title: Cytokinesis failure triggers hippo tumor suppressor pathway activation.
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.
authors.affiliation: 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.
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Ganem
authors.affiliation: 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.
authors.forename: Hauke
authors.initials: H
authors.lastname: Cornils
authors.affiliation: 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.
authors.forename: Shang-Yi
authors.initials: SY
authors.lastname: Chiu
authors.affiliation: 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.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: O'Rourke
authors.affiliation: CEA, Institut de Recherche en Technologie et Science pour le Vivant, UMR5168, CEA/UJF/INRA/CNRS, 17 rue des martyrs, 38054 Genoble, France.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Arnaud
authors.affiliation: Stem Cell Program, Children's Hospital Boston, Boston, MA 02115, USA.
authors.forename: Dean
authors.initials: D
authors.lastname: Yimlamai
authors.affiliation: 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.
authors.forename: Manuel
authors.initials: M
authors.lastname: Théry
authors.affiliation: Stem Cell Program, Children's Hospital Boston, Boston, MA 02115, USA.
authors.forename: Fernando D
authors.initials: FD
authors.lastname: Camargo
authors.affiliation: 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.
authors.forename: David
authors.initials: D
authors.lastname: Pellman
mesh_terms: D045744:Cell Line, Tumor; D018385:Centrosome / Q000378:metabolism; D048749:Cytokinesis; D004847:Epithelial Cells / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D000090683:Hippo Signaling Pathway; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D057891:Tetraploidy; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C066737:RHOA protein, human; C406449:LATS2 protein, human; D017346:Protein Serine-Threonine Kinases; D020742:rhoA GTP-Binding Protein