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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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Tissue distribution of transgenic eIF-5A2 protein and BrdU incorporation analysis of day 13.5 embryos. Expression of eIF-5A2 in developing liver, cartilage and neuroepithilium from transgenic and wild-type embryos (left) was detected by IHC (magnification, 400 ×). BrdU incorporation assay (right) was used to compare the proliferation rates between transgenic and wild-type embryos. No significant difference was observed in the percentage of BrdU positive cells between transgenic (56.3 ± 7.81) and wild-type embryos (52.73 ± 9.14, p > 0.05).
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Figure 2: Tissue distribution of transgenic eIF-5A2 protein and BrdU incorporation analysis of day 13.5 embryos. Expression of eIF-5A2 in developing liver, cartilage and neuroepithilium from transgenic and wild-type embryos (left) was detected by IHC (magnification, 400 ×). BrdU incorporation assay (right) was used to compare the proliferation rates between transgenic and wild-type embryos. No significant difference was observed in the percentage of BrdU positive cells between transgenic (56.3 ± 7.81) and wild-type embryos (52.73 ± 9.14, p > 0.05).

Mentions: To determine the effects of eIF-5A2 on mouse development, protein expression in13.5-day embryos and 12-week old mice was studied. On embryonic day 13.5, expression of eIF-5A2 was detected in the developing brain, liver and cartilage (Figure 2). At 12-week of age, EIF-5A2 protein expression was detected in all the tested adult tissues, including brain, lung, heart, liver, kidney, spleen, testis, uterus and ovary (sure 3A). Histological analysis showed that the morphologies of all tested tissues in eIF-5A2 transgenic embryos/mice were indistinguishable from their wild-type counterparts. To test the effects of eIF-5A2 overexpression on cell proliferation, BrdU incorporation assay and proliferating cell nuclear antigen (PCNA) immunostaining was applied to measure the proportion of cells in S phase in E13.5 embryos and12-week-old mice, respectively. However, the frequencies of BrdU positive cells in transgenic and wild-type embryos (56.3 ± 7.81 vs. 52.73 ± 9.14, respectively; p > 0.05) and PCNA positive cell percentages in transgenic and wild-type mice (46.2 ± 10.98 vs. 37.87 ± 10.44, respectively; p > 0.05) were comparable (Figure 2 and 3A).


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)

Tissue distribution of transgenic eIF-5A2 protein and BrdU incorporation analysis of day 13.5 embryos. Expression of eIF-5A2 in developing liver, cartilage and neuroepithilium from transgenic and wild-type embryos (left) was detected by IHC (magnification, 400 ×). BrdU incorporation assay (right) was used to compare the proliferation rates between transgenic and wild-type embryos. No significant difference was observed in the percentage of BrdU positive cells between transgenic (56.3 ± 7.81) and wild-type embryos (52.73 ± 9.14, p > 0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Tissue distribution of transgenic eIF-5A2 protein and BrdU incorporation analysis of day 13.5 embryos. Expression of eIF-5A2 in developing liver, cartilage and neuroepithilium from transgenic and wild-type embryos (left) was detected by IHC (magnification, 400 ×). BrdU incorporation assay (right) was used to compare the proliferation rates between transgenic and wild-type embryos. No significant difference was observed in the percentage of BrdU positive cells between transgenic (56.3 ± 7.81) and wild-type embryos (52.73 ± 9.14, p > 0.05).
Mentions: To determine the effects of eIF-5A2 on mouse development, protein expression in13.5-day embryos and 12-week old mice was studied. On embryonic day 13.5, expression of eIF-5A2 was detected in the developing brain, liver and cartilage (Figure 2). At 12-week of age, EIF-5A2 protein expression was detected in all the tested adult tissues, including brain, lung, heart, liver, kidney, spleen, testis, uterus and ovary (sure 3A). Histological analysis showed that the morphologies of all tested tissues in eIF-5A2 transgenic embryos/mice were indistinguishable from their wild-type counterparts. To test the effects of eIF-5A2 overexpression on cell proliferation, BrdU incorporation assay and proliferating cell nuclear antigen (PCNA) immunostaining was applied to measure the proportion of cells in S phase in E13.5 embryos and12-week-old mice, respectively. However, the frequencies of BrdU positive cells in transgenic and wild-type embryos (56.3 ± 7.81 vs. 52.73 ± 9.14, respectively; p > 0.05) and PCNA positive cell percentages in transgenic and wild-type mice (46.2 ± 10.98 vs. 37.87 ± 10.44, respectively; p > 0.05) were comparable (Figure 2 and 3A).

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