Limits...
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.

Show MeSH

Related in: MedlinePlus

Skeletal aging phenotypes in eIF-5A2 transgenic mice. (A) X-ray radiograph was used to examine skeletal changes in 24-week-old eIF-5A2 transgenic mouse (upper) and their wild-type sibling (lower). Kyphosis was observed in eIF5A2 mouse (indicated by an arrow). (B) Representative radiograph of the density of femur bone in an eIF-5A2 transgenic mouse (24-week-old) and a wild-type mouse. (C, D) Alcian blue and Alizarin red staining of skulls from a 2-week-old transgenic mouse (upper) and its wild-type sibling (lower). A wider cranial sutures (C) and fontanelle (D) were observed in transgenic pup (indicated by arrows). (E) Representative skeletal staining of hind limb in a 2-week-old transgenic mouse (upper) and its wild-type sibling (lower). A clear ossification of patella was observed in the knee joint of wild-type mouse but not in the transgenic mouse (indicated by arrows).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3118894&req=5

Figure 5: Skeletal aging phenotypes in eIF-5A2 transgenic mice. (A) X-ray radiograph was used to examine skeletal changes in 24-week-old eIF-5A2 transgenic mouse (upper) and their wild-type sibling (lower). Kyphosis was observed in eIF5A2 mouse (indicated by an arrow). (B) Representative radiograph of the density of femur bone in an eIF-5A2 transgenic mouse (24-week-old) and a wild-type mouse. (C, D) Alcian blue and Alizarin red staining of skulls from a 2-week-old transgenic mouse (upper) and its wild-type sibling (lower). A wider cranial sutures (C) and fontanelle (D) were observed in transgenic pup (indicated by arrows). (E) Representative skeletal staining of hind limb in a 2-week-old transgenic mouse (upper) and its wild-type sibling (lower). A clear ossification of patella was observed in the knee joint of wild-type mouse but not in the transgenic mouse (indicated by arrows).

Mentions: Radiographs were taken to examine for potential skeletal degeneration in eIF-5A2 transgenic mice (n = 6) and their wild-type siblings (n = 5) at 24 weeks of age. Almost all the eIF-5A2 transgenic mice showed varying severity of kyphosis at 24-week of age (Figure 5A). In addition, the transgenic mice exhibited severe osteoporosis by radiographic analysis compared with their wild-type siblings (Figure 5B). We also stained the whole mouse skeletons with Alcian blue and Alizarin red to look at bone and cartilage. Interestingly, we found that 2-week-old transgenic mice showed several signs of delay of ossification. Compared to their wild-type siblings, transgenic pups had wide fontanelle and cranial sutures (Figure 5C and 5D). In the hind limb, clear ossification of the patella at the knee joint was observed in wild-type mice, but not in transgenic mice (Figure 5E). These data suggest that eIF-5A2 overexpression impairs ossification during development and contributes to osteoporosis and spine degeneration in adulthood.


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)

Skeletal aging phenotypes in eIF-5A2 transgenic mice. (A) X-ray radiograph was used to examine skeletal changes in 24-week-old eIF-5A2 transgenic mouse (upper) and their wild-type sibling (lower). Kyphosis was observed in eIF5A2 mouse (indicated by an arrow). (B) Representative radiograph of the density of femur bone in an eIF-5A2 transgenic mouse (24-week-old) and a wild-type mouse. (C, D) Alcian blue and Alizarin red staining of skulls from a 2-week-old transgenic mouse (upper) and its wild-type sibling (lower). A wider cranial sutures (C) and fontanelle (D) were observed in transgenic pup (indicated by arrows). (E) Representative skeletal staining of hind limb in a 2-week-old transgenic mouse (upper) and its wild-type sibling (lower). A clear ossification of patella was observed in the knee joint of wild-type mouse but not in the transgenic mouse (indicated by arrows).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Skeletal aging phenotypes in eIF-5A2 transgenic mice. (A) X-ray radiograph was used to examine skeletal changes in 24-week-old eIF-5A2 transgenic mouse (upper) and their wild-type sibling (lower). Kyphosis was observed in eIF5A2 mouse (indicated by an arrow). (B) Representative radiograph of the density of femur bone in an eIF-5A2 transgenic mouse (24-week-old) and a wild-type mouse. (C, D) Alcian blue and Alizarin red staining of skulls from a 2-week-old transgenic mouse (upper) and its wild-type sibling (lower). A wider cranial sutures (C) and fontanelle (D) were observed in transgenic pup (indicated by arrows). (E) Representative skeletal staining of hind limb in a 2-week-old transgenic mouse (upper) and its wild-type sibling (lower). A clear ossification of patella was observed in the knee joint of wild-type mouse but not in the transgenic mouse (indicated by arrows).
Mentions: Radiographs were taken to examine for potential skeletal degeneration in eIF-5A2 transgenic mice (n = 6) and their wild-type siblings (n = 5) at 24 weeks of age. Almost all the eIF-5A2 transgenic mice showed varying severity of kyphosis at 24-week of age (Figure 5A). In addition, the transgenic mice exhibited severe osteoporosis by radiographic analysis compared with their wild-type siblings (Figure 5B). We also stained the whole mouse skeletons with Alcian blue and Alizarin red to look at bone and cartilage. Interestingly, we found that 2-week-old transgenic mice showed several signs of delay of ossification. Compared to their wild-type siblings, transgenic pups had wide fontanelle and cranial sutures (Figure 5C and 5D). In the hind limb, clear ossification of the patella at the knee joint was observed in wild-type mice, but not in transgenic mice (Figure 5E). These data suggest that eIF-5A2 overexpression impairs ossification during development and contributes to osteoporosis and spine degeneration in adulthood.

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