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  • Shp2 signaling suppresses senescence in PyMT‐induced mammary gland cancer in mice
    <div xmlns="http://www.w3.org/1999/xhtml">Shp2 signaling suppresses senescence in <em>PyMT</em>‐induced mammary gland cancer in mice</div>
    1. Linxiang Lan1,
    2. Jane D Holland1,
    3. Jingjing Qi1,
    4. Stefanie Grosskopf1,
    5. Regina Vogel1,
    6. Balázs Györffy2,3,
    7. Annika Wulf‐Goldenberg4 and
    8. Walter Birchmeier*,1
    1. 1Cancer Research Program, Max‐Delbrück Center for Molecular Medicine (MDC), Berlin, Germany
    2. 2MTA TTK Lendület Cancer Biomarker Research Group, Budapest, Hungary
    3. 32nd Department of Pediatrics, Semmelweis University, Budapest, Hungary
    4. 4Experimental Pharmacology & Oncology (EPO), Berlin, Germany
    1. *Corresponding author. Tel: +49 30 94063800; Fax: +49 30 94062656; E‐mail: wbirch{at}mdc-berlin.de

    Tyrosine phosphatase Shp2, upregulated in human breast cancer, regulates Src, FAK, and MAPK signaling pathway to suppress senescence and promote tumorigenesis in mouse models.

    Synopsis

    Ablation or inhibition of the tyrosine phosphatase Shp2 in PyMT mammary gland cancers of mice induces senescence via the inactivation of Src, Fak, and Mek and subsequent downregulation of the genes Skp2, Aurka, and Dll1. Small molecule inhibitors that target Shp2 block tumor growth by inducing senescence.

    • Shp2 is highly upregulated in PyMT‐induced mammary gland cancers in mice. Ablation of the Shp2 gene blocks tumor formation by inducing senescence.

    • Shp2 ablation or inhibition blocks the downstream signaling molecules Fak, Src, and Mek to inhibit the genes Skp2, Aurka, and Dll1, which suppress p27‐ and p53‐dependent senescence.

    • Shp2 and downstream gene signatures predict relapse‐free survival of patients with breast cancer.

    • Inhibition of Shp2 enzyme activity by small molecules blocks tumor growth in mice.

    • Kaplan–Meier analysis
    • pro‐senescence therapy
    • PTPN11
    • relapse‐free survival
    • Shp2‐dependent gene signature
    • Received May 16, 2014.
    • Revision received January 20, 2015.
    • Accepted February 4, 2015.
    Linxiang Lan, Jane D Holland, Jingjing Qi, Stefanie Grosskopf, Regina Vogel, Balázs Györffy, Annika Wulf‐Goldenberg, Walter Birchmeier
  • Astro‐logics with microRNAs
    Astro‐logics with microRNAs
    1. Chen Eitan1 and
    2. Eran Hornstein (eran.hornstein{at}weizmann.ac.il) 1
    1. 1Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel

    Astrocytes are a subtype of glial cells in the central nervous system that are critical for normal brain activity. In this issue of The EMBO Journal, Shenoy et al provide evidence for the involvement of miRNAs in the molecular mechanism underlying the in vitro differentiation of astrocytes from glial progenitor cells. Let‐7 and miR‐125 jointly silence multiple mRNA targets that would have potentially disrupted differentiation if expressed, and function in concert with JAK‐STAT signaling to promote astrocyte differentiation.

    See also: A Shenoy et al

    Differentiation of astrocytes requires the joint action of two miRNAs that repress a shared set of target genes whose expression would be disruptive for cell fate transitioning.

    Chen Eitan, Eran Hornstein
  • SIGNing a symbiotic treaty with gut microbiota
    SIGNing a symbiotic treaty with gut microbiota
    1. Geanncarlo Lugo‐Villarino (geanncarlo.lugo{at}ipbs.fr) 1,2 and
    2. Olivier Neyrolles1,2
    1. 1Département Tuberculosis and Infection Biology, Institut de Pharmacologie et de Biologie Structurale (IPBS) CNRS, Toulouse, France
    2. 2UPS, IPBS Université Paul Sabatier Université de Toulouse, Toulouse, France

    Beneficial microbes hold great promise for the treatment of a wide range of immune and inflammatory disorders. In this issue of The EMBO Journal, Lightfoot and colleagues report how the food‐grade bacterium Lactobacillus acidophilus helps the immune system to limit experimental colitis in mice through interaction between SIGNR3 and surface layer protein A (SlpA) in L. acidophilus. These results pave the way for future development of novel therapies for inflammatory diseases, including inflammatory bowel disease.

