The ATM–p53 pathway suppresses aneuploidy-induced tumorigenesis

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.

[1]  D. Baker,et al.  Bub1 mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis , 2007, The Journal of cell biology.

[2]  J. Ward,et al.  Heterozygous deletion of mitotic arrest-deficient protein 1 (MAD1) increases the incidence of tumors in mice. , 2007, Cancer research.

[3]  V. Guacci,et al.  Pds1p, an inhibitor of anaphase in budding yeast, plays a critical role in the APC and checkpoint pathway(s) , 1996, The Journal of cell biology.

[4]  W. Gerald,et al.  MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cells , 2001, Nature.

[5]  D. Baker,et al.  Rae1 is an essential mitotic checkpoint regulator that cooperates with Bub3 to prevent chromosome missegregation , 2003, The Journal of cell biology.

[6]  D. Cleveland,et al.  Boveri revisited: chromosomal instability, aneuploidy and tumorigenesis , 2009, Nature Reviews Molecular Cell Biology.

[7]  Francis Collins,et al.  Atm-Deficient Mice: A Paradigm of Ataxia Telangiectasia , 1996, Cell.

[8]  D. Burke,et al.  The spindle assembly and spindle position checkpoints. , 2003, Annual review of genetics.

[9]  Marc W. Kirschner,et al.  How Proteolysis Drives the Cell Cycle , 1996, Science.

[10]  Maitreya J. Dunham,et al.  Effects of Aneuploidy on Cellular Physiology and Cell Division in Haploid Yeast , 2007, Science.

[11]  Andrew W. Murray,et al.  Feedback control of mitosis in budding yeast , 1991, Cell.

[12]  Duane A. Compton,et al.  Proliferation of aneuploid human cells is limited by a p53-dependent mechanism , 2010, The Journal of cell biology.

[13]  Th. Boveri.  Concerning the Origin of Malignant Tumours by Theodor Boveri. Translated and annotated by Henry Harris , 2008, Journal of Cell Science.

[14]  S. Biggins,et al.  The spindle checkpoint: tension versus attachment. , 2005, Trends in cell biology.

[15]  K Weber,et al.  Identification of essential genes in cultured mammalian cells using small interfering RNAs. , 2001, Journal of cell science.

[16]  M. Kirschner,et al.  A 20s complex containing CDC27 and CDC16 catalyzes the mitosis-specific conjugation of ubiquitin to cyclin B , 1995, Cell.

[17]  Angelika Amon,et al.  Aneuploidy Affects Proliferation and Spontaneous Immortalization in Mammalian Cells , 2008, Science.

[18]  G. Mills,et al.  ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS , 2010, Proceedings of the National Academy of Sciences.

[19]  A. Terzic,et al.  Early aging–associated phenotypes in Bub3/Rae1 haploinsufficient mice , 2006, The Journal of cell biology.

[20]  M. Kirschner,et al.  Identification of a novel ubiquitin-conjugating enzyme involved in mitotic cyclin degradation , 1996, Current Biology.

[21]  R. Kumar,et al.  BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice , 2004, Nature Genetics.

[22]  B. Johansson,et al.  Isochromosomes in neoplasia , 1994, Genes, chromosomes & cancer.

[23]  R. Mahmood,et al.  Slippage of Mitotic Arrest and Enhanced Tumor Development in Mice with BubR1 Haploinsufficiency , 2004, Cancer Research.

[24]  E. Salmon,et al.  The spindle-assembly checkpoint in space and time , 2007, Nature Reviews Molecular Cell Biology.

[25]  M. Kirschner,et al.  Identification of a vertebrate sister-chromatid separation inhibitor involved in transformation and tumorigenesis. , 1999, Science.

[26]  D. Baker,et al.  Mitotic regulation of the anaphase-promoting complex , 2007, Cellular and Molecular Life Sciences.

[27]  K. Kinzler,et al.  Genetic instability in colorectal cancers , 1997, Nature.

[28]  Pumin Zhang,et al.  Loss of spindle assembly checkpoint–mediated inhibition of Cdc20 promotes tumorigenesis in mice , 2009, The Journal of cell biology.

[29]  Cristina Montagna,et al.  Aneuploidy acts both oncogenically and as a tumor suppressor. , 2007, Cancer cell.

[30]  N. Rahman,et al.  Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B , 2004, Nature Genetics.

[31]  B. Weaver,et al.  Aneuploidy: instigator and inhibitor of tumorigenesis. , 2007, Cancer research.