Activation of Wnt/β-Catenin Protein Signaling Induces Mitochondria-mediated Apoptosis in Hematopoietic Progenitor Cells
Activation of Wnt/β-Catenin Protein Signaling Induces Mitochondria-mediated Apoptosis in Hematopoietic Progenitor Cells
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DOI：
10.1074/jbc.m112.342089
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发表时间：
2012-06-29
影响因子：
4.8
通讯作者：
Qian, Zhijian
中科院分区：
文献类型：
--
作者：
Ming, Ming;Wang, Sheng;Qian, Zhijian
典型的Wnt/β-连环蛋白信号传导在发育、肿瘤发生和成人体内平衡过程中被激活，但其在维持造血干细胞/祖细胞中的作用尚未确定。在这里，我们证明，条件表达的活性形式的β-连环蛋白在体内诱导造血干/祖细胞（HSC/HPC）的凋亡的频率显着增加。体外HPC中Wnt/β连环蛋白信号传导的激活提高了半胱天冬酶3和9的活性，并导致线粒体膜电位（Delta Psi（m））的损失，表明其诱导了内在的线粒体凋亡途径。在体内，HPC中活化的β-连环蛋白的表达与Bcl 2的下调和Casp 3的表达相关。骨髓移植试验表明，通过Bcl 2转基因增强的细胞存活重新建立表达活化的β-连环蛋白的HSC/HPC的重建能力。此外，Bcl 2转基因防止这些HSC/HPC在体内耗尽。我们的数据表明，Wnt/β-连环蛋白通路的激活部分通过解除对HPC存活的调节而导致HPC功能缺陷。
The canonical Wnt/beta-catenin signaling is activated during development, tumorigenesis, and in adult homeostasis, yet its role in maintenance of hematopoietic stem/progenitor cells is not firmly established. Here, we demonstrate that conditional expression of an active form of beta-catenin in vivo induces a marked increase in the frequency of apoptosis in hematopoietic stem/progenitor cells (HSCs/HPCs). Activation of Wnt/beta catenin signaling in HPCs in vitro elevates the activity of caspases 3 and 9 and leads to a loss of mitochondrial membrane potential (Delta Psi(m)), indicating that it induces the intrinsic mitochondrial apoptotic pathway. In vivo, expression of activated beta-catenin in HPCs is associated with down-regulation of Bcl2 and expression of Casp3. Bone marrow transplantation assays reveal that enhanced cell survival by a Bcl2 transgene re-establishes the reconstitution capacity of HSCs/HPCs that express activated beta-catenin. In addition, a Bcl2 transgene prevents exhaustion of these HSCs/HPCs in vivo. Our data suggest that activation of the Wnt/beta-catenin pathway contributes to the defective function of HPCs in part by deregulating their survival.