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      Activation of Wnt/β-catenin protein signaling induces mitochondria-mediated apoptosis in hematopoietic progenitor cells.

      The Journal of Biological Chemistry
      Animals, Apoptosis, physiology, Bone Marrow Cells, cytology, metabolism, Bone Marrow Transplantation, Cell Survival, Cells, Cultured, Hematopoietic Stem Cells, Membrane Potential, Mitochondrial, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria, Proto-Oncogene Proteins c-bcl-2, genetics, Wnt Signaling Pathway, beta Catenin

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          Abstract

          The canonical Wnt/β-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 β-catenin in vivo induces a marked increase in the frequency of apoptosis in hematopoietic stem/progenitor cells (HSCs/HPCs). Activation of Wnt/β-catenin signaling in HPCs in vitro elevates the activity of caspases 3 and 9 and leads to a loss of mitochondrial membrane potential (ΔΨ(m)), indicating that it induces the intrinsic mitochondrial apoptotic pathway. In vivo, expression of activated β-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 β-catenin. In addition, a Bcl2 transgene prevents exhaustion of these HSCs/HPCs in vivo. Our data suggest that activation of the Wnt/β-catenin pathway contributes to the defective function of HPCs in part by deregulating their survival.

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