ZFP36L1 promotes monocyte/macrophage differentiation by repressing CDK6.
ZFP36L1 promotes monocyte/macrophage differentiation by repressing CDK6.
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ZFP36L1通过抑制CDK6促进单核细胞/巨噬细胞分化
DOI：
10.1038/srep16229
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发表时间：
2015-11-06
影响因子：
4.6
通讯作者：
Zhang JW
中科院分区：
文献类型：
--
作者：
Chen MT;Dong L;Zhang XH;Yin XL;Ning HM;Shen C;Su R;Li F;Song L;Ma YN;Wang F;Zhao HL;Yu J;Zhang JW
RNA 结合蛋白 (RBP) 介导的转录后控制参与影响 RNA 代谢的各个方面，并在哺乳动物发育和病理疾病中发挥重要作用。然而，特定 RBP 的功能及其在单核细胞/巨噬细胞分化中发挥作用的分子机制仍有待确定。在本研究中，通过生物信息学分析和实验验证，我们发现ZFP36锌指蛋白家族成员ZFP36L1在急性髓系白血病（AML）患者中与正常对照相比显着减少，并且在PMA诱导的THP-1和HL-60细胞的单核/巨噬细胞分化以及CD34+诱导培养过程中表现出显着的时程增加。 造血干/祖细胞（HSPC）。慢病毒介导的功能获得和丧失检测表明，ZFP36L1 作为正调节因子参与单核细胞/巨噬细胞分化。机制研究进一步表明，ZFP36L1 与含有富含腺嘌呤-尿苷元素的 CDK6 mRNA 3'非翻译区结合，负向调节 CDK6 的表达，随后证明这会阻碍 CD34+ HSPC 的体外单核细胞/巨噬细胞分化。总的来说，我们的工作通过抑制单核细胞/巨噬细胞分化过程中的 CDK6 表达，揭示了 ZFP36L1 介导的调节回路，这也可能为 AML 治疗提供治疗靶点。
RNA binding proteins (RBPs)-mediated post-transcriptional control has been implicated in influencing various aspects of RNA metabolism and playing important roles in mammalian development and pathological diseases. However, the functions of specific RBPs and the molecular mechanisms through which they act in monocyte/macrophage differentiation remain to be determined. In this study, through bioinformatics analysis and experimental validation, we identify that ZFP36L1, a member of ZFP36 zinc finger protein family, exhibits significant decrease in acute myeloid leukemia (AML) patients compared with normal controls and remarkable time-course increase during monocyte/macrophage differentiation of PMA-induced THP-1 and HL-60 cells as well as induction culture of CD34+ hematopoietic stem/progenitor cells (HSPCs). Lentivirus-mediated gain and loss of function assays demonstrate that ZFP36L1 acts as a positive regulator to participate in monocyte/macrophage differentiation. Mechanistic investigation further reveals that ZFP36L1 binds to the CDK6 mRNA 3′untranslated region bearing adenine-uridine rich elements and negatively regulates the expression of CDK6 which is subsequently demonstrated to impede the in vitro monocyte/macrophage differentiation of CD34+ HSPCs. Collectively, our work unravels a ZFP36L1-mediated regulatory circuit through repressing CDK6 expression during monocyte/macrophage differentiation, which may also provide a therapeutic target for AML therapy.