.
    • Revision received July 23, 2015.
    • Accepted July 24, 2015.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Sofie Deschoemaeker, Giusy Di Conza, Sergio Lilla, Rosa Martín‐Pérez, Daniela Mennerich, Lise Boon, Stefanie Hendrikx, Oliver DK Maddocks, Christian Marx, Praveen Radhakrishnan, Hans Prenen, Martin Schneider, Johanna Myllyharju, Thomas Kietzmann, Karen H Vousden, Sara Zanivan, Massimiliano Mazzone
  • Research Article
    Characterisation of the Cullin‐3 mutation that causes a severe form of familial hypertension and hyperkalaemia
    Characterisation of the Cullin‐3 mutation that causes a severe form of familial hypertension and hyperkalaemia
    1. Frances‐Rose Schumacher*,15,
    2. Keith Siew2,,
    3. Jinwei Zhang1,
    4. Clare Johnson1,
    5. Nicola Wood1,
    6. Sarah E Cleary2,
    7. Raya S Al Maskari2,
    8. James T Ferryman2,
    9. Iris Hardege2,
    10. Yasmin2,
    11. Nichola L Figg3,
    12. Radoslav Enchev4,
    13. Axel Knebel1,
    14. Kevin M O'Shaughnessy*,2 and
    15. Thimo Kurz*,1
    1. 1MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, UK
    2. 2Division of Experimental Medicine and Immunotherapeutics, University of Cambridge, Cambridge, UK
    3. 3Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, Cambridge, UK
    4. 4Institute of Biochemistry, ETH Zürich, Zürich, Switzerland
    5. 5Proteomics and Biological Resource Management, Department of Protein Chemistry Genentech, 1 DNA Way, South San Francisco, CA, USA
    1. * Corresponding author. Tel: +44 1382 384241; E‐mail: francesrose.schumacher{at}gmail.com

      Corresponding author. Tel: +44 1223 762578; E‐mail: kmo22{at}medschl.cam.ac.uk

      Corresponding author. Tel: +44 1382 388371; E‐mail: t.kurz{at}dundee.ac.uk

    1. These authors contributed equally to this work

    Molecular defects observed in a mutant form of the ubiquitin E3 protein CUL3 causing a severe form of familial hypertension (PHA2E) result in E3 ligase loss of function. A novel mouse model with the same CUL3 disease mutation was generated, and it closely recapitulates the human PHA2E phenotype.

    Synopsis

    Molecular defects observed in a mutant form of the ubiquitin E3 protein CUL3 causing a severe form of familial hypertension (PHA2E) result in E3 ligase loss of function. A novel mouse model with the same CUL3 disease mutation was generated, and it closely recapitulates the human PHA2E phenotype.

    • Mutations in CUL3 that cause hereditary hypertension prevent the ubiquitylation and degradation of WNK kinases probably due to increased flexibility of the cullin backbone.

    • The mutant CUL3Δ403–459 protein shows marked auto‐ubiquitylation and loss of binding to the critical cullin regulators, CSN and CAND1.

    • The phenotype of knock‐in mice carrying the CUL3Δ403–459 mutation closely recapitulates PHA2E; kidney DCTs contain striking accumulation of WNK and SPAK proteins.

    • The mice expressing CUL3Δ403–459 have a vascular phenotype suggesting increased vascular tone that may contribute to the severity of the hypertension seen in PHA2E compared to other forms (PHA2A‐D).

    • cullin
    • CUL3
    • monogenic hypertension syndromes
    • proteasome
    • ubiquitin
    • WNK/SPAK/OSR1 pathway
    • Received May 18, 2015.
    • Revision received July 17, 2015.
    • Accepted July 21, 2015.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Frances‐Rose Schumacher, Keith Siew, Jinwei Zhang, Clare Johnson, Nicola Wood, Sarah E Cleary, Raya S Al Maskari, James T Ferryman, Iris Hardege, Yasmin, Nichola L Figg, Radoslav Enchev, Axel Knebel, Kevin M O'Shaughnessy, Thimo Kurz
  • Research Article
    A novel mechano‐enzymatic cleavage mechanism underlies transthyretin amyloidogenesis
    A novel mechano‐enzymatic cleavage mechanism underlies transthyretin amyloidogenesis
    1. Julien Marcoux1,27,
    2. P Patrizia Mangione3,4,,
    3. Riccardo Porcari3,
    4. Matteo T Degiacomi1,
    5. Guglielmo Verona3,4,
    6. Graham W Taylor3,
    7. Sofia Giorgetti4,
    8. Sara Raimondi4,
    9. Sarah Sanglier‐Cianférani2,
    10. Justin LP Benesch1,
    11. Ciro Cecconi5,6,
    12. Mohsin M Naqvi6,
    13. Julian D Gillmore3,
    14. Philip N Hawkins3,
    15. Monica Stoppini4,
    16. Carol V Robinson1,
    17. Mark B Pepys3 and
    18. Vittorio Bellotti*,3,4
    1. 1Department of Chemistry, University of Oxford, Oxford, UK
    2. 2Laboratoire de Spectrométrie de Masse BioOrganique (LSMBO), University of Strasbourg UDS, Strasbourg, France
    3. 3Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London, UK
    4. 4Department of Molecular Medicine, Institute of Biochemistry, University of Pavia, Pavia, Italy
    5. 5Institute of Nanoscience S3, Consiglio Nazionale delle Ricerche, Modena, Italy
    6. 6Department of Physics, Informatics and Mathematics, University of Modena and Reggio Emilia, Modena, Italy
    7. 7CNRS, Institute of Pharmacology and Structural Biology (IPBS), Toulouse, France
    1. *Corresponding author. Tel: +44 20 7433 2773; Fax: +44 20 7433 2803; E‐mail: v.bellotti{at}ucl.ac.uk
    1. These authors contributed equally to this work

