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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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Aging-related phenotypes in eIF5A2 transgenic mice. (A) Cumulative plot of body weight versus age of male eIF-5A2 transgenic mice (n = 11) and their wild-type siblings (n = 8). * P < 0.05. (B) Quantification of the mean body weight of 5-month-old male eIF-5A2 transgenic mice and wild-type littermates is shown in the left (p < 0.05), and the representative image of a 24-week-old transgenic mouse and wild-type sibling was shown in the right. The body size of the transgenic mouse was significantly smaller than its wild-type sibling (P < 0.05). (C) Kaplan-Meier survival curve of male transgenic mice (n = 29, red line) and wild-type controls (n = 35, blue line). (D) Comparison of wound healing rates between 4-month-old eIF5A2 transgenic mice (15 wounds in 5 transgenic mice) and their wild-type siblings (12 wounds in 4 mice). * P < 0.05. (E) Representative HE-stained section at day 4 post-wounding in an eIF-5A2 transgenic mouse (left) and its wild-type sibling (right). The ability of re-epithelialization in the edges of wound was remarkably reduced in the transgenic mouse compared with its wild-type control (indicated by arrows). (F) Chronic skin lesions in eIF-5A2 transgenic mice (indicated by arrows).
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Figure 4: Aging-related phenotypes in eIF5A2 transgenic mice. (A) Cumulative plot of body weight versus age of male eIF-5A2 transgenic mice (n = 11) and their wild-type siblings (n = 8). * P < 0.05. (B) Quantification of the mean body weight of 5-month-old male eIF-5A2 transgenic mice and wild-type littermates is shown in the left (p < 0.05), and the representative image of a 24-week-old transgenic mouse and wild-type sibling was shown in the right. The body size of the transgenic mouse was significantly smaller than its wild-type sibling (P < 0.05). (C) Kaplan-Meier survival curve of male transgenic mice (n = 29, red line) and wild-type controls (n = 35, blue line). (D) Comparison of wound healing rates between 4-month-old eIF5A2 transgenic mice (15 wounds in 5 transgenic mice) and their wild-type siblings (12 wounds in 4 mice). * P < 0.05. (E) Representative HE-stained section at day 4 post-wounding in an eIF-5A2 transgenic mouse (left) and its wild-type sibling (right). The ability of re-epithelialization in the edges of wound was remarkably reduced in the transgenic mouse compared with its wild-type control (indicated by arrows). (F) Chronic skin lesions in eIF-5A2 transgenic mice (indicated by arrows).

Mentions: eIF-5A2 transgenic mice were indistinguishable from their wild-type siblings at birth. However, phenotypes of transgenic mice and wild-type littermates could be distinguished from postnatal week 3 according to body size and weight. From 3 weeks of age, the growth rate of transgenic mice was significantly reduced (about 20-40%, P < 0.05, Student's t tests) compared with wild-type controls (Figure 4A). At 5 months of age, the body weights of transgenic male mice (n = 11) and wild-type male littermates (n = 8) were compared, and we found the mean body weight of wild-type mice (57 ± 3.08 g) was significantly higher than that of transgenic littermates (37.1 ± 4.83 g, p < 0.05, Student's t tests) (Figure 4B). Strikingly, most of the transgenic mice died at 7-9 months without any apparent causes of death or visible changes observed by autopsy. The average lifespan of eIF-5A2 mice is 8 months (Figure 4C).


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)

Aging-related phenotypes in eIF5A2 transgenic mice. (A) Cumulative plot of body weight versus age of male eIF-5A2 transgenic mice (n = 11) and their wild-type siblings (n = 8). * P < 0.05. (B) Quantification of the mean body weight of 5-month-old male eIF-5A2 transgenic mice and wild-type littermates is shown in the left (p < 0.05), and the representative image of a 24-week-old transgenic mouse and wild-type sibling was shown in the right. The body size of the transgenic mouse was significantly smaller than its wild-type sibling (P < 0.05). (C) Kaplan-Meier survival curve of male transgenic mice (n = 29, red line) and wild-type controls (n = 35, blue line). (D) Comparison of wound healing rates between 4-month-old eIF5A2 transgenic mice (15 wounds in 5 transgenic mice) and their wild-type siblings (12 wounds in 4 mice). * P < 0.05. (E) Representative HE-stained section at day 4 post-wounding in an eIF-5A2 transgenic mouse (left) and its wild-type sibling (right). The ability of re-epithelialization in the edges of wound was remarkably reduced in the transgenic mouse compared with its wild-type control (indicated by arrows). (F) Chronic skin lesions in eIF-5A2 transgenic mice (indicated by arrows).
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Figure 4: Aging-related phenotypes in eIF5A2 transgenic mice. (A) Cumulative plot of body weight versus age of male eIF-5A2 transgenic mice (n = 11) and their wild-type siblings (n = 8). * P < 0.05. (B) Quantification of the mean body weight of 5-month-old male eIF-5A2 transgenic mice and wild-type littermates is shown in the left (p < 0.05), and the representative image of a 24-week-old transgenic mouse and wild-type sibling was shown in the right. The body size of the transgenic mouse was significantly smaller than its wild-type sibling (P < 0.05). (C) Kaplan-Meier survival curve of male transgenic mice (n = 29, red line) and wild-type controls (n = 35, blue line). (D) Comparison of wound healing rates between 4-month-old eIF5A2 transgenic mice (15 wounds in 5 transgenic mice) and their wild-type siblings (12 wounds in 4 mice). * P < 0.05. (E) Representative HE-stained section at day 4 post-wounding in an eIF-5A2 transgenic mouse (left) and its wild-type sibling (right). The ability of re-epithelialization in the edges of wound was remarkably reduced in the transgenic mouse compared with its wild-type control (indicated by arrows). (F) Chronic skin lesions in eIF-5A2 transgenic mice (indicated by arrows).
Mentions: eIF-5A2 transgenic mice were indistinguishable from their wild-type siblings at birth. However, phenotypes of transgenic mice and wild-type littermates could be distinguished from postnatal week 3 according to body size and weight. From 3 weeks of age, the growth rate of transgenic mice was significantly reduced (about 20-40%, P < 0.05, Student's t tests) compared with wild-type controls (Figure 4A). At 5 months of age, the body weights of transgenic male mice (n = 11) and wild-type male littermates (n = 8) were compared, and we found the mean body weight of wild-type mice (57 ± 3.08 g) was significantly higher than that of transgenic littermates (37.1 ± 4.83 g, p < 0.05, Student's t tests) (Figure 4B). Strikingly, most of the transgenic mice died at 7-9 months without any apparent causes of death or visible changes observed by autopsy. The average lifespan of eIF-5A2 mice is 8 months (Figure 4C).

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