A positive feedback loop between the p53 and Lats2 tumor suppressors prevents tetraploidization

Autor: Moshe Oren, Dan Michael, Yael Aylon, Norikazu Yabuta, Hiroshi Nojima, Ayelet Shmueli
Rok vydání: 2006
Předmět:
Zdroj: Genesdevelopment. 20(19)
ISSN: 0890-9369
Popis: 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.
Databáze: OpenAIRE