title: Ex vivo maintenance of hematopoietic stem cells by quiescence induction through Fbxw7&alpha; overexpression.
abstract: Cell-cycle quiescence in hematopoietic stem cells (HSCs) is essential for maintaining stemness by protecting cells from differentiation or senescence. F-box and WD-40 domain protein 7 (Fbxw7) maintains HSCs and suppresses leukemogenesis by mediating ubiquitin-dependent degradation of cell-cycle activators and oncoproteins. Fbxw7α was shown to be the preferentially expressed Fbxw7 isoform in primitive HSCs. Forced Fbxw7α expression in lineage marker Sca-1(+)c-Kit(+) cells led to cell-cycle dormancy by reducing the protein levels of the Fbxw7 substrates c-Myc, Notch1, and phosphorylated S6 (a key downstream element of mTOR). Hypoxia, an essential factor for HSC quiescence, suppressed c-Myc in an Fbxw7α-dependent manner. Fbxw7α-overexpressing lineage marker Sca-1(+)c-Kit(+) cells sustained high reconstitution capacities during in vitro culture. These data suggest that Fbxw7α sustains HSC dormancy through c-Myc, Notch1, and the mTOR pathways. The modulation of Fbxw7α expression or activity represents a promising new tool for ex vivo HSC maintenance.
authors.affiliation: Department of Cell Differentiation, Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Hirono
authors.initials: H
authors.lastname: Iriuchishima
authors.forename: Keiyo
authors.initials: K
authors.lastname: Takubo
authors.forename: Sahoko
authors.initials: S
authors.lastname: Matsuoka
authors.forename: Ichiro
authors.initials: I
authors.lastname: Onoyama
authors.forename: Keiichi I
authors.initials: KI
authors.lastname: Nakayama
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Nojima
authors.forename: Toshio
authors.initials: T
authors.lastname: Suda
mesh_terms: D018929:Cell Culture Techniques / Q000379:methods; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000494:pharmacology*; D044783:F-Box Proteins / Q000235:genetics / Q000494:pharmacology*; D000073979:F-Box-WD Repeat-Containing Protein 7; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D051881:Receptor, Notch1 / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000494:pharmacology*; D054875:Ubiquitination
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C489427:MYC protein, human; C497761:NOTCH1 protein, human; D016271:Proto-Oncogene Proteins c-myc; D051881:Receptor, Notch1; D044767:Ubiquitin-Protein Ligases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases