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Cited by 40Cancer-related Molecular PathwaysMicrotubule and mitosis dynamicsTelomeres, Telomerase, and Senescence

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

Open access
Lushnikova, T, Bouska, A, Odvody, J, Dupont, W D, Eischen, C M·2011·Oncogene
DOI 10.1038/onc.2011.172PMC PMC3161162
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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.

AI snapshot

Written from the paper’s full text.

TL;DR

Aging wild-type C57Bl/6 mice showed increased chromosome instability, and elevated Mdm2 expression in pre-cancerous Mdm2 transgenic littermates exacerbated several age-related chromosomal abnormalities. Mdm2 overexpression particularly cooperated with age to increase chromosome fusions, aneuploidy, polyploidy, and gains of chromosomes, but not chromosome loss.

Key findings

  • In approximately 3,600 metaphase spreads from 72 littermate-matched wild-type and Mdm2 hemizygous transgenic mice aged 2–14 months, Mdm2 transgenic mice had a marked age-related increase in total chromosomal abnormalities (p<0.0005); at 14 months the number of chromosomal abnormalities in Mdm2 transgenic mice was twice that in wild-type mice.
  • Chromosome and chromatid breaks were significantly higher in Mdm2 transgenic mice than wild-type mice at all ages evaluated (p=0.001), but the rate of increase in breaks with age was statistically similar between genotypes (p=0.49).
  • Chromosome fusions were more frequent in Mdm2 transgenic mice, with the greatest difference at older ages (p=0.05); 66% of fusions in both genotypes were centromeric-centromeric Robertsonian translocations, about a quarter were centromeric-telomeric, and less than 10% were telomeric-telomeric.
  • Polyploid metaphases with 50–80 chromosomes increased significantly with age in Mdm2 transgenic mice (p=0.04) but remained relatively constant in wild-type mice; aneuploidy increased in wild-type mice (p=0.04) and more strongly in Mdm2 transgenic mice (p<0.0005), with Mdm2 transgenic mice having more than twice the mean aneuploid cells at 14 months versus 2 months.
  • Chromosome loss increased with age in both genotypes (p=0.003) at a similar rate (p=0.88), whereas chromosome gain increased significantly only in Mdm2 transgenic mice (p=0.003), with triple the mean number of metaphases with >40 chromosomes at 14 months compared to 2 months.

Methods

  • Pre-cancerous wild-type C57Bl/6 and littermate-matched Mdm2 hemizygous transgenic mice expressing Mdm2 under its native promoter were sacrificed at 2, 5, 8, 10, 12, and 14 months; mice older than 14 months were excluded due to tumor development in Mdm2 transgenic mice, and mice with overt or suspected malignancy were excluded.
  • Splenocytes were stimulated to mitosis, metaphase spreads were prepared, stained with propidium iodide and DAPI, blinded, and 48–52 metaphases per mouse per genotype per age were visualized and photographed; chromosome abnormalities and chromosome numbers were scored.
  • Statistical analysis used multiple linear regression for total abnormalities and negative binomial regression for event rates, including genotype, age, and genotype-by-age interaction terms, with the log number of evaluated metaphases as an offset; GEE models were used as sensitivity analyses and gave similar results.

Limitations

  • The paper states that mice older than 14 months were excluded because of tumor development in Mdm2 transgenic mice, and any mouse with overt cancer or suspected malignancy was excluded from the study.
  • The paper does not include a dedicated limitations section; evident from the text, the study is limited to splenocytes from a single Mdm2 transgenic mouse model, so findings may not generalize to other tissues, other Mdm2 expression models, or humans.
  • The study reports associations between age, Mdm2 overexpression, and chromosomal abnormalities but does not directly establish the mechanisms by which Mdm2 overexpression leads to specific abnormalities such as chromosome gains versus losses.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/onc.2011.172

Cites

39 of 39 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 28 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In Mdm2 transgenic mice, chromosome instability increases markedly with age.

    “In contrast, Mdm2 transgenic mice had a marked increase in CIN with increasing age (p<0.0005).”
    Quote in the paperSubstantial claim
  • Findingown data

    Mdm2 transgenic mice have triple the mean number of metaphases with greater than 40 chromosomes at 14 months compared to at 2 months of age.

