Journal
STEM CELLS
Volume 31, Issue 4, Pages 717-728Publisher
WILEY-BLACKWELL
DOI: 10.1002/stem.1315
Keywords
Embryonic stem cells; miR-335; Oct4; pRb
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Funding
- Italian Association for Cancer Research (AIRC) [42/08, 6352, 10299]
- Young Investigator Grant, Ministry of Health [GR-2007-683407]
- [LR26/06]
- [D. 2007/LAVFOR/1461]
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The pluripotency of mouse embryonic stem cells (mESCs) is controlled by a network of transcription factors, mi-RNAs, and signaling pathways. Here, we present a new regulatory circuit that connects miR-335, Oct4, and the Retinoblastoma pathway to control mESC self-renewal and differentiation. Oct4 drives the expression of Nipp1 and Ccnf that inhibit the activity of the protein phosphatase 1 (PP1) complex to establish hyperphosphorylation of the retinoblastoma protein 1 (pRb) as a hallmark feature of self-renewing mESCs. The Oct4-Nipp1/Ccnf-PP1-pRb axis promoting mESC self-renewal is under control of miR-335 that regulates Oct4 and Rb expression. During mESC differentiation, miR-335 upregulation co-operates with the transcriptional repression of Oct4 to facilitate the collapse of the Oct4-Nipp1/Ccnf-PP1-pRb axis, pRb dephosphorylation, the exit from self-renewal, and the establishment of a pRb-regulated cell cycle program. Our results introduce Oct4-dependent control of the Rb pathway as novel regulatory circuit controlling mESC self-renewal and differentiation. STEM CELLS 2013;31:717728
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