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Overexpression of eIF-5A2 in mice causes accelerated organismal aging by increasing chromosome instability.

Chen M, Huang JD, Deng HK, Dong S, Deng W, Tsang SL, Huen MS, Chen L, Zan T, Zhu GX, Guan XY - BMC Cancer (2011)

Bottom Line: Recently, we isolated a novel oncogene eIF-5A2 within the 3q26 region.This included decreased growth rate and body weight, shortened life span, kyphosis, osteoporosis, delay of wound healing and ossification.This subsequently allowed for the accumulation of chromosomal instability, such as errors in cell dividing during metaphase and anaphase.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Clinical Oncology, Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Hong Kong, China.

ABSTRACT

Background: Amplification of 3q26 is one of the most frequent genetic alterations in many human malignancies. Recently, we isolated a novel oncogene eIF-5A2 within the 3q26 region. Functional study has demonstrated the oncogenic role of eIF-5A2 in the initiation and progression of human cancers. In the present study, we aim to investigate the physiological and pathological effect of eIF-5A2 in an eIF-5A2 transgenic mouse model.

Methods: An eIF-5A2 transgenic mouse model was generated using human eIF-5A2 cDNA. The eIF-5A2 transgenic mice were characterized by histological and immunohistochemistry analyses. The aging phenotypes were further characterized by wound healing, bone X-ray imaging and calcification analysis. Mouse embryo fibroblasts (MEF) were isolated to further investigate molecular mechanism of eIF-5A2 in aging.

Results: Instead of resulting in spontaneous tumor formation, overexpression of eIF-5A2 accelerated the aging process in adult transgenic mice. This included decreased growth rate and body weight, shortened life span, kyphosis, osteoporosis, delay of wound healing and ossification. Investigation of the correlation between cellular senescence and aging showed that cellular senescence is not required for the aging phenotypes in eIF-5A2 mice. Interestingly, we found that activation of eIF-5A2 repressed p19 level and therefore destabilized p53 in transgenic mouse embryo fibroblast (MEF) cells. This subsequently allowed for the accumulation of chromosomal instability, such as errors in cell dividing during metaphase and anaphase. Additionally, a significantly increase in number of aneuploidy cells (p < 0.05) resulted from an increase in the incidences of misaligned and lagging chromosomal materials, anaphase bridges, and micronuclei in the transgenic mice.

Conclusion: These observations suggest that eIF-5A2 mouse models could accelerate organismal aging by increasing chromosome instability.

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Chromosome instability in eIF-5A2 transgenic mice. (A) Representative SKY images (left) and reversed DAPI stain (right) of bone marrow metaphase spreads from wild-type and transgenic mice. (B, C) Detection of hallmarks of chromosomal instability in eIF-5A2 transgenic MEFs, including misaligned chromosomes separated from the metaphase plate (a'), lagging chromosomes in anaphase (b' and c'), and micronuclei in interphase cells (C). (D) Quantification of the incidence of the micronuclei, misaligned and lagging chromosomes.
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Figure 7: Chromosome instability in eIF-5A2 transgenic mice. (A) Representative SKY images (left) and reversed DAPI stain (right) of bone marrow metaphase spreads from wild-type and transgenic mice. (B, C) Detection of hallmarks of chromosomal instability in eIF-5A2 transgenic MEFs, including misaligned chromosomes separated from the metaphase plate (a'), lagging chromosomes in anaphase (b' and c'), and micronuclei in interphase cells (C). (D) Quantification of the incidence of the micronuclei, misaligned and lagging chromosomes.

Mentions: Considering the role of p53 in maintenance of genetic stability and its down-regulation in eIF-5A2 transgenic mice, the correlation of eIF-5A2 expression and chromosomal instability was investigated. Metaphases from MEFs and adult mouse bone marrow were cytogenetically characterized and compared between eIF-5A2 transgenic mice and their wild-type littermates. Karyotyping analysis showed that the frequency of aneuploidy cells was significantly higher in transgenic MEFs (18.5%, n = 200) than that in wild-type MEFs (4.5%, n = 200, p < 0.05). In adult mouse bone marrow cells, the frequency of aneuploidy cells was significantly higher in transgenic mice (11.5%, n = 200) than that in wild-type mice (3%, n = 200, p < 0.05). Spectral karyotyping (SKY) analysis also found an increased number of aneuploidy cells in adult transgenic mice (16/100 metaphases) compared to wild-type controls (6/100 metaphases) (Figure 7A).


