Format

Send to

Choose Destination
See comment in PubMed Commons below
Cell. 2014 Aug 14;158(4):833-48. doi: 10.1016/j.cell.2014.06.029.

Cytokinesis failure triggers hippo tumor suppressor pathway activation.

Author information

1
Howard Hughes Medical Institute, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children's Hospital and Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: nganem@bu.edu.
2
Howard Hughes Medical Institute, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children's Hospital and Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
3
CEA, Institut de Recherche en Technologie et Science pour le Vivant, UMR5168, CEA/UJF/INRA/CNRS, 17 rue des martyrs, 38054 Genoble, France.
4
Stem Cell Program, Children's Hospital Boston, Boston, MA 02115, USA.
5
CEA, Institut de Recherche en Technologie et Science pour le Vivant, UMR5168, CEA/UJF/INRA/CNRS, 17 rue des martyrs, 38054 Genoble, France; Physics of Cytoskeleton and Morphogenesis, Hopital Saint Louis, Institut Universitaire d'Hematologie, U1160, INSERM/AP-HP/Université Paris Diderot, Paris 75010, France.
6
Howard Hughes Medical Institute, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children's Hospital and Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: david_pellman@dfci.harvard.edu.

Abstract

Genetically unstable tetraploid cells can promote tumorigenesis. Recent estimates suggest that ∼37% of human tumors have undergone a genome-doubling event during their development. This potentially oncogenic effect of tetraploidy is countered by a p53-dependent barrier to proliferation. However, the cellular defects and corresponding signaling pathways that trigger growth suppression in tetraploid cells are not known. Here, we combine RNAi screening and in vitro evolution approaches to demonstrate that cytokinesis failure activates the Hippo tumor suppressor pathway in cultured cells, as well as in naturally occurring tetraploid cells in vivo. Induction of the Hippo pathway is triggered in part by extra centrosomes, which alter small G protein signaling and activate LATS2 kinase. LATS2 in turn stabilizes p53 and inhibits the transcriptional regulators YAP and TAZ. These findings define an important tumor suppression mechanism and uncover adaptive mechanisms potentially available to nascent tumor cells that bypass this inhibitory regulation.

PMID:
25126788
PMCID:
PMC4136486
DOI:
10.1016/j.cell.2014.06.029
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Support Center