期刊
CANCER CELL
卷 31, 期 5, 页码 669-+出版社
CELL PRESS
DOI: 10.1016/j.ccell.2017.04.004
关键词
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资金
- National Natural Science Foundation of China [31625010, U1505224, J1310027, 81422018, U1405225, 81372617, 81472229]
- National Basic Research Program (973) of China [2015CB910502]
- Fundamental Research Funds for the Central Universities of China-Xiamen University [20720140551, 2013121034, 20720140537]
Polyploidy can lead to aneuploidy and tumorigenesis. Here, we report that the Hippo pathway effector Yap promotes the diploid-polyploid conversion and polyploid cell growth through the Akt-Skp2 axis. Yap strongly induces the acetyltransferase p300-mediated acetylation of the E3 ligase Skp2 via Akt signaling. Acetylated Skp2 is exclusively localized to the cytosol, which causes hyper-accumulation of the cyclin-dependent kinase inhibitor p27, leading to mitotic arrest and subsequently cell polyploidy. In addition, the pro-apoptotic factors FoxO1/3 are overly degraded by acetylated Skp2, resulting in polyploid cell division, genomic instability, and oncogenesis. Importantly, the depletion or inactivation of Akt or Skp2 abrogated Hippo signal deficiency-induced liver tumorigenesis, indicating their epistatic interaction. Thus, we conclude that Hippo-Yap signaling suppresses cell polyploidy and oncogenesis through Skp2.
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