Medline ® Abstract for Reference 28
of 'Molecular biology and pathogenesis of von Hippel-Lindau disease'
The ATM-p53 pathway suppresses aneuploidy-induced tumorigenesis.
Li M, Fang X, Baker DJ, Guo L, Gao X, Wei Z, Han S, van Deursen JM, Zhang P
Proc Natl Acad Sci U S A. 2010 Aug;107(32):14188-93. Epub 2010 Jul 27.
The spindle assembly checkpoint (SAC) is essential for proper sister chromatid segregation. Defects in this checkpoint can lead to chromosome missegregation and aneuploidy. An increasing body of evidence suggests that aneuploidy can play a causal role in tumorigenesis. However, mutant mice that are prone to aneuploidy have only mild tumor phenotypes, suggesting that there are limiting factors in the aneuploidy-induced tumorigenesis. Here we provide evidence that p53 is such a limiting factor. We show that aneuploidy activates p53 and that loss of p53 drastically accelerates tumor development in two independent aneuploidy models. The p53 activation depends on the ataxia-telangiectasia mutated (ATM) gene product and increased levels of reactive oxygen species. Thus, the ATM-p53 pathway safeguards not only DNA damage but also aneuploidy.
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.