    Selective proteolysis of TTR generates a highly amyloidogenic truncated protomer. Shear stress generated by turbulent flow of physiological fluids makes TTR susceptible to cleavage. This mechanism may play a crucial role in the development of cardiac TTR amyloidosis, and offers new therapeutic targets for treating the disease.

    Synopsis

    Selective proteolysis of TTR generates a highly amyloidogenic truncated protomer. Shear stress generated by turbulent flow of physiological fluids makes TTR susceptible to cleavage. This mechanism may play a crucial role in the development of cardiac TTR amyloidosis, and offers new therapeutic targets for treating the disease.

    • Shear forces are required to prime proteolysis of wild‐type and other variant TTRs and to release the amyloidogenic fragment.

    • These forces are present in the heart, offering an explanation for tissue specificity in cardiac TTR amyloidosis.

    • TTR stabilizers, currently used to treat amyloidosis, can inhibit this mechanism; however, their efficacy differs for each variant.

    • amyloid
    • mechano‐enzymatic cleavage
    • transthyretin
    • Received April 23, 2015.
    • Revision received July 24, 2015.
    • Accepted July 29, 2015.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Julien Marcoux, P Patrizia Mangione, Riccardo Porcari, Matteo T Degiacomi, Guglielmo Verona, Graham W Taylor, Sofia Giorgetti, Sara Raimondi, Sarah Sanglier‐Cianférani, Justin LP Benesch, Ciro Cecconi, Mohsin M Naqvi, Julian D Gillmore, Philip N Hawkins, Monica Stoppini, Carol V Robinson, Mark B Pepys, Vittorio Bellotti
  • Research Article
    AID‐expressing epithelium is protected from oncogenic transformation by an NKG2D surveillance pathway
    AID‐expressing epithelium is protected from oncogenic transformation by an NKG2D surveillance pathway
    1. Arantxa Pérez‐García1,
    2. Pablo Pérez‐Durán14,
    3. Thomas Wossning15,
    4. Isora V Sernandez16,
    5. Sonia M Mur1,
    6. Marta Cañamero2,
    7. Francisco X Real3 and
    8. Almudena R Ramiro*,1
    1. 1B Cell Biology Lab, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
    2. 2Roche Diagnostics GmbH, Penzberg, Germany
    3. 3Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
    4. 4Department of Pathology, NYU Cancer Institute New York University School of Medicine, New York, NY, USA
    5. 5 Klinik für Tumorbiologie, Freiburg, Germany
    6. 6 Otsuka Pharmaceutical, Barcelona, Spain
    1. *Corresponding author. Tel: +34 91 4531200; Fax: +34 91 4531245; E‐mail: aramiro{at}cnic.es

    AID expression in epithelial cells does not lead to inflammation‐related carcinogenesis; rather, AID genotoxicity in pancreas promotes a protective NKG2D immunosurveillance pathway that seemingly prevents neoplastic transformation.

    Synopsis

    AID expression in epithelial cells does not lead to inflammation‐related carcinogenesis; rather, AID genotoxicity in pancreas promotes a protective NKG2D immunosurveillance pathway that seemingly prevents neoplastic transformation.

    • Mouse models were developed for specific expression of AID in pancreatic and colonic epithelia.

    • AID expression in epithelial cells promoted mutations and genotoxic lesions, but mice did not develop carcinomas.

    • AID‐expressing epithelium triggered an NKGD2 immunosurveillance response that very likely neutralized AID oncogenic potential.

    • Our data highlight the diversity of safeguarding events in AID‐expressing cells and encourage a refined view of the previously acknowledged contribution of endogenous AID to epithelial‐derived tumors.

    • activation‐induced deaminase
    • cancer
    • epithelium
    • NKG2D
    • pancreas
    • Received April 16, 2015.
    • Revision received July 16, 2015.
    • Accepted July 21, 2015.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Arantxa Pérez‐García, Pablo Pérez‐Durán, Thomas Wossning, Isora V Sernandez, Sonia M Mur, Marta Cañamero, Francisco X Real, Almudena R Ramiro