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

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.
Mesh Terms:
Animals, Cell Cycle, Cell Cycle Proteins, Cell Line, Cell Line, Tumor, Cells, Cultured, Centrosome, Flow Cytometry, Fluorescent Antibody Technique, Gene Expression Regulation, Humans, Immunoprecipitation, Mice, Microtubules, Mitotic Spindle Apparatus, Nocodazole, Polymerase Chain Reaction, Polyploidy, Protein Binding, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-mdm2, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, Two-Hybrid System Techniques, Ubiquitin-Protein Ligases
Genes Dev.
Date: Oct. 01, 2006
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