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  • IAP antagonization promotes inflammatory destruction of vascular endothelium
    IAP antagonization promotes inflammatory destruction of vascular endothelium
    1. Axel Witt1,
    2. Jens M Seeger1,
    3. Oliver Coutelle1,
    4. Paola Zigrino2,
    5. Pia Broxtermann1,
    6. Maria Andree1,
    7. Kerstin Brinkmann1,
    8. Christian Jüngst3,
    9. Astrid C Schauss3,
    10. Stephan Schüll1,
    11. Dirk Wohlleber4,
    12. Percy A Knolle4,
    13. Martin Krönke1,3,
    14. Cornelia Mauch2 and
    15. Hamid Kashkar*,1,3
    1. 1Center for Molecular Medicine Cologne (CMMC) and Institute for Medical Microbiology, Immunology and Hygiene (IMMIH) University of Cologne, Cologne, Germany
    2. 2Department of Dermatology, University of Cologne, Cologne, Germany
    3. 3Cologne Excellence Cluster on Cellular Stress Responses in Aging‐Associated Diseases (CECAD), University of Cologne, Cologne, Germany
    4. 4Institute of Molecular Immunology, Technische Universität München, München, Germany
    1. *Corresponding author. Tel: +49 221 478 84091; Fax: +49 221 84092; E‐mail: h.kashkar{at}uni-koeln.de

    Treatment of mice bearing B16 melanomas with an IAP antagonist (Comp A) inhibits tumor growth by disrupting the tumor vasculature. Upon exposure to Comp A tumor cells produce TNF, which together with Comp A induces endothelial cell death.

    Synopsis

    Treatment of mice bearing B16 melanomas with an IAP antagonist (Comp A) inhibits tumor growth by disrupting the tumor vasculature. Upon exposure to Comp A tumor cells produce TNF, which together with Comp A induces endothelial cell death.

    • Inhibition of IAPs induces NF‐κB activity in tumor cells and leads to TNF production.

    • The increased local concentration of TNF in the tumor microenvironment together with Comp A induces endothelial cell death.

    • IAP inhibition promotes inflammatory destruction of tumor‐associated vascular endothelium and attenuates tumor growth while minimizing collateral damage to normal blood vessels.

    • IAPs
    • tumor
    • TNF
    • angiogenesis
    • Received September 24, 2014.
    • Revision received March 9, 2015.
    • Accepted March 10, 2015.
    Axel Witt, Jens M Seeger, Oliver Coutelle, Paola Zigrino, Pia Broxtermann, Maria Andree, Kerstin Brinkmann, Christian Jüngst, Astrid C Schauss, Stephan Schüll, Dirk Wohlleber, Percy A Knolle, Martin Krönke, Cornelia Mauch, Hamid Kashkar
  • The unfolded protein response is shaped by the NMD pathway
    The unfolded protein response is shaped by the NMD pathway
    1. Rachid Karam14,
    2. Chih‐Hong Lou1,
    3. Heike Kroeger2,
    4. Lulu Huang15,
    5. Jonathan H Lin2 and
    6. Miles F Wilkinson*,1,3
    1. 1Department of Reproductive Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA
    2. 2Department of Pathology, School of Medicine, University of California San Diego, La Jolla, CA, USA
    3. 3Institute of Genomic Medicine, University of California San Diego, La Jolla, CA, USA
    4. 4Ambry Genetics, Aliso Viejo, CA, USA
    5. 5 ISIS Pharmaceuticals, Carlsbad, CA, USA
    1. *Corresponding author. Tel: +1 858 822 4819; E‐mail: mfwilkinson{at}ucsd.edu

    The threshold for UPR triggering and its timely termination are shown to depend on the nonsense‐mediated RNA decay (NMD) pathway. NMD regulates the mRNAs of several UPR components, which underpins this effect.

    Synopsis

    This study shows that both the threshold for triggering the unfolded protein response (UPR) and its timely termination depend on the nonsense‐mediated RNA decay (NMD) pathway. The mRNAs of several UPR components are directly regulated through NMD, which underpins this effect.

    • UPR induction in response to innocuous stress is prevented by the NMD RNA decay pathway.

    • NMD is downregulated in response to bona fide stress to permit a maximal UPR response.

    • NMD acts by driving the rapid decay of several UPR component transcripts, including IRE1α mRNA.

    • NMD promotes timely UPR termination, thereby reducing the likelihood of stress‐induced apoptosis.

