IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v9y2018i1d10.1038_s41467-018-05955-2.html
   My bibliography  Save this article

P38α/JNK signaling restrains erythropoiesis by suppressing Ezh2-mediated epigenetic silencing of Bim

Author

Listed:
  • Ping Hu

    (Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis)

  • Angel R. Nebreda

    (Institute for Research in Biomedicine (IRB Barcelona). Barcelona Institute of Science and Technology)

  • Helmut Hanenberg

    (University Children’s Hospital Essen, University of Duisburg-Essen)

  • Garrett H. Kinnebrew

    (Indiana University School of Medicine, Indianapolis)

  • Mircea Ivan

    (Indiana University School of Medicine, Indianapolis)

  • Mervin C. Yoder

    (Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis)

  • Marie-Dominique Filippi

    (Cincinnati Children’s Research Foundation, University of Cincinnati College of Medicine)

  • Hal E. Broxmeyer

    (Indiana University School of Medicine)

  • Reuben Kapur

    (Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis)

Abstract

While erythropoietin (EPO) constitutes the major treatment for anemia, a range of anemic disorders remain resistant to EPO treatment. The need for alternative therapeutic strategies requires the identification of mechanisms that physiologically restrain erythropoiesis. Here we show that P38α restrains erythropoiesis in mouse and human erythroblasts independently of EPO by integrating apoptotic signals during recovery from anemia. P38α deficiency promotes JNK activation through increased expression of Map3k4 via a negative feedback mechanism. JNK prevents Cdk1-mediated phosphorylation and subsequent degradation by Smurf2 of the epigenetic silencer Ezh2. Stabilized Ezh2 silences Bim expression and protects erythroblasts from apoptosis. Thus, we identify P38α/JNK signaling as a molecular brake modulating erythropoiesis through epigenetic silencing of Bim. We propose that inhibition of P38α, by enhancing erythropoiesis in an EPO-independent fashion, may provide an alternative strategy for the treatment of anemia.

Suggested Citation

  • Ping Hu & Angel R. Nebreda & Helmut Hanenberg & Garrett H. Kinnebrew & Mircea Ivan & Mervin C. Yoder & Marie-Dominique Filippi & Hal E. Broxmeyer & Reuben Kapur, 2018. "P38α/JNK signaling restrains erythropoiesis by suppressing Ezh2-mediated epigenetic silencing of Bim," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05955-2
    DOI: 10.1038/s41467-018-05955-2
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-018-05955-2
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-018-05955-2?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05955-2. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.