    “Mdm2 transgenic mice had triple the mean number of metaphases with greater than 40 chromosomes at 14 months old compared to at 2 months of age.”
    Quote in the paperSubstantial claim
  • Findingown data

    Severe structurally abnormal chromosomes are detected only in pre-cancerous cells from Mdm2 transgenic mice, not in wild-type cells.

    “Moreover, severe structurally abnormal chromosomes were only detected in pre-cancerous cells in Mdm2 transgenics and not in wild-type cells.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Mdm2 transgenic mice have cells containing more than 4N DNA.

    “Furthermore, Mdm2 transgenic mice also had cells that contained more than 4N DNA (Fig. 4E).”
    Quote in the paperSubstantial claim
  • Findingown data

    Aging Mdm2 transgenic mice have a large significant, non-linear increase in aneuploid cells, with the mean number at 14 months more than twice that at 2 months (p<0.0005).

    “Notably, aging Mdm2 transgenic mice had a large significant, non-linear increase in aneuploid cells such that the mean number of aneuploid cells in mice 14 months old was more than twice that in mice 2 months old (p<0.0005) (Fig. 5D).”
    Quote in the paperSubstantial claim
  • May combine two claims. 31
  • Classified as probably not a substantial claim. 13

  • May combine two claims.

    Findingown data

    The rate of increase in chromatid and chromosome breaks in aging mice is similar between wild-type and Mdm2 transgenic mice, although Mdm2 transgenic cells have more DNA breaks at every age evaluated.

    “Unexpectedly, the rate of increase in chromatid and chromosome breaks in aging mice was similar between wild-type and Mdm2 transgenics, although Mdm2 transgenic cells had more DNA breaks than their wild-type littermates at every age evaluated.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    As mice age, the number of metaphases with 50-80 chromosomes significantly increases in Mdm2 transgenic mice (p=0.04), but remains relatively constant in wild-type mice.

    “As the mice aged, the number of metaphases with 50–80 chromosomes significantly increased in Mdm2 transgenic mice (p=0.04), but remained relatively constant for wild-type mice (Fig. 4D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Centromeric-telomeric fusions account for about a quarter of fusions, and telomeric-telomeric fusions are rare (<10%) in both genotypes.

    “Centromeric-telomeric fusions accounted for a quarter of the fusions detected (Fig. 3C), and telomeric-telomeric fusions were rare for both genotypes and accounted for less than 10% of the fusions identified.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Mdm2 overexpression leads to a greater frequency of gains of chromosomes compared to wild-type mice, and this increased with age.

    “In contrast, Mdm2 overexpression led to a greater frequency of gains of chromosomes compared to the rate in wild-type mice, and this increased with age.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    As mice age, both wild-type and Mdm2 transgenic mice have increased numbers of metaphases with less than 40 chromosomes (p=0.003), doubling the mean frequency between 2 and 14 months.

    “As mice aged, both wild-type and Mdm2 transgenic mice had increased numbers of metaphases with less than 40 chromosomes (p=0.003), doubling the mean frequency between 2 months and 14 months of age (Fig. 6A & 6B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    As mice age, the number of metaphases with greater than 40 chromosomes slightly increases in wild-type mice, but this increase is not significant (p=0.34).

    “However, as the mice aged, the number of metaphases with greater than 40 chromosomes slightly increased in wild-type mice, but this increase was not significant (p=0.34).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Mdm2 transgenic mice have both increased polyploid and aneuploid cells that correlate with age.

    “Notably, Mdm2 transgenic mice had both increased polyploid and aneuploid cells that correlated with age.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At 2 months of age, wild-type and Mdm2 transgenic mice have a similar low number of metaphases with fused chromosomes, and both genotypes show an increase in metaphases with fused chromosomes as they age.

    “At 2 months of age, wild-type and Mdm2 transgenic mice had a similar low number of metaphases with fused chromosomes, and both genotypes showed an increase in metaphases with fused chromosomes as the mice aged (Fig. 3D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Mdm2 transgenic mice have a greater percentage of metaphases with fused chromosomes than wild-type mice, with the greatest difference at older ages (p=0.05).

