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

BMC Cancer

Xin-Yuan Guan⁴  Gui-Xia Zhu²  Tong Zan³  Leilei Chen⁴  Michael SY Huen²  Sze Lan Tsang²  Wen Deng¹  Suisui Dong⁴  Hong Kui Deng³  Jian-Dong Huang²  Muhan Chen⁴ 

[1]Department of Anatomy, Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Hong Kong

[2]Department of Biochemistry, Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Hong Kong, China

[3]Department of Cell Biology, College of Life Sciences, Peking University, Beijing, China

[4]Department of Clinical Oncology, Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Hong Kong, China

关键词: oncogene;    transgenic mouse;    chromosome instability;    aging;    eIF-5A2;   

Others  :  1080936
DOI  :  10.1186/1471-2407-11-199

 received in 2010-05-31, accepted in 2011-05-26,  发布年份 2011

【 摘 要 】

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.

【 授权许可】

   
2011 Chen et al; licensee BioMed Central Ltd.

【 图 表 】

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