title: Protein kinase C-induced early growth response protein-1 binding to SNAIL promoter in epithelial-mesenchymal transition of human embryonic stem cells.
abstract: Epithelial-mesenchymal transition (EMT) has been thought to occur during early embryogenesis, and also the differentiation process of human embryonic stem (hES) cells. Spontaneous differentiation is sometimes observed at the peripheral of the hES cell colonies in conventional culture conditions, indicating that EMT occurs in hES cell culture. However, the triggering mechanism of EMT is not yet fully understood. The balance between self-renewal and differentiation of human pluripotent stem (hPS) cells is controlled by various signal pathways, including the fibroblast growth factor (FGF)-2. However, FGF-2 has a complex role for self-renewal of hES cells. FGF-2 activates phosphatidylinositol-3 kinase/AKT, mitogen-activated protein kinase/extracellular signal-regulated kinase-1/2 kinase, and also protein kinase C (PKC). Here, we showed that a PKC rapidly induced an early growth response protein-1 (EGR-1) in hES cells, which was followed by upregulation of EMT-related genes. Before the induction of EMT-related genes, EGR-1 was translocated into the nucleus, and then bound directly to the promoter region of SNAIL, which is a master regulator of EMT. SNAIL expression was attenuated by knockdown of EGR-1, but upregulated by ectopic expression of EGR-1. EGR-1 as the downstream signal of PKC might play a key role in EMT initiation during early differentiation of hES cells. This study would lead to a more robust understanding of the mechanisms underlying the balance between self-renewal and initiation of differentiation in hPS cells.
authors.affiliation: 1 Laboratory of Stem Cell Cultures, Department of Disease Bioresources Research, National Institute of Biomedical Innovation , Ibaraki, Japan .
authors.forename: Masaki
authors.initials: M
authors.lastname: Kinehara
authors.forename: Suguru
authors.initials: S
authors.lastname: Kawamura
authors.forename: Sumiyo
authors.initials: S
authors.lastname: Mimura
authors.forename: Mika
authors.initials: M
authors.lastname: Suga
authors.forename: Akiko
authors.initials: A
authors.lastname: Hamada
authors.forename: Mari
authors.initials: M
authors.lastname: Wakabayashi
authors.forename: Hiroki
authors.initials: H
authors.lastname: Nikawa
authors.forename: Miho K
authors.initials: MK
authors.lastname: Furue
mesh_terms: D002460:Cell Line; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism*; D000071250:Snail Family Transcription Factors; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D051766:Early Growth Response Protein 1; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate