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Stem Cell Reports. 2017 Nov 14;9(5):1604-1617. doi: 10.1016/j.stemcr.2017.10.006.

Elevated p53 Activities Restrict Differentiation Potential of MicroRNA-Deficient Pluripotent Stem Cells.

Author information

1
Department of Biochemistry and Molecular Genetics, Stem Cell Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
2
Department of Molecular Pharmacology and Experimental Therapeutics, Center for Individualized Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
3
Cancer Biology and Genetics Program, Center for Cell Engineering, Center for Stem Cell Biology, Sloan-Kettering Institute, Cell and Developmental Biology Program, Weill Medical College of Cornell University, New York, NY 10065, USA.
4
Cook County Health and Hospital System, John H. Stroger Hospital, Chicago, IL 60612, USA.
5
Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
6
Cancer Biology and Genetics Program, Center for Cell Engineering, Center for Stem Cell Biology, Sloan-Kettering Institute, Cell and Developmental Biology Program, Weill Medical College of Cornell University, New York, NY 10065, USA. Electronic address: kimk@mskcc.org.
7
Department of Biochemistry and Molecular Genetics, Stem Cell Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA. Electronic address: ruizhao@uab.edu.

Abstract

Pluripotent stem cells (PSCs) deficient for microRNAs (miRNAs), such as Dgcr8-/- or Dicer-/- embryonic stem cells (ESCs), contain no mature miRNA and cannot differentiate into somatic cells. How miRNA deficiency causes differentiation defects remains poorly understood. Here, we report that miR-302 is sufficient to enable neural differentiation of differentiation-incompetent Dgcr8-/- ESCs. Our data showed that miR-302 directly suppresses the tumor suppressor p53, which is modestly upregulated in Dgcr8-/- ESCs and serves as a barrier restricting neural differentiation. We demonstrated that direct inactivation of p53 by SV40 large T antigen, a short hairpin RNA against Trp53, or genetic ablation of Trp53 in Dgcr8-/- PSCs enables neural differentiation, while activation of p53 by the MDM2 inhibitor nutlin-3a in wild-type ESCs inhibits neural differentiation. Together, we demonstrate that a major function of miRNAs in neural differentiation is suppression of p53 and that modest activation of p53 blocks neural differentiation of miRNA-deficient PSCs.

KEYWORDS:

Dgcr8; apoptosis; differentiation; miR-302; microRNA; neural differentiation; nutlin-3a; p53; pluripotent stem cells

PMID:
29141234
PMCID:
PMC5688240
DOI:
10.1016/j.stemcr.2017.10.006
[Indexed for MEDLINE]
Free PMC Article

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