title: Importin alpha subtypes determine differential transcription factor localization in embryonic stem cells maintenance.
abstract: We recently demonstrated that the expression of the importin α subtype is switched from α2 to α1 during neural differentiation in mouse embryonic stem cells (ESCs) and that this switching has a major impact on cell differentiation. In this study, we report a cell-fate determination mechanism in which importin α2 negatively regulates the nuclear import of certain transcription factors to maintain ESC properties. The nuclear import of Oct6 and Brn2 was inhibited via the formation of a transport-incompetent complex of the cargo bound to a nuclear localization signal binding site in importin α2. Unless this dominant-negative effect was downregulated upon ESC differentiation, inappropriate cell death was induced. We propose that although certain transcription factors are necessary for differentiation in ESCs, these factors are retained in the cytoplasm by importin α2, thereby preventing transcription factor activity in the nucleus until the cells undergo differentiation.
authors.affiliation: Department of Biochemistry, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan. yasuhara@anat3.med.osaka-u.ac.jp
authors.forename: Noriko
authors.initials: N
authors.lastname: Yasuhara
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Yamagishi
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Arai
authors.forename: Rashid
authors.initials: R
authors.lastname: Mehmood
authors.forename: Chihiro
authors.initials: C
authors.lastname: Kimoto
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Fujita
authors.forename: Kenichi
authors.initials: K
authors.lastname: Touma
authors.forename: Azumi
authors.initials: A
authors.lastname: Kaneko
authors.forename: Yasunao
authors.initials: Y
authors.lastname: Kamikawa
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Moriyama
authors.forename: Toshio
authors.initials: T
authors.lastname: Yanagida
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kaneko
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yoneda
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D019913:Nuclear Localization Signals / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D050816:Octamer Transcription Factor-6 / Q000378:metabolism*; D050809:POU Domain Factors / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction; D028901:alpha Karyopherins; D028961:beta Karyopherins / Q000378:metabolism
chemical_list: C490631:Kpna2 protein, mouse; D009419:Nerve Tissue Proteins; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins; D050814:Octamer Transcription Factor-3; D050809:POU Domain Factors; D028901:alpha Karyopherins; D028961:beta Karyopherins; D050816:Octamer Transcription Factor-6; C074066:Pou3f2 protein, mouse