    See also: YL Lightfoot et al

    Mouse C‐type lectin SIGNR3 and Lactobacillus acidophilus surface layer protein A interactions mediate the immune benefits of this food‐grade bacterium.

    Geanncarlo Lugo‐Villarino, Olivier Neyrolles
  • Interrupting synoviolin play at the ER: a plausible action to elevate mitochondrial energetics and silence obesity
    Interrupting synoviolin play at the ER: a plausible action to elevate mitochondrial energetics and silence obesity
    1. Meghan S Soustek1 and
    2. Pere Puigserver (pere_puigserver{at}dfci.harvard.edu) 1
    1. 1Department of Cancer Biology, Dana‐Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA, USA

    Obesity is a global concern, which has been linked to increased risk for cardiovascular disease, type 2 diabetes, atherosclerosis, non‐alcoholic fatty liver, and cancer. In this issue of The EMBO Journal, Fujita et al (2015) describe the role of an endoplasmic reticulum (ER)‐resident E3 ubiquitin ligase, synoviolin, and its ability to control body weight and energy expenditure by targeting PGC‐1β, a transcriptional modulator of mitochondrial oxidative metabolism.

    See also: H Fujita et al

    Inhibiting the E3 ligase synoviolin with the specific inhibitor LS‐102 can be potentially exploited to fight obesity, as this ligase is now shown to control body weight and energy expenditure in mice.

    Meghan S Soustek, Pere Puigserver
  • Toward beta cell replacement for diabetes
    Toward beta cell replacement for diabetes
    1. Bjarki Johannesson1,
    2. Lina Sui2,
    3. Donald O Freytes1,
    4. Remi J Creusot3 and
    5. Dieter Egli*,1,2
    1. 1The New York Stem Cell Foundation Research Institute, New York, NY, USA
    2. 2Naomi Berrie Diabetes Center & Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY, USA
    3. 3Columbia Center for Translational Immunology, Department of Medicine and Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA
    1. *Corresponding author. Tel: +1 212 851 4890; E‐mail: de2220{at}cumc.columbia.edu

    Dieter Egli & colleagues provide a stem cell perspective on pancreatic beta‐cells for diabetes therapies and disease modeling.

    • beta cells
    • cell replacement therapy
    • stem cells
    • type 1 diabetes
    • Received November 27, 2014.
    • Revision received January 13, 2015.
    • Accepted January 22, 2015.
    Bjarki Johannesson, Lina Sui, Donald O Freytes, Remi J Creusot, Dieter Egli
  • Metabolic remodeling: a pyruvate transport affair
    Metabolic remodeling: a pyruvate transport affair
    1. Heike Rampelt1 and
    2. Martin van der Laan (martin.van.der.laan{at}biochemie.uni-freiburg.de) 1,2
    1. 1Institut für Biochemie und Molekularbiologie, Universität Freiburg, Freiburg, Germany
    2. 2BIOSS Centre for Biological Signalling Studies, Universität Freiburg, Freiburg, Germany

    Metabolic remodeling is a major determinant for many cell fate decisions, and a switch from respiration to aerobic glycolysis is generally considered as a hallmark of cancer cell transformation. Pyruvate is a key metabolite at the major junction of carbohydrate metabolism between cytosolic glycolysis and the mitochondrial Krebs cycle. In this issue of The EMBO Journal, Bender et al show that yeast cells regulate pyruvate uptake into mitochondria, and thus its metabolic fate, by expressing alternative pyruvate carrier complexes with different activities.

    See also: T Bender et al

    A new study in yeast links metabolic changes to the expression of alternative mitochondrial pyruvate carriers (MPCs) displaying different activities, adding to recent studies in cancer cells that associated MPC function to metabolic reprogramming and cell fate.

    Heike Rampelt, Martin van der Laan
  • Regulatory T cell differentiation: cooperation saves the day
    Regulatory T cell differentiation: cooperation saves the day
    1. Adrian Liston (adrian.liston{at}vib.be) 1,2 and
    2. Susan M Schlenner1,2
    1. 1Autoimmune Genetics Laboratory, VIB, Leuven, Belgium
    2. 2Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium

    MicroRNA are important regulators of CD4 T cell differentiation, altering the balance between the immunogenic and tolerogenic pathways. Studies in mice with microRNA‐deficient T cells have revealed defects in differentiation into the regulatory T cell lineage; however, the individual microRNA responsible have remained elusive. A recent paper in The EMBO Journal uses a systematic screen to find a novel cooperative action between an inducible and a constitutive microRNA in aiding regulatory T cell induction.

    See also: SC Warth et al

    An inducible microRNA cooperates with a constitutive one to fine‐tune regulatory T cell induction.

    Adrian Liston, Susan M Schlenner