Regulation of Trib2 by an E2F1-C/EBPα feedback loop in AML cell proliferation
Regulation of Trib2 by an E2F1-C/EBPα feedback loop in AML cell proliferation
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DOI：
10.1182/blood-2013-07-511683
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发表时间：
2014-04-10
期刊：
影响因子：
20.3
通讯作者：
Keeshan, Karen
中科院分区：
文献类型：
--
作者：
Rishi, Loveena;Hannon, Maura;Keeshan, Karen
细胞增殖调控的丧失是白血病转化的关键事件，并且癌基因tribbles（Trib）2正在成为急性白血病中转录因子的关键靶点。转录因子E2 F1通常被CCAAT增强子结合蛋白a（C/EBP α）-p42抑制，在急性髓性白血病（AML）中发生失调，导致细胞周期紊乱和细胞凋亡，强调其在AML的分子发病机制中的重要性。在这里，我们表明E2 F家族成员直接调节Trib 2在白血病细胞中，并确定一个反馈调节环E2 F1，C/EBP α，Trib 2在AML细胞增殖和生存。进一步的分析显示，E2 F1介导的Trib 2表达被C/EBP α-p42抑制，在正常粒细胞/巨噬细胞祖细胞中，我们检测到C/EBP α与Trib 2启动子结合。细胞周期的药理学抑制或Trib 2敲低导致AML细胞增殖的阻断。我们的工作提出了一种新的范式，E2 F1在AML细胞增殖控制重要的Trib 2表达调控中发挥关键作用。重要的是，我们确定了失调的C/EBP α和E2 F1对Trib 2表达升高和白血病细胞存活的贡献，这可能有助于AML的启动和维持，并可能对正常和恶性造血产生重大影响。
The loss of regulation of cell proliferation is a key event in leukemic transformation, and the oncogene tribbles (Trib)2 is emerging as a pivotal target of transcription factors in acute leukemias. Deregulation of the transcription factor E2F1, normally repressed by CCAAT enhancer-binding protein a (C/EBP alpha)-p42, occurs in acute myeloid leukemia (AML), resulting in the perturbation of cell cycle and apoptosis, emphasizing its importance in the molecular pathogenesis of AML. Here we show that E2F family members directly regulate Trib2 in leukemic cells and identify a feedback regulatory loop for E2F1, C/EBP alpha, and Trib2 inAML cell proliferation and survival. Further analyses revealed that E2F1-mediated Trib2 expression was repressed by C/EBP alpha-p42, and in normal granulocyte/macrophage progenitor cells, we detect C/EBP alpha bound to the Trib2 promoter. Pharmacological inhibition of the cell cycle or Trib2 knockdown resulted in a block in AML cell proliferation. Our work proposes a novel paradigm whereby E2F1 plays a key role in the regulation of Trib2 expression important for AML cell proliferation control. Importantly, we identify the contribution of dysregulated C/EBP alpha and E2F1 to elevated Trib2 expression and leukemic cell survival, which likely contributes to the initiation and maintenance of AML and may have significant implications for normal and malignant hematopoiesis.