MicroRNA-125b is a novel negative regulator of p53

  1. Minh T.N. Le1,2,
  2. Cathleen Teh3,7,
  3. Ng Shyh-Chang2,7,
  4. Huangming Xie1,2,4,
  5. Beiyan Zhou4,
  6. Vladimir Korzh3,
  7. Harvey F. Lodish1,4,5,9 and
  8. Bing Lim1,2,6,8
  1. 1Computation and Systems Biology, Singapore-Massachusetts Institute of Technology Alliance, Singapore 117576;
  2. 2Stem Cell and Developmental Biology, Genome Institute of Singapore, Genome, Singapore 138672;
  3. 3Fish Developmental Biology, Institute of Molecular and Cell Biology, Proteos, Singapore 138673;
  4. 4Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA;
  5. 5Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA;
  6. 6CLS 442 Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA
    1. 7 These authors contributed equally to this work.

    Abstract

    The p53 transcription factor is a key tumor suppressor and a central regulator of the stress response. To ensure a robust and precise response to cellular signals, p53 gene expression must be tightly regulated from the transcriptional to the post-translational levels. Computational predictions suggest that several microRNAs are involved in the post-transcriptional regulation of p53. Here we demonstrate that miR-125b, a brain-enriched microRNA, is a bona fide negative regulator of p53 in both zebrafish and humans. miR-125b-mediated down-regulation of p53 is strictly dependent on the binding of miR-125b to a microRNA response element in the 3′ untranslated region of p53 mRNA. Overexpression of miR-125b represses the endogenous level of p53 protein and suppresses apoptosis in human neuroblastoma cells and human lung fibroblast cells. In contrast, knockdown of miR-125b elevates the level of p53 protein and induces apoptosis in human lung fibroblasts and in the zebrafish brain. This phenotype can be rescued significantly by either an ablation of endogenous p53 function or ectopic expression of miR-125b in zebrafish. Interestingly, miR-125b is down-regulated when zebrafish embryos are treated with γ-irradiation or camptothecin, corresponding to the rapid increase in p53 protein in response to DNA damage. Ectopic expression of miR-125b suppresses the increase of p53 and stress-induced apoptosis. Together, our study demonstrates that miR-125b is an important negative regulator of p53 and p53-induced apoptosis during development and during the stress response.

    Keywords:

    Keywords

    Footnotes

    • 8 Corresponding authors.

      E-MAIL limb1{at}gis.a-star.edu.sg and blim{at}bidmc.havard.edu; FAX (617) 667-3299.

    • 9 E-MAIL lodish{at}wi.mit.edu; FAX (617) 258-6768.

    • Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1767609.

    • Supplemental material is available at http://www.genesdev.org.

      • Received November 27, 2008.
      • Accepted February 20, 2009.
    | Table of Contents

    Life Science Alliance