    “However, Mdm2 transgenic mice had a greater percentage of metaphases with fused chromosomes than wild-type mice with the greatest difference detected at older ages (p=0.05) (Fig. 3E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Chromosomal fusions are rare but occur in both wild-type and Mdm2 transgenic mice.

    “Although fusions were rare, they were identified in both wild-type and Mdm2 transgenic mice (Fig. 3A–3C).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Ring chromosomes are observed in Mdm2 transgenic mice as young as 5 months and in 14-month-old mice.

    “Additionally, a very rare fusion, a ring chromosome, was observed in cells from Mdm2 transgenic mice as young as 5 months old and in 14 month old mice (Fig. 3G).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The number of metaphases with greater than 40 chromosomes profoundly increases with age in Mdm2 transgenic mice and is statistically significant (p=0.003).

    “In contrast, the number of metaphases with greater than 40 chromosomes profoundly increased with age in Mdm2 transgenic mice and was statistically significant (p=0.003) (Fig. 6D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Mdm2 overexpression in primary fibroblasts causes an Nbs1-dependent delay in DNA double-strand break repair, leading to longer-persisting breaks and increased chromatid and chromosome breaks.

    “Previously we reported that Mdm2 overexpression in primary fibroblasts results in an Nbs1-dependent delay in DNA double-strand break repair, resulting in DNA breaks persisting longer and an increase in chromatid and chromosome breaks (Alt et al., 2005, Bouska et al., 2008).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Alt et al., 2005 source

      Not checked in the free run.

    • cites Bouska et al., 2008 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    DNA breaks can be substrates for fusions and translocations of chromosomes, which can accumulate in aging mice.

    “DNA breaks can be substrates for fusions and translocations of chromosomes (Morgan et al., 1998), which can accumulate in aging mice (Dolle and Vijg, 2002).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Morgan et al., 1998 source

      Not checked in the free run.

    • cites Dolle and Vijg, 2002 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Aneuploidy frequently arises due to defects in chromosome segregation during mitosis.

    “Aneuploidy frequently arises due to defects in chromosome segregation during mitosis (Thompson et al., 2010).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Thompson et al., 2010

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Polyploidy is considered a prerequisite to aneuploidy.

    “Polyploidy is considered a prerequisite to aneuploidy (Fujiwara et al., 2005, Ganem et al., 2007, Storchova and Kuffer, 2008, Thompson et al., 2010, Vitale et al., 2010)”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Fujiwara et al., 2005 source

      Not checked in the free run.

    • cites Ganem et al., 2007 source

      Not checked in the free run.

    • cites Storchova and Kuffer, 2008 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Age has little effect on the development of polyploidy in wild-type mice, but elevated Mdm2 significantly increases the rate of emergence of polyploid cells in mice over 14 months.

    “Our results indicate that age had little effect on the development of polyploidy in wild-type mice, but elevated levels of Mdm2 significantly increased the rate of emergence of polyploid cells in mice over 14 months.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Mdm2 overexpression exacerbates the rate of chromosome gains but not chromosome losses.

    “However, Mdm2 overexpression only resulted in an exacerbation of the rate of gains in chromosomes and not in the loss of chromosomes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    As wild-type and Mdm2 transgenic mice age, both gains and losses of chromosomes increase.

    “These data indicate that as wild-type and Mdm2 transgenic mice age, both gains and losses of chromosomes increased.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    This study shows that specific numerical and structural chromosomal changes increase with age in wild-type C57Bl/6 mice and are exacerbated by Mdm2 overexpression.

    “This study shows that specific numerical and structural chromosomal changes increased with age in wild-type C57Bl/6 mice and were exacerbated with Mdm2 overexpression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    As mice age, the frequency of chromosome instability increases, and elevated Mdm2 significantly augments this increase.

    “Therefore, as mice age, the frequency of CIN increases, and this is significantly augmented by elevated levels of Mdm2.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Mdm2 overexpression increases the frequency of chromosome and chromatid breaks at every age evaluated, but does not accelerate the rate at which breaks occur with age.

    “Therefore, although Mdm2 overexpression increased the frequency of chromosome and chromatid breaks at every age evaluated, Mdm2 overexpression did not accelerate the rate at which breaks occurred with age.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Genome instability precedes tumorigenesis and likely contributes to the development of tumors.

