Activation of Wnt/β-Catenin Protein Signaling Induces Mitochondria-mediated Apoptosis in Hematopoietic Progenitor Cells

被引:91
作者
Ming, Ming [1 ]
Wang, Sheng [1 ]
Wu, Wenshu [5 ]
Senyuk, Vitalyi [1 ]
Le Beau, Michelle M. [3 ,4 ]
Nucifora, Giuseppina [1 ,2 ]
Qian, Zhijian [1 ,2 ]
机构
[1] Univ Illinois, Dept Med, Chicago, IL 60621 USA
[2] Univ Illinois, Canc Res Ctr, Chicago, IL 60621 USA
[3] Univ Chicago, Hematol Oncol Sect, Chicago, IL 60637 USA
[4] Univ Chicago, Ctr Comprehens Canc, Chicago, IL 60637 USA
[5] Childrens Hosp Oakland Res Inst, Oakland, CA 94609 USA
基金
美国国家卫生研究院;
关键词
ACUTE MYELOID-LEUKEMIA; BETA-CATENIN; STEM-CELLS; IN-VIVO; SELF-RENEWAL; EXPRESSION; SURVIVAL; PATHWAY; APC; TRANSDUCTION;
D O I
10.1074/jbc.M112.342089
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
070307 [化学生物学]; 071010 [生物化学与分子生物学];
摘要
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.
引用
收藏
页码:22683 / 22690
页数:8
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