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Cell. 2014 Feb 27;156(5):893-906. doi: 10.1016/j.cell.2013.12.043.

Hippo signaling regulates microprocessor and links cell-density-dependent miRNA biogenesis to cancer.

Author information

1
Stem Cell Program, Boston Children's Hospital, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Department of Biological Chemistry and Molecular Pharmacology and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Boston, MA 02115, USA.
2
Stem Cell Program, Boston Children's Hospital, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Boston, MA 02115, USA.
3
Stem Cell Program, Boston Children's Hospital, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Boston, MA 02115, USA.
4
Stem Cell Program, Boston Children's Hospital, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Boston, MA 02115, USA. Electronic address: fernando.camargo@childrens.harvard.edu.
5
Stem Cell Program, Boston Children's Hospital, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Boston, MA 02115, USA. Electronic address: rgregory@enders.tch.harvard.edu.

Abstract

Global downregulation of microRNAs (miRNAs) is commonly observed in human cancers and can have a causative role in tumorigenesis. The mechanisms responsible for this phenomenon remain poorly understood. Here, we show that YAP, the downstream target of the tumor-suppressive Hippo-signaling pathway regulates miRNA biogenesis in a cell-density-dependent manner. At low cell density, nuclear YAP binds and sequesters p72 (DDX17), a regulatory component of the miRNA-processing machinery. At high cell density, Hippo-mediated cytoplasmic retention of YAP facilitates p72 association with Microprocessor and binding to a specific sequence motif in pri-miRNAs. Inactivation of the Hippo pathway or expression of constitutively active YAP causes widespread miRNA suppression in cells and tumors and a corresponding posttranscriptional induction of MYC expression. Thus, the Hippo pathway links contact-inhibition regulation to miRNA biogenesis and may be responsible for the widespread miRNA repression observed in cancer.

PMID:
24581491
PMCID:
PMC3982296
DOI:
10.1016/j.cell.2013.12.043
[Indexed for MEDLINE]
Free PMC Article
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