AMP‐activated protein kinase mediates the antioxidant effects of resveratrol through regulation of the transcription factor FoxO1

• Published in: The FEBS journal 2014-10, Vol.281 (19), p.4421-4438
• Main Authors: Yun, Hee, Park, Seolhui, Kim, Min‐Jung, Yang, Woo Kyeom, Im, Dong Uk, Yang, Ki Ryeol, Hong, Jongki, Choe, Wonchae, Kang, Insug, Kim, Sung Soo, Ha, Joohun
• Format: Article
• Language: English
• Subjects: Active Transport, Cell Nucleus; agonists; AMP-activated protein kinase; AMP-Activated Protein Kinases - physiology; Animals; antioxidant activity; Antioxidants; Antioxidants - pharmacology; carcinogenesis; catalase; energy; forkhead box O; Forkhead Box Protein O1; Forkhead Transcription Factors - metabolism; HEK293 Cells; Hep G2 Cells; homeostasis; Humans; Kinases; longevity; Mice; Molecular biology; mutagenesis; Oxidative stress; Phosphorylation; Protein Processing, Post-Translational; Protein Stability; Proteins; reactive oxygen species; Reactive Oxygen Species - metabolism; redox regulation; resveratrol; signal transduction; Stilbenes - pharmacology; superoxide dismutase; transcription; transcription (genetics); Transcription factors; Transcription, Genetic; Transcriptional Activation
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.12949

Numerous physiological functions are controlled by redox‐responsive signaling pathways. Disruption of redox balance by oxidative stress is recognized as a major cause of many pathological conditions, including aging, highlighting the importance of investigating how antioxidants maintain redox homeostasis. AMP‐activated protein kinase (AMPK) is activated in response to cellular conditions that accompany energy depletion and plays a central role in the regulation of energy homeostasis, tumorigenesis and longevity. Recently, several antioxidants have been reported to activate AMPK, although the mechanisms by which AMPK acts to adjust the levels of cellular reactive oxygen species are not fully characterized. In the present study, we investigated the role of AMPK in mediating resveratrol‐induced antioxidant effects and the molecular mechanisms underlying its actions. We demonstrate that AMPK activity plays an indispensable role in the operation of the ROS defense system by inducing the expression of the antioxidant enzymes, manganese superoxide dismutase and catalase, in response to resveratrol or the AMPK agonist 5‐aminoimidazole‐4‐carboxamide‐1‐β‐d‐ribonucleotide. In addition, we identified the mechanism involved in the antioxidant function of AMPK, demonstrating that AMPK directly phosphorylates human FoxO1 (forkhead box O1) at Thr⁶⁴⁹ in vitro and increases FoxO1‐dependent transcription of manganese superoxide dismutase and catalase. Mutagenesis studies showed that this AMPK‐mediated phosphorylation of FoxO1 is critical for FoxO1 stability and nuclear localization, establishing the molecular basis for the induction of FoxO1 transcriptional activity. Our results reveal a novel FoxO1‐dependent mechanism by which AMPK controls the expression of antioxidant enzymes and suggest that AMPK has an important role in maintaining redox homeostasis.