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The ASK1-Signalosome regulates p38 MAPK activity in response to levels of endogenous oxidative stress in the Klotho mouse models of aging.

Hsieh CC, Kuro-o M, Rosenblatt KP, Brobey R, Papaconstantinou J - Aging (Albany NY) (2010)

Bottom Line: Reactive oxygen species (ROS) and elevated levels of p38 MAPK activity accelerate physiological aging.Our results suggest that increased endogenous ROS generated by Klotho(-/-) and resistance to oxidative stress in Klotho overexpression are linked to the regulation of ASK1-signalosome -> p38 activity.We conclude that the Klotho suppressor-of-aging activity is linked to the ASK1-signalsome, a physiological ROS-sensitive signaling center.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.

ABSTRACT
Reactive oxygen species (ROS) and elevated levels of p38 MAPK activity accelerate physiological aging. This emphasizes the importance of understanding the molecular mechanism(s) that link ROS production to activation of the p38 mediated promotion of aging, longevity, and resistance to oxidative stress. We examined Klotho(-/-) (elevated ROS) and Klotho overexpressing mice (low ROS and resistance to ROS) to determine whether the ROS-sensitive apoptosis signal-regulating kinase (ASK1)-signalosome -> p38 MAPK pathway plays a role in the accelerated aging of Klotho(-/-), and resistance to oxidative stress and extended lifespan in the Klotho overexpressing models. Our results suggest that increased endogenous ROS generated by Klotho(-/-) and resistance to oxidative stress in Klotho overexpression are linked to the regulation of ASK1-signalosome -> p38 activity. We propose that (a) the ASK1-signalosome -> p38 MAPK pathway is activated by oxidative stress due to ablation of the Klotho gene; (b) increased longevity by Klotho overexpression is linked to suppression of the ASK1-signalosome-p38 MAPK activity; (c) the ROS-responsive ASK1-signalosome regulates physiological aging via its regulation of p38 MAPK, through a mechanism that balances the levels of inhibitory vs. activating ASK1-signalosomes. We conclude that the Klotho suppressor-of-aging activity is linked to the ASK1-signalsome, a physiological ROS-sensitive signaling center.

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Western blot analysis of pool level of ASK1 in the livers of Klotho(-/-) and Klotho overexpressing mice.Western blot analyses of levels of ASK1 in the livers of (A) Klotho(-/-)(129)and WT (129) mice and (B) the EFmKL46 Klotho overexpressing and WT mice. The bar graphs depict the mean +/- SE of samples from WT, Klotho(-/-) and EFmKL 46 Klotho overexpressing mice.
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Figure 5: Western blot analysis of pool level of ASK1 in the livers of Klotho(-/-) and Klotho overexpressing mice.Western blot analyses of levels of ASK1 in the livers of (A) Klotho(-/-)(129)and WT (129) mice and (B) the EFmKL46 Klotho overexpressing and WT mice. The bar graphs depict the mean +/- SE of samples from WT, Klotho(-/-) and EFmKL 46 Klotho overexpressing mice.

Mentions: The data in Figure 5A and 5B show that there is no change in the ASK1 protein pool levels in Koltho(-/-) or the Klotho overexpressing models compared to their wild type controls. We conclude that the responses to Klotho ablation or overexpression involve post-translational modifications of the ASK1-signalosome.


The ASK1-Signalosome regulates p38 MAPK activity in response to levels of endogenous oxidative stress in the Klotho mouse models of aging.

Hsieh CC, Kuro-o M, Rosenblatt KP, Brobey R, Papaconstantinou J - Aging (Albany NY) (2010)

Western blot analysis of pool level of ASK1 in the livers of Klotho(-/-) and Klotho overexpressing mice.Western blot analyses of levels of ASK1 in the livers of (A) Klotho(-/-)(129)and WT (129) mice and (B) the EFmKL46 Klotho overexpressing and WT mice. The bar graphs depict the mean +/- SE of samples from WT, Klotho(-/-) and EFmKL 46 Klotho overexpressing mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2984608&req=5

Figure 5: Western blot analysis of pool level of ASK1 in the livers of Klotho(-/-) and Klotho overexpressing mice.Western blot analyses of levels of ASK1 in the livers of (A) Klotho(-/-)(129)and WT (129) mice and (B) the EFmKL46 Klotho overexpressing and WT mice. The bar graphs depict the mean +/- SE of samples from WT, Klotho(-/-) and EFmKL 46 Klotho overexpressing mice.
Mentions: The data in Figure 5A and 5B show that there is no change in the ASK1 protein pool levels in Koltho(-/-) or the Klotho overexpressing models compared to their wild type controls. We conclude that the responses to Klotho ablation or overexpression involve post-translational modifications of the ASK1-signalosome.

Bottom Line: Reactive oxygen species (ROS) and elevated levels of p38 MAPK activity accelerate physiological aging.Our results suggest that increased endogenous ROS generated by Klotho(-/-) and resistance to oxidative stress in Klotho overexpression are linked to the regulation of ASK1-signalosome -> p38 activity.We conclude that the Klotho suppressor-of-aging activity is linked to the ASK1-signalsome, a physiological ROS-sensitive signaling center.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.

ABSTRACT
Reactive oxygen species (ROS) and elevated levels of p38 MAPK activity accelerate physiological aging. This emphasizes the importance of understanding the molecular mechanism(s) that link ROS production to activation of the p38 mediated promotion of aging, longevity, and resistance to oxidative stress. We examined Klotho(-/-) (elevated ROS) and Klotho overexpressing mice (low ROS and resistance to ROS) to determine whether the ROS-sensitive apoptosis signal-regulating kinase (ASK1)-signalosome -> p38 MAPK pathway plays a role in the accelerated aging of Klotho(-/-), and resistance to oxidative stress and extended lifespan in the Klotho overexpressing models. Our results suggest that increased endogenous ROS generated by Klotho(-/-) and resistance to oxidative stress in Klotho overexpression are linked to the regulation of ASK1-signalosome -> p38 activity. We propose that (a) the ASK1-signalosome -> p38 MAPK pathway is activated by oxidative stress due to ablation of the Klotho gene; (b) increased longevity by Klotho overexpression is linked to suppression of the ASK1-signalosome-p38 MAPK activity; (c) the ROS-responsive ASK1-signalosome regulates physiological aging via its regulation of p38 MAPK, through a mechanism that balances the levels of inhibitory vs. activating ASK1-signalosomes. We conclude that the Klotho suppressor-of-aging activity is linked to the ASK1-signalsome, a physiological ROS-sensitive signaling center.

Show MeSH
Related in: MedlinePlus