An Oct4-pRb Axis, Controlled by MiR-335, Integrates Stem Cell Self-Renewal and Cell Cycle Control§

Authors

  • Stefan Schoeftner,

    1. Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie (LNCIB), Area Science Park, Padriciano 99, Trieste, Italy
    2. Italian National Cancer Institute, Molecular Medicine Department, Regina Elena, Rome, Italy
    Current affiliation:
    1. Italian National Cancer Institute, Regina Elena, Rome, Italy
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  • Michele Scarola,

    1. Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie (LNCIB), Area Science Park, Padriciano 99, Trieste, Italy
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  • Elisa Comisso,

    1. Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie (LNCIB), Area Science Park, Padriciano 99, Trieste, Italy
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  • Claudio Schneider,

    1. Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie (LNCIB), Area Science Park, Padriciano 99, Trieste, Italy
    2. Dipartimento di Scienze Mediche e Biologiche, Università degli Studi di Udine, Udine, Italy
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  • Roberta Benetti

    Corresponding author
    1. Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie (LNCIB), Area Science Park, Padriciano 99, Trieste, Italy
    2. Dipartimento di Scienze Mediche e Biologiche, Università degli Studi di Udine, Udine, Italy
    • Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie (LNCIB), Oncoepigenetic Unit, Area Science Park, Padriciano 99, Trieste, Italy
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    • Telephone: +39-040-3756805; Fax: +39-040-398990


  • Author contributions: S.S.: conception and design, collection and assembly of data, data analysis and interpretation, and manuscript writing; M.S.: conception and design, collection and assembly of data, and data analysis and interpretation; E.C.: collection and assembly of data and data analysis and interpretation; C.S.: conception and design and manuscript writing; R.B.: conception and design, data analysis and interpretation, manuscript writing, and financial support. S.S. and M.S. contributed equally to this article.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLS EXPRESS January 10, 2013.

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. STEM CELLS 2013;31:717–728

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