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Aging Mice Have Increased Chromosome Instability That Is Exacerbated by Elevated Mdm2 Expression

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Aging Mice Have Increased Chromosome Instability That Is Exacerbated by Elevated Mdm2 Expression Oncogene (2011) 30, 4622–4631 & 2011 Macmillan Publishers Limited All rights reserved 0950-9232/11 www.nature.com/onc ORIGINAL ARTICLE Aging mice have increased chromosome instability that is exacerbated by elevated Mdm2 expression T Lushnikova1, A Bouska2, J Odvody1, WD Dupont3 and CM Eischen1 1Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN, USA; 2Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA and 3Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN, USA Aging is thought to negatively affect multiple cellular Introduction processes including the ability to maintain chromosome stability. Chromosome instability (CIN) is a common Genomic instability refers to the accumulation or property of cancer cells and may be a contributing factor acquisition of numerical and/or structural abnormali- to cellular transformation. The types of DNA aberrations ties in chromosomes. It has long been observed that that arise during aging before tumor development and that chromosome instability (CIN) is a hallmark of cancer contribute to tumorigenesis are currently unclear. Mdm2, cells and is postulated to be required for tumorigenesis a key regulator of the p53 tumor suppressor and (Lengauer et al., 1998; Negrini et al., 2010). Genomic modulator of DNA break repair, is frequently over- changes, such as chromosome breaks, translocations, expressed in malignancies and contributes to CIN. To genome rearrangements, aneuploidy and telomere short- determine the relationship between aging and CIN and the ening have been observed in aging organisms (Nisitani role of Mdm2, precancerous wild-type C57Bl/6 and et al., 1990; Tucker et al., 1999; Dolle and Vijg, 2002; littermate-matched Mdm2 transgenic mice at various Aubert and Lansdorp, 2008; Zietkiewicz et al., 2009). ages were evaluated. Metaphase analyses of wild-type Characteristics of genetically unstable cells include cells showed a direct correlation between age and structural changes, such as insertions, deletions and increased chromosome and chromatid breaks, chromo- translocations, as well as changes in the number of some fusions and aneuploidy, but the frequency of chromosomes (aneuploidy or polyploidy). Cells can gain polyploidy remained stable over time. Elevated levels of or lose one or more chromosomes (aneuploidy) or gain Mdm2 in precancerous mice increased both the numerical part of or an entire genome (polyploidy) (Lengauer and the structural chromosomal abnormalities observed. et al., 1998; Ganem et al., 2007). Additionally, cells with Chromosome and chromatid breaks, chromosome fusions, genomic instability frequently display increased chro- aneuploidy and polyploidy were increased in older Mdm2 mosome or chromatid breaks, chromosomal fusions and transgenic mice compared with wild-type littermates. centrosome amplification, which itself promotes CIN. Unexpectedly, chromosome fusions, aneuploidy and poly- Mechanisms leading to CIN are diverse and incom- ploidy rates in Mdm2 transgenic mice, but not chromo- pletely understood. Unrepaired DNA double-strand some and chromatid breaks, showed cooperation between breaks or eroded telomeres can lead to CIN by serving Mdm2 overexpression and age. Notably, Mdm2 over- as substrates for chromosomal fusions and transloca- expression promoted gains in one or more chromosomes tions (Morgan et al., 1998). Amplification of centro- with age, while it did not affect the rate of chromosome somes may lead to the missegregation of chromosomes loss. Therefore, aging increased specific forms of genomic and result in aneuploidy (Ganem et al., 2007). The instability, and elevated Mdm2 expression cooperated uncoupling of DNA replication and mitosis can result in with aging to increase the likelihood of gaining certain polyploidy, which is postulated to be a precursor to chromosomal abnormalities of the kind thought to lead to aneuploidy (Fujiwara et al., 2005; Ganem et al., 2007; cancer development. Thompson et al., 2010; Vitale et al., 2010). Whether this Oncogene (2011) 30, 4622–4631; doi:10.1038/onc.2011.172; genomic instability, commonly observed in cancer cells, published online 23 May 2011 precedes tumorigenesis or is a by-product of transfor- mation is not clear. However, mice with mutations in Keywords: aging; Mdm2; p53; chromosome instability; genes encoding proteins involved in cell cycle control or aneuploidy DNA damage signaling or repair have increased CIN and many spontaneously develop cancer (Garinis et al., 2008; Negrini et al., 2010). Therefore, maintaining geno- mic stability appears essential to limit tumorigenesis. Correspondence: Dr CM