P38α/JNK signaling restrains erythropoiesis by suppressing Ezh2-mediated epigenetic silencing of Bim.
P38α/JNK signaling restrains erythropoiesis by suppressing Ezh2-mediated epigenetic silencing of Bim.
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DOI：
10.1038/s41467-018-05955-2
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发表时间：
2018-08-29
影响因子：
16.6
通讯作者：
Kapur R
中科院分区：
文献类型：
--
作者：
Hu P;Nebreda AR;Hanenberg H;Kinnebrew GH;Ivan M;Yoder MC;Filippi MD;Broxmeyer HE;Kapur R
虽然促红细胞生成素（EPO）构成贫血的主要治疗，但一系列贫血性疾病仍然对EPO治疗具有抗性。替代治疗策略的需要需要确定生理抑制红细胞生成的机制。在此，我们发现P38α通过整合贫血恢复过程中的凋亡信号，独立于EPO抑制小鼠和人成红细胞的红细胞生成。P38α缺陷通过负反馈机制通过增加Map 3 k4的表达促进JNK活化。JNK阻止Cdk 1介导的磷酸化和随后的降解由Smurf 2的表观遗传沉默Ezh 2。稳定的Ezh 2沉默Bim表达并保护成红细胞免于凋亡。因此，我们确定P38α/JNK信号传导作为通过Bim的表观遗传沉默调节红细胞生成的分子制动器。我们认为，抑制P38α，通过以EPO非依赖性方式增强红细胞生成，可能为贫血的治疗提供一种替代策略。促红细胞生成素（EPO）刺激红细胞生成，通常用于治疗贫血。Hu等人发现P38α/JNK信号通过调节促凋亡蛋白Bim的表观遗传沉默，独立于EPO抑制红细胞生成，从而确定了治疗EPO耐药贫血疾病的假定靶点。
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. Erythropoietin (EPO) stimulates erythropoiesis and is commonly used to treat anemia. Here Hu et al. find that P38α/JNK signaling restrains erythropoiesis independently of EPO by regulating epigenetic silencing of the proapoptotic protein Bim, and thus identify putative targets for the treatment of anemic disorders resistant to EPO.
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影响因子：
64.5
作者：
Kim AR;Ulirsch JC;Wilmes S;Unal E;Moraga I;Karakukcu M;Yuan D;Kazerounian S;Abdulhay NJ;King DS;Gupta N;Gabriel SB;Lander ES;Patiroglu T;Ozcan A;Ozdemir MA;Garcia KC;Piehler J;Gazda HT;Klein DE;Sankaran VG
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作者：
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通讯作者：
Huang, Lily Jun-shen
影响因子：
30.8
作者：
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