    “indicating genome instability precedes tumorigenesis and likely contributes to the development of tumors.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Mdm2 expression can lead to degradation of p21, and loss of p21 results in endoreduplication and polyploid cells.

    “Moreover, Mdm2 expression can lead to the degradation of the p53 transcriptional target gene and cell cycle inhibitor p21, and loss of p21 results in endoreduplication and polyploid cells (Jin et al., 2003, Stewart et al., 1999).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Jin et al., 2003 source

      Not checked in the free run.

    • cites Stewart et al., 1999 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Mdm2 transgenic mice have greatly increased and more severe chromosomal alterations than wild-type mice that correlate with age.

    “Moreover, Mdm2 transgenic mice had greatly increased and more severe chromosomal alterations than wild-type mice that correlated to age”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Fused chromosomes are more common in Mdm2 transgenic mice; prevalence increases with age in both genotypes, but the rate of increase is greater for Mdm2 transgenic mice, suggesting an interaction between Mdm2 and age on chromosomal fusions.

    “Therefore, fused chromosomes were more common in Mdm2 transgenic mice. The prevalence of these abnormalities increased with age in both wild-type and Mdm2 transgenic mice, but the rate of increase was greater for Mdm2 transgenic mice, suggesting an interaction between Mdm2 and age on chromosomal fusions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Elevated Mdm2 expression over time increases fusion events, possibly due to increased total breaks but possibly also other uncharacterized mechanisms.

    “Thus, elevated expression of Mdm2 over time increased fusion events, which may be due to the increase in total overall breaks in the cells of these mice, but may also be due to other uncharacterized mechanisms.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    GEE models gave results very similar to negative binomial regression models.

    “These models gave results that were very similar to those obtained from our negative binomial regression models.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Statistical models included an interaction term between genotype and age.

    “An interaction term between genotype and age at sacrifice was included in this model.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Prolonged Mdm2 overexpression worsens the genomic abnormalities observed over time, and chromosomal alterations accumulate with age prior to tumor development.

    “Here our data reveal that prolonged Mdm2 overexpression worsens the genomic abnormalities observed over time, and that chromosomal alterations accumulate with age prior to tumor development.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The chromosomal structure of three chromosomes fused centromere to telomere is typical of a breakage-fusion-bridge cycle that can lead to gene amplifications or translocations and is associated with tumorigenesis.

    “The chromosomal structure of three chromosomes fused centromere to telomere is typical of a breakage-fusion-bridge cycle that can lead to gene amplifications or translocations and is associated with tumorigenesis (DePinho and Polyak, 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites DePinho and Polyak, 2004 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Only breaks visible by both PI and DAPI staining were scored as breaks.

    “Only breaks visible by both PI and DAPI staining were scored as a break.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Studies have shown age-related changes in DNA repair mechanisms.

    “Studies using a variety of techniques have shown age-related changes in DNA repair mechanisms (Gorbunova et al., 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Gorbunova et al., 2007 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Signaling from ATM and the response of other DNA repair proteins declines with age.

    “For example, signaling from the DNA damage kinase, ATM, and the response of other DNA repair proteins declines with age (Feng et al., 2007, Gorbunova et al., 2007).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Feng et al., 2007 source

      Not checked in the free run.

    • cites Gorbunova et al., 2007 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The study used littermate-matched wild-type and Mdm2 transgenic mice.

    “Experimental mice were generated by breeding hemizygous Mdm2 transgenic males to C57Bl/6 females to generate hemizygous Mdm2 transgenic mice and wild-type littermate controls.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Mice with overt cancer or suspected malignancy were excluded from the study.

    “Tissues from each mouse were carefully evaluated for malignancies; any mouse with overt cancer or suspected of having a malignancy were excluded from the study.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Mdm2 negatively regulates both p53 and mediators of ATM activation, the Mre11/Rad50/Nbs1 DNA repair complex.

    “Mdm2 negatively regulates both p53 and mediators of ATM activation, the Mre11/Rad50/Nbs1 DNA repair complex (Alt et al., 2005, Bouska et al., 2008, Marine and Lozano, 2010).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Alt et al., 2005 source

      Not checked in the free run.

