Open Access Research article

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

Muhan Chen1, Jian-Dong Huang2, Hong Kui Deng3, Suisui Dong1, Wen Deng4, Sze Lan Tsang2, Michael SY Huen2, Leilei Chen1, Tong Zan3, Gui-Xia Zhu2 and Xin-Yuan Guan1*

Author Affiliations

1 Department of Clinical Oncology, Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Hong Kong, China

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 Anatomy, Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Hong Kong

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BMC Cancer 2011, 11:199  doi:10.1186/1471-2407-11-199

Published: 26 May 2011

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.

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