Overexpression of eIF-5A2 in mice causes accelerated organismal aging by increasing chromosome instability.

Chen M, Huang JD, Deng HK, Dong S, Deng W, Tsang SL, Huen MS, Chen L, Zan T, Zhu GX, Guan XY - BMC Cancer (2011)

Chromosome instability in eIF-5A2 transgenic mice. (A) Representative SKY images (left) and reversed DAPI stain (right) of bone marrow metaphase spreads from wild-type and transgenic mice. (B, C) Detection of hallmarks of chromosomal instability in eIF-5A2 transgenic MEFs, including misaligned chromosomes separated from the metaphase plate (a'), lagging chromosomes in anaphase (b' and c'), and micronuclei in interphase cells (C). (D) Quantification of the incidence of the micronuclei, misaligned and lagging chromosomes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3118894&req=5

Figure 7: Chromosome instability in eIF-5A2 transgenic mice. (A) Representative SKY images (left) and reversed DAPI stain (right) of bone marrow metaphase spreads from wild-type and transgenic mice. (B, C) Detection of hallmarks of chromosomal instability in eIF-5A2 transgenic MEFs, including misaligned chromosomes separated from the metaphase plate (a'), lagging chromosomes in anaphase (b' and c'), and micronuclei in interphase cells (C). (D) Quantification of the incidence of the micronuclei, misaligned and lagging chromosomes.
Mentions: Considering the role of p53 in maintenance of genetic stability and its down-regulation in eIF-5A2 transgenic mice, the correlation of eIF-5A2 expression and chromosomal instability was investigated. Metaphases from MEFs and adult mouse bone marrow were cytogenetically characterized and compared between eIF-5A2 transgenic mice and their wild-type littermates. Karyotyping analysis showed that the frequency of aneuploidy cells was significantly higher in transgenic MEFs (18.5%, n = 200) than that in wild-type MEFs (4.5%, n = 200, p < 0.05). In adult mouse bone marrow cells, the frequency of aneuploidy cells was significantly higher in transgenic mice (11.5%, n = 200) than that in wild-type mice (3%, n = 200, p < 0.05). Spectral karyotyping (SKY) analysis also found an increased number of aneuploidy cells in adult transgenic mice (16/100 metaphases) compared to wild-type controls (6/100 metaphases) (Figure 7A).

Bottom Line: Recently, we isolated a novel oncogene eIF-5A2 within the 3q26 region.This included decreased growth rate and body weight, shortened life span, kyphosis, osteoporosis, delay of wound healing and ossification.This subsequently allowed for the accumulation of chromosomal instability, such as errors in cell dividing during metaphase and anaphase.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Clinical Oncology, Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Hong Kong, China.

ABSTRACT

Background: Amplification of 3q26 is one of the most frequent genetic alterations in many human malignancies. Recently, we isolated a novel oncogene eIF-5A2 within the 3q26 region. Functional study has demonstrated the oncogenic role of eIF-5A2 in the initiation and progression of human cancers. In the present study, we aim to investigate the physiological and pathological effect of eIF-5A2 in an eIF-5A2 transgenic mouse model.

Methods: An eIF-5A2 transgenic mouse model was generated using human eIF-5A2 cDNA. The eIF-5A2 transgenic mice were characterized by histological and immunohistochemistry analyses. The aging phenotypes were further characterized by wound healing, bone X-ray imaging and calcification analysis. Mouse embryo fibroblasts (MEF) were isolated to further investigate molecular mechanism of eIF-5A2 in aging.

Results: Instead of resulting in spontaneous tumor formation, overexpression of eIF-5A2 accelerated the aging process in adult transgenic mice. This included decreased growth rate and body weight, shortened life span, kyphosis, osteoporosis, delay of wound healing and ossification. Investigation of the correlation between cellular senescence and aging showed that cellular senescence is not required for the aging phenotypes in eIF-5A2 mice. Interestingly, we found that activation of eIF-5A2 repressed p19 level and therefore destabilized p53 in transgenic mouse embryo fibroblast (MEF) cells. This subsequently allowed for the accumulation of chromosomal instability, such as errors in cell dividing during metaphase and anaphase. Additionally, a significantly increase in number of aneuploidy cells (p < 0.05) resulted from an increase in the incidences of misaligned and lagging chromosomal materials, anaphase bridges, and micronuclei in the transgenic mice.

Conclusion: These observations suggest that eIF-5A2 mouse models could accelerate organismal aging by increasing chromosome instability.

Show MeSH
Related in: MedlinePlus