title: An Oct4-pRb axis, controlled by MiR-335, integrates stem cell self-renewal and cell cycle control.
abstract: 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.
authors: Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie (LNCIB), Area Science Park, Padriciano 99, Trieste, Italy.
authors: Stefan
authors: S
authors: Schoeftner
authors: Michele
authors: M
authors: Scarola
authors: Elisa
authors: E
authors: Comisso
authors: Claudio
authors: C
authors: Schneider
authors: Roberta
authors: R
authors: Benetti
mesh_terms: D000818:Animals; D015153:Blotting, Western; D059447:Cell Cycle Checkpoints / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D005434:Flow Cytometry; D047468:Immunoprecipitation; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; C541986:Mirn335 microRNA, mouse; D050814:Octamer Transcription Factor-3; D016160:Retinoblastoma Protein