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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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The effects of Klotho(-/-) and Klotho overexpression on the nuclear and cytoplasmic localization of Nrf2.(A) Cytoplasmic and (B) nuclear levels of Nrf2 in the KL(-/-) and EFmKL46 Klotho overexpressing mice.
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Figure 4: The effects of Klotho(-/-) and Klotho overexpression on the nuclear and cytoplasmic localization of Nrf2.(A) Cytoplasmic and (B) nuclear levels of Nrf2 in the KL(-/-) and EFmKL46 Klotho overexpressing mice.

Mentions: Nrf2 is a cytoplasmically localized transcription factor that, in response to oxidative stress, translocates to the nucleus where it controls the expression and coordinated induction of a battery of genes critical for cellular protection and survival. This mechanism involves the binding of Nrf2 to genes whose promoters carry the antioxidant response element (ARE; [57,58]. Thus, the ARE genes contribute to the physiological defense against oxidative stress and to the development of resistance to oxidative stress [59,60]. We therefore, propose that intracellular localization of Nrf2 would respond to the increased oxidative stress in Klotho(-/-) and decreased oxidative stress in Klotho overexpressors. Interestingly, the data in Figure 4A and 4B show a significant decrease of levels of both cytoplasmic and nuclear-localized Nrf2 in Klotho(-/-) compared to WT suggesting that this mutant may exhibit a decreased level of the protective activity of Nrf2 targeted genes and therefore, may explain its accelerated aging. On the other hand, the overexpression of Klotho results in significantly increased levels of Nrf2 sequestered in the WT cytoplasm compared to nuclear levels. Furthermore the nuclear localization of Nrf2 in EFmLK 46 increase while the cytoplasmic level decreases suggesting activation of the anti-oxidant ARE targeted genes. These data are consistent with the development of resistance to oxidative stress in the Klotho overexpressing model and suggest that activation of Nrf2 may be an as yet uncharacterized function of Klotho.


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)

The effects of Klotho(-/-) and Klotho overexpression on the nuclear and cytoplasmic localization of Nrf2.(A) Cytoplasmic and (B) nuclear levels of Nrf2 in the KL(-/-) and EFmKL46 Klotho overexpressing mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: The effects of Klotho(-/-) and Klotho overexpression on the nuclear and cytoplasmic localization of Nrf2.(A) Cytoplasmic and (B) nuclear levels of Nrf2 in the KL(-/-) and EFmKL46 Klotho overexpressing mice.
Mentions: Nrf2 is a cytoplasmically localized transcription factor that, in response to oxidative stress, translocates to the nucleus where it controls the expression and coordinated induction of a battery of genes critical for cellular protection and survival. This mechanism involves the binding of Nrf2 to genes whose promoters carry the antioxidant response element (ARE; [57,58]. Thus, the ARE genes contribute to the physiological defense against oxidative stress and to the development of resistance to oxidative stress [59,60]. We therefore, propose that intracellular localization of Nrf2 would respond to the increased oxidative stress in Klotho(-/-) and decreased oxidative stress in Klotho overexpressors. Interestingly, the data in Figure 4A and 4B show a significant decrease of levels of both cytoplasmic and nuclear-localized Nrf2 in Klotho(-/-) compared to WT suggesting that this mutant may exhibit a decreased level of the protective activity of Nrf2 targeted genes and therefore, may explain its accelerated aging. On the other hand, the overexpression of Klotho results in significantly increased levels of Nrf2 sequestered in the WT cytoplasm compared to nuclear levels. Furthermore the nuclear localization of Nrf2 in EFmLK 46 increase while the cytoplasmic level decreases suggesting activation of the anti-oxidant ARE targeted genes. These data are consistent with the development of resistance to oxidative stress in the Klotho overexpressing model and suggest that activation of Nrf2 may be an as yet uncharacterized function of Klotho.

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