Cytokinesis failure triggers hippo tumor suppressor pathway activation.
2014
Ganem, Neil J | Cornils, Hauke | Chiu, Shang-Yi | O'Rourke, Kevin P | Arnaud, Jonathan | Yimlamai, Dean | Théry, Manuel | Camargo, Fernando D | Pellman, David | Howard Hughes Medical Institute [Boston] (HHMI) ; Howard Hughes Medical Institute (HHMI)-Harvard Medical School [Boston] (HMS) | Department of Pediatric Oncology ; Harvard Medical School [Boston] (HMS) | Laboratoire de physiologie cellulaire végétale (LPCV) ; Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG) ; Direction de Recherche Fondamentale (CEA) (DRF (CEA)) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA) | Boston Children's Hospital | NIH grant 1S10RR026582-01; NCI K99 award (K99CA154531-01); NIH grant DK099559; NIH grant GM083299-1; ERC grant 31047
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Show more [+] Less [-]English. 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.
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