Eischen, Department of Pathology, Vander- The oncogene Mdm2 is frequently amplified or bilt University Medical Center, 1161 21st Avenue South, C3321 MCN, overexpressed in many human and murine cancers; Nashville, TN 37232-2561, USA. B E-mail: [email protected] 10% of all human cancers harbor MDM2 amplifica- Received 3 October 2010; revised 3 April 2011; accepted 6 April 2011; tions (Rayburn et al., 2005; Marine and Lozano, 2010). published online 23 May 2011 Elevated levels of Mdm2 are associated with increased Genomic instability in aging Mdm2-overexpressing mice T Lushnikova et al 4623 transformation in vitro and in vivo (Marine and Lozano, Mdm2 overexpression in wild-type or p53-null mouse 2010). Mdm2 is an E3 ubiquitin ligase that functions as embryonic fibroblasts inhibited DNA double-strand a critical negative regulator of the tumor suppressor break repair, leading to genomic instability and trans- p53, and Mdm2 can also delay DNA repair through formation (Alt et al., 2005; Bouska et al., 2008). Thus, association with a DNA repair complex (Bouska and elevated expression of Mdm2 is linked to genomic Eischen, 2009; Marine and Lozano, 2010). Mdm2 instability, but whether elevated levels of Mdm2 affect interferes with the transcriptional activity of p53 by chromosomal stability as a mammal ages is unknown. binding to and ubiquitinating p53, targeting it for Therefore, we performed an in-depth study of the effect degradation by the proteasome (Marine and Lozano, of aging alone and together with Mdm2 overexpression 2010). Inactivation of p53 function results in a loss of on genome stability. We show that specific chromoso- cell cycle checkpoint control and polyploidy, aneuploidy mal alterations linked to chromosomal instability and tumorigenesis (Fujiwara et al., 2005; Levine and increase with age, and elevated levels of Mdm2 lead to Oren, 2009). Mdm2 also binds to Nbs1, a protein in the a greater amount of chromosomal instability that Mre11/Rad50/Nbs1 DNA repair complex, and inhibits accumulated with age before tumor development. The DNA double-strand break repair (Alt et al., 2005; increased numerical and structural chromosome ab- Bouska et al., 2008). Cells with reduced levels of Nbs1 or normalities in Mdm2 transgenic mice likely contribute to that contain mutated Nbs1 have an altered response to their increased predisposition to cancer. DNA damage and are delayed in repairing DNA damage (Williams et al., 2002; Difilippantonio et al., 2005). Humans with mutations in NBS1 frequently develop malignancies (Demuth and Digweed, 2007). Therefore, Mdm2 regulates Results two proteins essential for monitoring, signaling and/or repairing DNA damage, which is thought to be a CIN increases as mice age contributing factor to tumorigenesis. To determine the specific effects of aging on overall Several studies have linked Mdm2 overexpression to genome stability and the contribution of increased genomic instability through both p53-dependent and Mdm2 levels to this process, B3600 metaphase spreads p53-independent mechanisms. Overexpression of human of splenocytes from 72 littermate-matched precancerous Mdm2 in murine fibroblasts that contain wild-type p53 wild-type C57Bl/6 and Mdm2 hemizygous transgenic resulted in aneuploidy and centrosome amplification mice 2–14 month of age were analyzed for chromosomal (Carroll et al., 1999). Recently, loss of p53 was alterations. Mice older than 14 months were not demonstrated to be important for the survival and evaluated because of the emergence of cancer in the proliferation of aneuploid cells (Fujiwara et al., 2005; Mdm2 hemizygous transgenic mice. The number of Thompson et al., 2010; Vitale et al., 2010). Mammary chromosomal aberrations, including chromosome and epithelial cells from mammary specific-Mdm2 transgenic chromatid breaks, chromosome fusions and metaphases mice have increased polyploidy, likely due to endo- with an abnormal number of chromosomes, were reduplication, and this occurred irrespective of p53 quantified in B50 metaphases from each mouse. There status (Lundgren et al., 1997). Additionally, B cells from was a small, gradual increase in the total number of juvenile Mdm2 transgenic mice, where Mdm2 expression chromosomal abnormalities in wild-type mice as they was driven from its native promoter, have increased aged (Figures 1a and b). In contrast, Mdm2 transgenic chromosome and chromatid breaks, and aneuploidy mice had a marked increase in CIN with increasing age compared with B cells from wild-type mice (Wang et al., (Po0.0005). The frequency of chromosomal abnormal- 2008). Furthermore, through interaction with Nbs1, ities in wild-type and Mdm2 transgenic mice were similar Figure 1 Increased chromosomal instability with age. Metaphases from splenocytes from wild-type or littermate-matched Mdm2 transgenic mice aged 2–14 months were evaluated
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