Loss of Brap Results in Premature G1/S Phase Transition and Impeded Neural Progenitor Differentiation
| Autor: | Yicong Le, Alison A. Lanctot, Richard S. Nowakowski, Yuanyi Feng, Brittany M. Edens, Yan Guo |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Ubiquitin-Protein Ligases Biology General Biochemistry Genetics and Molecular Biology S Phase Mice 03 medical and health sciences Neural Stem Cells Ubiquitin SKP2 Animals S-Phase Kinase-Associated Proteins lcsh:QH301-705.5 Progenitor Neurons G1 Phase Cell Differentiation G1/S transition Cell cycle Mice Mutant Strains Neural stem cell Cell biology Ubiquitin ligase G2 Phase Cell Cycle Checkpoints 030104 developmental biology lcsh:Biology (General) Cell Cycle Kinetics biology.protein Cyclin-Dependent Kinase Inhibitor p27 Signal Transduction |
| Zdroj: | Cell Reports, Vol 20, Iss 5, Pp 1148-1160 (2017) |
| ISSN: | 2211-1247 |
| Popis: | Summary: Cells initiate fate decisions during G1 phase by converting extracellular signals into distinctive cell cycle kinetics. The DNA replication timing is determined in G1 phase; lengthened G1 and hastened S phases correlate with increased neurogenic propensity of neural progenitor cells (NPCs), although the underlying molecular control remains elusive. Here, we report that proper G1 phase completion in NPCs requires Brap, a Ras-Erk signaling modulator with ubiquitin E3 ligase activity. We identified Skp2 and Skp2-associated SCF ubiquitin ligase as a key target of Brap-mediated polyubiquitination. Loss of Brap resulted in elevated Skp2, which increased p27Kip1 destruction, leading to G1 phase truncation and premature S phase entry. The aberrantly executed G1 in Brap-mutant NPCs, followed by hindered S phase progression and increased G2 phase arrest, which together prolonged the cell cycle, impeded neuronal differentiation and culminated in microcephaly. These findings demonstrate that neuronal differentiation is potentiated during G1 phase by Brap-directed cascade of events in cell signaling and protein turnover. : Lanctot et al. show that the capacity of neural progenitors to generate cerebral cortical neurons relies on the integration of cell signaling and ubiquitin-mediated protein turnover to complete G1 phase of the cell cycle. Keywords: cell cycle, G1 phase, G1/S transition, stem/progenitor, differentiation, ubiquitination, cerebral cortical neurogenesis |
| Databáze: | OpenAIRE |
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