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Transgenic mice overexpressing glia maturation factor-β, an oxidative stress inducible gene, show premature aging due to Zmpste24 down-regulation.

Imai R, Asai K, Hanai J, Takenaka M - Aging (Albany NY) (2015)

Bottom Line: The GMF-TG mice exhibited appearance phenotypes associated with premature aging.The production of an abnormal lamin A, a nuclear envelope protein, plays a causal role in both normal aging and accelerated aging diseases, known as laminopathies.The gene expression of p21/waf1 was increased at an earlier stage of life, at 10 weeks, which was in turn down-regulated at a later stage, at 60 weeks.

View Article: PubMed Central - PubMed

Affiliation: Clinical Nutrition and Internal Medicine, Kobe Women's University, Kobe 654-8585, Japan.

ABSTRACT
Glia Maturation Factor-β (GMF), a brain specific protein, is induced by proteinuria in renal tubules. Ectopic GMF overexpression causes apoptosisin vitro via cellular vulnerability to oxidative stress. In order to examine the roles of GMF in non-brain tissue, we constructed transgenic mice overexpressing GMF (GMF-TG). The GMF-TG mice exhibited appearance phenotypes associated with premature aging. The GMF-TG mice also demonstrated short lifespans and reduced hair regrowth, suggesting an accelerated aging process. The production of an abnormal lamin A, a nuclear envelope protein, plays a causal role in both normal aging and accelerated aging diseases, known as laminopathies. Importantly, we identified the abnormal lamin A (prelamin A), accompanied by a down-regulation of a lamin A processing enzyme (Zmpste24) in the kidney of the GMF-TG mice. The GMF-TG mice showed accelerated aging in the kidney, compared with wild-type mice, showing increased TGF-β1, CTGF gene and serum creatinine. The gene expression of p21/waf1 was increased at an earlier stage of life, at 10 weeks, which was in turn down-regulated at a later stage, at 60 weeks. In conclusion, we propose that GMF-TG mice might be a novel mouse model of accelerated aging, due to the abnormal lamin A.

No MeSH data available.


Related in: MedlinePlus

Hypothetical schematic representation of the novel role of GMF overexpression in non-brain tissue in vivoThis study showed that the GMF-TG mice developed accelerated aging phenotypes due to lamin injury caused by oxidative stress-related reduction of Zmpste24. Zmpste24 is down-regulated in response to oxidative stress [19, 20], which appears to be associated with the activation of p53 and p16-Rb pathways [19]. Oxidative stress activates the p53 and p16-Rb pathways, inducing senescence and eventually leading to accelerated aging [22, 23]. It is conceivable that the ectopic GMF overexpression might be a factor connecting aging and lamin injury through oxidative stress.
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Figure 10: Hypothetical schematic representation of the novel role of GMF overexpression in non-brain tissue in vivoThis study showed that the GMF-TG mice developed accelerated aging phenotypes due to lamin injury caused by oxidative stress-related reduction of Zmpste24. Zmpste24 is down-regulated in response to oxidative stress [19, 20], which appears to be associated with the activation of p53 and p16-Rb pathways [19]. Oxidative stress activates the p53 and p16-Rb pathways, inducing senescence and eventually leading to accelerated aging [22, 23]. It is conceivable that the ectopic GMF overexpression might be a factor connecting aging and lamin injury through oxidative stress.

Mentions: In conclusion, this study demonstrated that the GMF-TG mice showed mild accelerated aging phenotypes, as a consequence of secondary laminopathy. In regard to the mechanisms involved in this process, we propose that the ectopic GMF overexpression induced an oxidative stress-related reduction of Zmpste24. This might be associated with the activation of the signaling-pathway via the disassembly of nuclear envelope proteins, leading to senescence in cells and tissue [39]. On the basis of the findings reported here, we propose a hypothetical, novel role of GMF overexpression in non-brain tissue in vivo (Figure 10). Much attention has been paid to a functional link between lamin A and the physiological aging process [17–20]. It is also well known that enhanced oxidative stress has been implicated in aging, and age-related diseases, such as cardiovascular disease, cancer, neurodegenerative diseases, and other chronic conditions [22, 23, 40]. Our findings suggest the possibility that GMF-TG mice might provide a novel premature-aging model useful in clarifying the relationship between aging, the pathophysiology of laminopathies and the clinical relevance for various chronic disease states.