    • cites Bouska et al., 2008 source

      Not checked in the free run.

    • cites Marine and Lozano, 2010 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    Mice older than 14 months were excluded due to tumor development in Mdm2 transgenic mice.

    “Mice greater than 14 moths old were excluded from the study due to tumor development in Mdm2 transgenic mice.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Slides were blinded before metaphase visualization and scoring.

    “Slides were mounted with Vectashield (Vector Laboratories, Burlingame, CA), blinded, and 48–52 metaphases for each mouse for each genotype for each age were visualized and then photographed”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Mdm2 overexpression should both induce and allow chromosomal aberrations to accumulate over a lifetime, ultimately leading to cellular transformation and tumorigenesis.

    “Thus, Mdm2 overexpression should both induce and allow chromosomal aberrations to accumulate in cells over the course of a lifetime, ultimately leading to cellular transformation and tumorigenesis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    Negative binomial regression was used to model event rates.

    “Negative binomial regression was used to model the event rates (the proportion of metaphase cells with the genetic abnormality of interest) in terms of genotype and age at sacrificed was performed (Agresti, 2002).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Agresti, 2002 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A reduction in ATM and p53 function results in decreased DNA repair, reduced apoptosis, and an increase in CIN and tumorigenesis.

    “A reduction in ATM and p53 function results in decreased DNA repair, reduced apoptosis, and an increase in CIN and tumorigenesis (Negrini et al., 2010).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Negrini et al., 2010 source

      Not checked in the free run.

42 of 42

  • The paper relies on this without support.

    Mdm2 transgenic mice develop cancer earlier than wild-type mice, and wild-type mice may never develop malignancy.

    “they also develop cancer significantly earlier in life than wild-type mice, which may never develop a malignancy.”

  • The paper relies on this without support.

    Mouse aging is a valid model for mammalian aging.

    “whether elevated levels of Mdm2 affect chromosomal stability as a mammal ages is unknown.”

  • The paper relies on this without support.

    Splenocytes are representative of organism-wide chromosomal instability.

    “approximately 3,600 metaphase spreads of splenocytes from 72 littermate-matched pre-cancerous wild-type C57Bl/6 and Mdm2 hemizygous transgenic mice 2–14 months old were analyzed for chromosomal alterations.”

  • The paper relies on this without support.

    Mdm2 transgenic mice without overt tumors are pre-cancerous.

    “pre-cancerous wild-type C57Bl/6 and littermate-matched Mdm2 transgenic mice at various ages were evaluated.”
4 of 4

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Authors
Lushnikova, T., Bouska, A., Odvody, J., Dupont, W. D., & Eischen, C. M.
Affiliations
  • Vanderbilt University (US)
  • University of Nebraska Medical Center (US)
Corresponding author
Eischen, C M
ORCID
Venue
Oncogene
Publisher
Springer Science and Business Media LLC
Published
2011-05-23
Volume
30
Issue
46
Pages
4622-4631
ISSN
  • 0950-9232 (ISSN-L)
  • 1476-5594
DOI
10.1038/onc.2011.172
PMC
PMC3161162
OpenAlex
W2002656606
Semantic Scholar
edeb2d5eb449cf5e61c4ce4c8424ac68d55fbf32
Cited by
40
References
39
Citations by year
2026: 1 · 2025: 5 · 2024: 2 · 2023: 1 · 2022: 1 · 2021: 3 · 2020: 1 · 2019: 3 · 2018: 1 · 2017: 2 · 2016: 6 · 2015: 3 · 2014: 3 · 2013: 1 · 2012: 6
FWCI
1.73
Type
journal article
Language
en
Open access
Licence
Locations
  • Oncogene (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Vanderbilt University
  • National Cancer Institute (R01CA117935, P30CA068485)
Topics
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
Keywords
aging, chromosomal instability, MDM2, genomic instability, aneuploidy, chromosome fusion, polyploidy, chromatid breaks, p53, DNA repair, transgenic mice, precancerous cells, carcinogenesis, chromosomal abnormalities
MeSH terms
Aging, Animals, Gene Expression Regulation, Humans, Mice, Transgenic, Polyploidy, Precancerous Conditions, Chromosomal Instability, Mice, Proto-Oncogene Proteins c-mdm2

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