The phosphoinositide-3-kinase/Akt pathway mediates the transient increase in Nanog expression during differentiation of F9 cells.
Nanog is a key determinant that maintains self-renewal and pluripotency of embryonic stem cells and represses their differentiation to endoderm. In this study, we examined the regulation of Nanog expression by phosphoinositide-3-kinase (PI3K)/Akt pathway during retinoic acid (RA)-induced differentiation of F9 embryonic carcinoma cells. Nanog protein expression was transiently upregulated up to 6 h after RA treatment and then declined. In agreement, a murine Nanog promoter reporter assay revealed that promoter activity increased during early stage of differentiation, but decreased when F9 cells became fully differentiated. RA treatment of F9 cells also led to a transient and parallel increase in both Akt and glycogen synthase kinase 3beta phosphorylations. Nanog expression was diminished in the early stage by LY294002, a PI3K inhibitor, but was not affected in the late stage despite considerable inhibition of Akt phosphorylation and endoderm marker expression by the inhibitor. These data suggest that RA-induced PI3K/Akt activation in the early stage of differentiation is required for Nanog expression, which becomes independent of PI3K/Akt signaling once the differentiation is established. Thus, Nanog expression appears to be differently regulated by the PI3K/Akt pathway depending on differentiation stage.
Kim
Jung Sun
JS
Hanyang University, Ansan, Korea.
Kim
Byung Soo
BS
Kim
Jiha
J
Park
Choon-Sik
CS
Chung
Il Yup
IY
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002867:Chromones / Q000494:pharmacology; D054278:Embryonal Carcinoma Stem Cells / Q000166:cytology / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018398:Homeodomain Proteins / Q000096:biosynthesis*; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D000071317:Nanog Homeobox Protein; D058539:Phosphatidylinositol 3-Kinase / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011401:Promoter Regions, Genetic / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014212:Tretinoin / Q000494:pharmacology
D002867:Chromones; D018398:Homeodomain Proteins; D009025:Morpholines; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D000081082:Phosphoinositide-3 Kinase Inhibitors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D014212:Tretinoin; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt