title: Activation of Wnt/β-catenin protein signaling induces mitochondria-mediated apoptosis in hematopoietic progenitor cells.
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.
authors.affiliation: Department of Medicine, University of Illinois, Chicago, Illinois 60621, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Ming
authors.forename: Sheng
authors.initials: S
authors.lastname: Wang
authors.forename: Wenshu
authors.initials: W
authors.lastname: Wu
authors.forename: Vitalyi
authors.initials: V
authors.lastname: Senyuk
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Le Beau
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Nucifora
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Qian
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C495267:CTNNB1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D051176:beta Catenin