title: The ATM-p53 pathway suppresses aneuploidy-induced tumorigenesis.
abstract: 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.
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Xiao
authors.initials: X
authors.lastname: Fang
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Baker
authors.forename: Linjie
authors.initials: L
authors.lastname: Guo
authors.forename: Xue
authors.initials: X
authors.lastname: Gao
authors.forename: Zhubo
authors.initials: Z
authors.lastname: Wei
authors.forename: Shuhua
authors.initials: S
authors.lastname: Han
authors.forename: Jan M
authors.initials: JM
authors.lastname: van Deursen
authors.forename: Pumin
authors.initials: P
authors.lastname: Zhang
mesh_terms: D000782:Aneuploidy; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000209:etiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases