title: Akt-signal integration is involved in the differentiation of embryonal carcinoma cells.
abstract: The mechanism by which Akt modulates stem cell homeostasis is still incompletely defined. Here we demonstrate that Akt phosphorylates special AT-rich sequences binding protein 1 (SATB1) at serine 47 and protects SATB1 from apoptotic cleavage. Meanwhile, Akt phosphorylates Oct4 at threonine 228 and Klf4 at threonine 399, and accelerates their degradation. Moreover, PI3K/Akt signaling enhances the binding of SATB1 to Sox2, thereby probably impairing the formation of Oct4/Sox2 regulatory complexes. During retinoic acid (RA)-induced differentiation of mouse F9 embryonal carcinoma cells (ECCs), the Akt activation profile as well as its substrate spectrum is strikingly correlated with the down-regulation of Oct4, Klf4 and Nanog, which suggests Akt activation is coupled to the onset of differentiation. Accordingly, Akt-mediated phosphorylation is crucial for the capability of SATB1 to repress Nanog expression and to activate transcription of Bcl2 and Nestin genes. Taken together, we conclude that Akt is involved in the differentiation of ECCs through coordinated phosphorylations of pluripotency/differentiation factors.
authors.affiliation: Department of Cell Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Chen
authors.forename: Zheng
authors.initials: Z
authors.lastname: Xue
authors.forename: Guanghui
authors.initials: G
authors.lastname: Yang
authors.forename: Bingyang
authors.initials: B
authors.lastname: Shi
authors.forename: Ben
authors.initials: B
authors.lastname: Yang
authors.forename: Yuemin
authors.initials: Y
authors.lastname: Yan
authors.forename: Xue
authors.initials: X
authors.lastname: Wang
authors.forename: Daishu
authors.initials: D
authors.lastname: Han
authors.forename: Yue
authors.initials: Y
authors.lastname: Huang
authors.forename: Wenji
authors.initials: W
authors.lastname: Dong
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D054278:Embryonal Carcinoma Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D036961:Matrix Attachment Region Binding Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D000071317:Nanog Homeobox Protein; D064231:Nestin / Q000235:genetics / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D018398:Homeodomain Proteins; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D036961:Matrix Attachment Region Binding Proteins; D000071317:Nanog Homeobox Protein; D064231:Nestin; D050814:Octamer Transcription Factor-3; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins; D055748:SOXB1 Transcription Factors; D014212:Tretinoin; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; C475540:Nanog protein, mouse; C577485:Nes protein, mouse; C494173:POU5F1 protein, human; C076189:SATB1 protein, human; C527782:SOX2 protein, human