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GENES & DEVELOPMENT 20:2687-2700, 2006
©2006 by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/ $5.00
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A positive feedback loop between the p53 and Lats2 tumor suppressors prevents tetraploidization

Yael Aylon1, Dan Michael1, Ayelet Shmueli1, Norikazu Yabuta2, Hiroshi Nojima2 and Moshe Oren1,3

1 Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel; 2 Department of Molecular Genetics, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan

Damage to the mitotic spindle and centrosome dysfunction can lead to cancer. To prevent this, cells trigger a succession of checkpoint responses, where an initial mitotic delay is followed by slippage without cytokinesis, spawning tetraploid G1 cells that undergo a p53-dependent G1/S arrest. We describe the importance of Lats2 (Large Tumor Suppressor 2) in this checkpoint response. Lats2 binds Mdm2, inhibits its E3 ligase activity, and activates p53. Nocodazole, a microtubule poison that provokes centrosome/mitotic apparatus dysfunction, induces Lats2 translocation from centrosomes to the nucleus and p53 accumulation. In turn, p53 rapidly and selectively up-regulates Lats2 expression in G2/M cells, thereby defining a positive feedback loop. Abrogation of Lats2 promotes accumulation of polyploid cells upon exposure to nocodazole, which can be prevented by direct activation of p53. The Lats2–Mdm2–p53 axis thus constitutes a novel checkpoint pathway critical for the maintenance of proper chromosome number.

[Keywords: Lats2; Mdm2; p53; tetraploidy checkpoint]

Received May 3, 2006; revised version accepted August 18, 2006.

3 Corresponding author.

E-MAIL moshe.oren{at}weizmann.ac.il; FAX 972-8-9346004.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1447006.


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