Aging mice have increased chromosome instability that is exacerbated by elevated Mdm2 expression

Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN 37232-2561, USA.
Oncogene (Impact Factor: 8.56). 05/2011; 30(46):4622-31. DOI: 10.1038/onc.2011.172
Source: PubMed

ABSTRACT Aging is thought to negatively affect multiple cellular processes including the ability to maintain chromosome stability. Chromosome instability (CIN) is a common property of cancer cells and may be a contributing factor to cellular transformation. The types of DNA aberrations that arise during aging before tumor development and that contribute to tumorigenesis are currently unclear. Mdm2, a key regulator of the p53 tumor suppressor and modulator of DNA break repair, is frequently overexpressed in malignancies and contributes to CIN. To determine the relationship between aging and CIN and the role of Mdm2, precancerous wild-type C57Bl/6 and littermate-matched Mdm2 transgenic mice at various ages were evaluated. Metaphase analyses of wild-type cells showed a direct correlation between age and increased chromosome and chromatid breaks, chromosome fusions and aneuploidy, but the frequency of polyploidy remained stable over time. Elevated levels of Mdm2 in precancerous mice increased both the numerical and the structural chromosomal abnormalities observed. Chromosome and chromatid breaks, chromosome fusions, aneuploidy and polyploidy were increased in older Mdm2 transgenic mice compared with wild-type littermates. Unexpectedly, chromosome fusions, aneuploidy and polyploidy rates in Mdm2 transgenic mice, but not chromosome and chromatid breaks, showed cooperation between Mdm2 overexpression and age. Notably, Mdm2 overexpression promoted gains in one or more chromosomes with age, while it did not affect the rate of chromosome loss. Therefore, aging increased specific forms of genomic instability, and elevated Mdm2 expression cooperated with aging to increase the likelihood of gaining certain chromosomal abnormalities of the kind thought to lead to cancer development.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Frequent overexpression of MDM2 in human cancers suggests that the protein confers a survival advantage to cancer cells. However, overexpression of MDM2 in normal cells seems to restrict cell proliferation. This review discusses the cell growth regulatory functions of MDM2 in normal and genetically defective cells to assess how cancer cells evade the growth-restricting consequence of MDM2 overexpression. Similar to oncoproteins that induce a DNA damage response and oncogene induced senescence in non-transformed cells, MDM2 induces G1-arrest and intra-S phase checkpoint responses that control untimely DNA replication in the face of genetic challenges.
    Sub-cellular biochemistry 01/2014; 85:215-234. DOI:10.1007/978-94-017-9211-0_12
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aging involves a deterioration of cell functions and changes that may predispose the cell to undergo an oncogenic transformation. The carcinogenic risks following radiation exposure rise with age among adults. Increasing inflammatory response, loss of oxidant/antioxidant equilibrium, ongoing telomere attrition, decline in the DNA damage response efficiency, and deleterious nuclear organization are age-related cellular changes that trigger a serious threat to genomic integrity. In this review, we discuss the mechanistic interplay between all these factors, providing an integrated view of how they contribute to the observed age-related increase in radiation sensitivity. As life expectancy increases and so it does the medical intervention, it is important to highlight the benefits of radiation protection in the elderly. Thus, a deep understanding of the mechanistic processes confining the threat of aging-related radiosensitivity is currently of foremost relevance.
    Aging cell 02/2015; 14(2). DOI:10.1111/acel.12306 · 5.94 Impact Factor
  • Source

Full-text (3 Sources)

Available from
Mar 29, 2015