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

Ping Hu, Angel R. Nebreda, Helmut Hanenberg, Garrett H. Kinnebrew, Mircea Ivan, Mervin Yoder, Marie Dominique Filippi, Hal Broxmeyer, Reuben Kapur

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Article number3518
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

Fingerprint

anemias
Erythropoiesis
Erythropoietin
Epigenomics
Anemia
Erythroblasts
silencers
phosphorylation
negative feedback
brakes
apoptosis
Phosphorylation
mice
recovery
Brakes
activation
disorders
degradation
Chemical activation
Apoptosis

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

P38α/JNK signaling restrains erythropoiesis by suppressing Ezh2-mediated epigenetic silencing of Bim. / Hu, Ping; Nebreda, Angel R.; Hanenberg, Helmut; Kinnebrew, Garrett H.; Ivan, Mircea; Yoder, Mervin; Filippi, Marie Dominique; Broxmeyer, Hal; Kapur, Reuben.

In: Nature Communications, Vol. 9, No. 1, 3518, 01.12.2018.

Research output: Contribution to journalArticle

Hu, Ping ; Nebreda, Angel R. ; Hanenberg, Helmut ; Kinnebrew, Garrett H. ; Ivan, Mircea ; Yoder, Mervin ; Filippi, Marie Dominique ; Broxmeyer, Hal ; Kapur, Reuben. / P38α/JNK signaling restrains erythropoiesis by suppressing Ezh2-mediated epigenetic silencing of Bim. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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AU - Ivan, Mircea

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