    • cancer
    • ER stress
    • IRE1
    • NMD
    • UPR
    • Received October 8, 2014.
    • Revision received February 13, 2015.
    • Accepted February 24, 2015.
    Rachid Karam, Chih‐Hong Lou, Heike Kroeger, Lulu Huang, Jonathan H Lin, Miles F Wilkinson
  • RNA metabolism: putting the brake on the UPR
    RNA metabolism: putting the brake on the UPR
    1. Amado Carreras‐Sureda1,2 and
    2. Claudio Hetz (chetz{at}med.uchile.cl) (chetz{at}hsph.harvard.edu) 1,2,3
    1. 1Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile
    2. 2Program of Cellular and Molecular Biology, Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of Chile, Santiago, Chile
    3. 3Department of Immunology and Infectious diseases, Harvard School of Public Health, Boston, MA, USA

    The unfolded protein response (UPR) is a major signaling cascade that determines cell fate under conditions of endoplasmic reticulum (ER) stress. The kinetics and amplitude of UPR responses are tightly controlled by several feedback loops and the expression of positive and negative regulators. In this issue of EMBO Reports, the Wilkinson lab uncovers a novel function of nonsense‐mediated RNA decay (NMD) in fine‐tuning the UPR [1]. NMD is an mRNA quality control mechanism known to destabilize aberrant mRNAs that contain premature termination codons. In this work, NMD was shown to determine the threshold of stress necessary to activate the UPR, in addition to adjusting the amplitude of downstream responses and the termination phase. These effects were mapped to the control of the mRNA stability of IRE1, a major ER stress transducer. This study highlights the dynamic crosstalk between mRNA metabolism and the proteostasis network demonstrating the physiological relevance of normal mRNA regulation by the NMD pathway.

    See also: R Karam et al

    In this issue of EMBO Reports, nonsense‐mediated RNA decay (NMD) is shown to fine‐tune the unfolded protein response (UPR). NMD determines the threshold of UPR activation, the amplitude of downstream responses and its termination.

    Amado Carreras‐Sureda, Claudio Hetz
  • Risks inherent to mitochondrial replacement
    Risks inherent to mitochondrial replacement
    1. Edward H Morrow*,1,
    2. Klaus Reinhardt2,
    3. Jonci N Wolff3 and
    4. Damian K Dowling3
    1. 1Evolution, Behaviour and Environment Group, School of Life Sciences, University of Sussex, Brighton, UK
    2. 2Applied Zoology, Department of Biology, Technische Universitaet Dresden, Dresden, Germany
    3. 3School of Biological Sciences, Monash University, Clayton, Vic., Australia
    1. *Corresponding author. Tel: +44 1273 87 2862; E‐mail: ted.morrow{at}sussex.ac.uk

    Questions remain about the long‐term safety of mitochondrial replacement.

    • Received May 30, 2014.
    • Revision received January 15, 2015.
    • Accepted March 2, 2015.
    Edward H Morrow, Klaus Reinhardt, Jonci N Wolff, Damian K Dowling
  • Rap1 promotes endothelial mechanosensing complex formation, NO release and normal endothelial function
    Rap1 promotes endothelial mechanosensing complex formation, NO release and normal endothelial function
    1. Sribalaji Lakshmikanthan1,
    2. Xiaodong Zheng2,36,
    3. Yoshinori Nishijima2,3,
    4. Magdalena Sobczak17,
    5. Aniko Szabo4,
    6. Jeannette Vasquez‐Vivar5,
    7. David X Zhang2,3 and
    8. Magdalena Chrzanowska‐Wodnicka*,1
    1. 1Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI, USA
    2. 2Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
    3. 3Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, USA
    4. 4Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI, USA
    5. 5Department of Biophysics and Redox Biology Program, Medical College of Wisconsin, Milwaukee, WI, USA
    6. 6Department of Pathophysiology, Harbin Medical University, Daqing, China
    7. 7Nencki Institute of Experimental Biology, Warsaw, Poland
    1. *Corresponding author. Tel: +1 414 937 3890; Fax: +1 414 937 6284; E‐mail: magdalena.chrzanowska{at}bcw.edu

    Rap1 is shown to be a new crucial regulator of endothelial mechanosensing that enables the formation of the mechanosensing complex and nitric oxide release. Importantly, endothelial Rap1 deficiency causes hypertension in mice.

    Synopsis

    Rap1 is shown to be a new crucial regulator of endothelial mechanosensing that enables the formation of the mechanosensing complex and nitric oxide release. Importantly, endothelial Rap1 deficiency causes hypertension in mice.

    • Endothelial‐specific Rap1 deletion in mice leads to cardiac hypertrophy and hypertension, but does not affect basal vascular permeability. Underlying hypertension in EC‐Rap1KO mice is severely decreased NO‐dependent vasodilation and NO bioavailability.

