Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Nature communications, 2018-08, Vol.9 (1), p.3518-15, Article 3518

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2018

Link zum Volltext

Quelle

Elektronische Zeitschriftenbibliothek

Beschreibungen/Notizen

• 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.