Abstract
BackgroundAmplification 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.MethodsAn 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.ResultsInstead 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.ConclusionThese observations suggest that eIF-5A2 mouse models could accelerate organismal aging by increasing chromosome instability.
Highlights
Amplification of 3q26 is one of the most frequent genetic alterations in many human malignancies
Zender et al identified that eIF-5A2 is amplified in human cancer using representational oligonucleotide microarray analysis (ROMA), and is required for proliferation of XPO4-deficient tumor cells and promotes hepatocellular carcinoma in mice [11]
To confirm the single integration event, an eIF-5A2 probe was used to hybridize to the metaphase spreads from bone marrow lymphocytes by fluorescence in situ hybridization (FISH)
Summary
Amplification of 3q26 is one of the most frequent genetic alterations in many human malignancies. 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. It is believed that the process of malignant tumor is a multiple-step process caused by the accumulation of abnormal expression of oncogenes and tumor suppressor genes. We showed that overexpression of eIF-5A2 at the protein level was significantly associated with the advanced stages of ovarian cancer [8]. Marchet et al recently reported that overexpression of eIF-5A2 is associated with a higher risk of lymph node metastasis in human gastric adenocarcinomas [10]. Zender et al identified that eIF-5A2 is amplified in human cancer using representational oligonucleotide microarray analysis (ROMA), and is required for proliferation of XPO4-deficient tumor cells and promotes hepatocellular carcinoma in mice [11]. The in vivo function of eIF-5A2 is still not clear
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