Perturbed differentiation of murine embryonic stem cells upon Pelota deletion due to dysregulated FOXO1/β‐catenin signaling
| Autor: | Gunsmaa Nyamsuren, Manar Elkenani, Ibrahim M. Adham, Karl Toischer, Belal A. Mohamed |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Primary Cell Culture Cell Cycle Proteins FOXO1 Biology Biochemistry Mice Phosphatidylinositol 3-Kinases 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Animals Molecular Biology Protein kinase B beta Catenin Cell Proliferation Mice Knockout Reporter gene Glycogen Synthase Kinase 3 beta Forkhead Box Protein O1 Kinase Wnt signaling pathway Gene Expression Regulation Developmental Cell Differentiation Mouse Embryonic Stem Cells Cell Biology Embryo Mammalian Endonucleases Embryonic stem cell Culture Media Cell biology 030104 developmental biology 030220 oncology & carcinogenesis embryonic structures Genes Lethal Signal transduction TCF Transcription Factors Octamer Transcription Factor-3 Proto-Oncogene Proteins c-akt Protein Binding Signal Transduction |
| Zdroj: | The FEBS Journal. 288:3317-3329 |
| ISSN: | 1742-4658 1742-464X |
| DOI: | 10.1111/febs.15643 |
| Popis: | Differentiation of the embryonic stem cells (ESCs) is regulated by a variety of different signaling pathways. Genetic depletion of murine Pelota gene (Pelo) leads to early embryonic lethality. Here, we aimed at determining the embryonic stage and deciphering the dysregulated signaling pathways affected upon Pelo deletion. We found that development of PELO-null embryos is perturbed between the embryonic day E4.5 and E5.5, at which first differentiation process of ESCs takes place. Molecular analysis revealed enhanced activity of phosphoinositide 3-kinase-protein kinase B/ AKT (PI3K-PKB/AKT) signaling, but nuclear accumulation of forkhead box O1 (FOXO1), and upregulation of the pluripotency-related gene, Oct4, in mutant ESCs cultured under differentiation condition. Despite increased levels of nuclear β-catenin in PELO-null ESCs as a result of decreased activity of glycogen synthase kinase-3β, the activity of the canonical Wingless (Wnt)/β-catenin/T cell factor (TCF) was significantly attenuated as judged by the promoter reporter assay, downregulated Wnt/β-catenin target genes, and impaired cell proliferation. Interestingly, we demonstrated an increased binding of β-catenin to FOXO1 in PELO-mutant ESCs cultured under differentiation condition that could explain, on one side, the nuclear accumulation of FOXO1 protein and hence persistent pluripotency of PELO-mutant ESCs, and on the other side, the dysregulated transcriptional activity of β-catenin/TCF and therefore attenuated PELO-null ESCs self-renewal. Taken together, our results strongly suggest that PELO deletion averts ESCs differentiation through promoting FOXO1/β-catenin binding with subsequent dysregulation of FOXO1 and canonical β-catenin/TCF signaling pathways. |
| Databáze: | OpenAIRE |
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