title: 14-3-3σ regulates β-catenin-mediated mouse embryonic stem cell proliferation by sequestering GSK-3β.
abstract: BACKGROUND
  Pluripotent embryonic stem cells are considered to be an unlimited cell source for tissue regeneration and cell-based therapy. Investigating the molecular mechanism underlying the regulation of embryonic stem cell expansion is thus important. 14-3-3 proteins are implicated in controlling cell division, signaling transduction and survival by interacting with various regulatory proteins. However, the function of 14-3-3 in embryonic stem cell proliferation remains unclear.
  
  
  RESULTS
  In this study, we show that all seven 14-3-3 isoforms were detected in mouse embryonic stem cells. Retinoid acid suppressed selectively the expression of 14-3-3σ isoform. Knockdown of 14-3-3σ with siRNA reduced embryonic stem cell proliferation, while only 14-3-3σ transfection increased cell growth and partially rescued retinoid acid-induced growth arrest. Since the growth-enhancing action of 14-3-3σ was abrogated by β-catenin knockdown, we investigated the influence of 14-3-3σ overexpression on β-catenin/GSK-3β. 14-3-3σ bound GSK-3β and increased GSK-3β phosphorylation in a PI-3K/Akt-dependent manner. It disrupted β-catenin binding by the multiprotein destruction complex. 14-3-3σ overexpression attenuated β-catenin phosphorylation and rescued the decline of β-catenin induced by retinoid acid. Furthermore, 14-3-3σ enhanced Wnt3a-induced β-catenin level and GSK-3β phosphorylation. DKK, an inhibitor of Wnt signaling, abolished Wnt3a-induced effect but did not interfere GSK-3β/14-3-3σ binding.
  
  
  CONCLUSIONS
  Our findings show for the first time that 14-3-3σ plays an important role in regulating mouse embryonic stem cell proliferation by binding and sequestering phosphorylated GSK-3β and enhancing Wnt-signaled GSK-3β inactivation. 14-3-3σ is a novel target for embryonic stem cell expansion.
authors: Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan.
authors: Tzu-Ching
authors: TC
authors: Chang
authors: Chia-Chia
authors: CC
authors: Liu
authors: En-Wei
authors: EW
authors: Hsing
authors: Shu-Man
authors: SM
authors: Liang
authors: Ya-Hui
authors: YH
authors: Chi
authors: Li-Ying
authors: LY
authors: Sung
authors: Shau-Ping
authors: SP
authors: Lin
authors: Tang-Long
authors: TL
authors: Shen
authors: Bor-Sheng
authors: BS
authors: Ko
authors: B Linju
authors: BL
authors: Yen
authors: Shaw-Fang
authors: SF
authors: Yet
authors: Kenneth K
authors: KK
authors: Wu
authors: Jun-Yang
authors: JY
authors: Liou
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D000818:Animals; D060466:Axin Protein / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000201:enzymology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D051379:Mice; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism; D011485:Protein Binding; D055550:Protein Stability; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000378:metabolism; D051153:Wnt Proteins; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D048948:14-3-3 Proteins; D060466:Axin Protein; D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; C499130:Sfn protein, mouse; D051153:Wnt Proteins; D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3