A positive feedback loop between the p53 and Lats2 tumor suppressors prevents tetraploidization
Abstract
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.
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Footnotes
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↵3 Corresponding author.
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E-MAIL moshe.oren{at}weizmann.ac.il; FAX 972-8-9346004.
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Supplemental material is available at http://www.genesdev.org.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1447006.
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- Received May 3, 2006.
- Accepted August 18, 2006.
- Copyright © 2006 RNA Society