    • Deletion of Rap1 in ECs attenuates shear‐stress‐induced NO release and signaling from the endothelial mechanosensory complex (PECAM‐1, VEGFR2, VE‐cadherin) to Akt and eNOS activation.

    • Rap1, activated by shear stress, promotes NO release: a novel, critical function of Rap1 in endothelium.

    • mechanotransduction
    • nitric oxide
    • shear stress
    • small GTPase Rap1
    • vasodilation
    • Received November 7, 2014.
    • Revision received February 28, 2015.
    • Accepted March 2, 2015.
    Sribalaji Lakshmikanthan, Xiaodong Zheng, Yoshinori Nishijima, Magdalena Sobczak, Aniko Szabo, Jeannette Vasquez‐Vivar, David X Zhang, Magdalena Chrzanowska‐Wodnicka
  • Induction of hematopoietic and endothelial cell program orchestrated by ETS transcription factor ER71/ETV2
    Induction of hematopoietic and endothelial cell program orchestrated by ETS transcription factor ER71/ETV2
    1. Fang Liu1,
    2. Daofeng Li2,
    3. Yik Yeung Lawrence Yu1,
    4. Inyoung Kang1,
    5. Min‐Ji Cha16,
    6. Ju Young Kim3,
    7. Changwon Park3,
    8. Dennis K Watson4,
    9. Ting Wang*,2 and
    10. Kyunghee Choi*,1,5
    1. 1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
    2. 2Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USA
    3. 3Department of Pediatrics, Children's Heart Research and Outcomes Center, Emory University School of Medicine, Atlanta, GA, USA
    4. 4Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA
    5. 5Developmental, Regenerative, and Stem Cell Biology Program, Washington University School of Medicine, St. Louis, MO, USA
    6. 6Catholic Kwandong University, Institute for Bio‐Medical Convergence, College of Medicine, Korea
    1. * Corresponding author. Tel: +1 3142 860865; E‐mail: twang{at}genetics.wustl.edu

      Corresponding author. Tel: +1 3143 628716; E‐mail: kchoi{at}wustl.edu

    ETV2 controls the gene regulatory network and signaling involved in the hemangiogenic progenitor specification from mesoderm.

    Synopsis

    ETV2 controls the gene regulatory network and signaling involved in the hemangiogenic progenitor specification from mesoderm.

    • ETV2 induces key genes regulating hematopoietic and endothelial cell lineage specification.

    • ETV2 function is specifically required for the generation of the FLK1highPDGFRα cell population.

    • ETV2 induces other Ets genes, which subsequently maintain ETV2‐initiated blood and endothelial cell programs through an ETS switching mechanism.

    • ChIP‐Seq
    • ER71/ETV2
    • ETS hierarchy
    • ETS switching
    • hemangioblast
    • VEGFR2/FLK1
    • Received December 2, 2014.
    • Revision received February 24, 2015.
    • Accepted February 26, 2015.
    Fang Liu, Daofeng Li, Yik Yeung Lawrence Yu, Inyoung Kang, Min‐Ji Cha, Ju Young Kim, Changwon Park, Dennis K Watson, Ting Wang, Kyunghee Choi
  • Nuclear lamins are not required for lamina‐associated domain organization in mouse embryonic stem cells
    Nuclear lamins are not required for lamina‐associated domain organization in mouse embryonic stem cells
    1. Mario Amendola1 and
    2. Bas van Steensel*,1
    1. 1Division of Gene Regulation, Netherlands Cancer Institute, Amsterdam, the Netherlands
    1. *Corresponding author. Tel: +31 20 5122040; E‐mail: b.v.steensel{at}nki.nl

    Nuclear lamins have no detectable role in mediating genome‐wide lamina‐associated domain organization in mESC, implying a role for non‐lamin components of the nuclear lamina as molecular players in genome organization.

    Synopsis

    Nuclear lamins have no detectable role in mediating genome‐wide lamina associated domain organization in mESC, implying a role for non‐lamin components of the nuclear lamina as molecular players in genome organization.

    • Lamins in mouse ES cells are dispensable for lamina‐associated domain organization.

    • Lamins in mouse ES cells are dispensable for silencing genes at the nuclear periphery.

    • interphase chromosome organization
    • genome‐wide mapping; nuclear architecture
    • nuclear lamina
    • Received October 27, 2014.
    • Revision received February 16, 2015.
    • Accepted February 16, 2015.
    Mario Amendola, Bas van Steensel