Transgenic mice overexpressing glia maturation factor-β, an oxidative stress inducible gene, show premature aging due to Zmpste24 down-regulation.

Imai R, Asai K, Hanai J, Takenaka M - Aging (Albany NY) (2015)

Hypothetical schematic representation of the novel role of GMF overexpression in non-brain tissue in vivoThis study showed that the GMF-TG mice developed accelerated aging phenotypes due to lamin injury caused by oxidative stress-related reduction of Zmpste24. Zmpste24 is down-regulated in response to oxidative stress [19, 20], which appears to be associated with the activation of p53 and p16-Rb pathways [19]. Oxidative stress activates the p53 and p16-Rb pathways, inducing senescence and eventually leading to accelerated aging [22, 23]. It is conceivable that the ectopic GMF overexpression might be a factor connecting aging and lamin injury through oxidative stress.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4543038&req=5

Figure 10: Hypothetical schematic representation of the novel role of GMF overexpression in non-brain tissue in vivoThis study showed that the GMF-TG mice developed accelerated aging phenotypes due to lamin injury caused by oxidative stress-related reduction of Zmpste24. Zmpste24 is down-regulated in response to oxidative stress [19, 20], which appears to be associated with the activation of p53 and p16-Rb pathways [19]. Oxidative stress activates the p53 and p16-Rb pathways, inducing senescence and eventually leading to accelerated aging [22, 23]. It is conceivable that the ectopic GMF overexpression might be a factor connecting aging and lamin injury through oxidative stress.
Mentions: In conclusion, this study demonstrated that the GMF-TG mice showed mild accelerated aging phenotypes, as a consequence of secondary laminopathy. In regard to the mechanisms involved in this process, we propose that the ectopic GMF overexpression induced an oxidative stress-related reduction of Zmpste24. This might be associated with the activation of the signaling-pathway via the disassembly of nuclear envelope proteins, leading to senescence in cells and tissue [39]. On the basis of the findings reported here, we propose a hypothetical, novel role of GMF overexpression in non-brain tissue in vivo (Figure 10). Much attention has been paid to a functional link between lamin A and the physiological aging process [17–20]. It is also well known that enhanced oxidative stress has been implicated in aging, and age-related diseases, such as cardiovascular disease, cancer, neurodegenerative diseases, and other chronic conditions [22, 23, 40]. Our findings suggest the possibility that GMF-TG mice might provide a novel premature-aging model useful in clarifying the relationship between aging, the pathophysiology of laminopathies and the clinical relevance for various chronic disease states.

Bottom Line: The GMF-TG mice exhibited appearance phenotypes associated with premature aging.The production of an abnormal lamin A, a nuclear envelope protein, plays a causal role in both normal aging and accelerated aging diseases, known as laminopathies.The gene expression of p21/waf1 was increased at an earlier stage of life, at 10 weeks, which was in turn down-regulated at a later stage, at 60 weeks.

View Article: PubMed Central - PubMed

Affiliation: Clinical Nutrition and Internal Medicine, Kobe Women's University, Kobe 654-8585, Japan.

ABSTRACT
Glia Maturation Factor-β (GMF), a brain specific protein, is induced by proteinuria in renal tubules. Ectopic GMF overexpression causes apoptosisin vitro via cellular vulnerability to oxidative stress. In order to examine the roles of GMF in non-brain tissue, we constructed transgenic mice overexpressing GMF (GMF-TG). The GMF-TG mice exhibited appearance phenotypes associated with premature aging. The GMF-TG mice also demonstrated short lifespans and reduced hair regrowth, suggesting an accelerated aging process. The production of an abnormal lamin A, a nuclear envelope protein, plays a causal role in both normal aging and accelerated aging diseases, known as laminopathies. Importantly, we identified the abnormal lamin A (prelamin A), accompanied by a down-regulation of a lamin A processing enzyme (Zmpste24) in the kidney of the GMF-TG mice. The GMF-TG mice showed accelerated aging in the kidney, compared with wild-type mice, showing increased TGF-β1, CTGF gene and serum creatinine. The gene expression of p21/waf1 was increased at an earlier stage of life, at 10 weeks, which was in turn down-regulated at a later stage, at 60 weeks. In conclusion, we propose that GMF-TG mice might be a novel mouse model of accelerated aging, due to the abnormal lamin A.

No MeSH data available.


Related in: MedlinePlus