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A functional interaction between Hippo-YAP signalling and FoxO1 mediates the oxidative stress response

Author

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  • Dan Shao

    (Cardiovascular Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences)

  • Peiyong Zhai

    (Cardiovascular Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences)

  • Dominic P. Del Re

    (Cardiovascular Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences)

  • Sebastiano Sciarretta

    (Cardiovascular Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences)

  • Norikazu Yabuta

    (Research Institute for Microbial Diseases, Osaka University)

  • Hiroshi Nojima

    (Research Institute for Microbial Diseases, Osaka University)

  • Dae-Sik Lim

    (National Creative Research Initiatives Center, Biomedical Research Center, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology)

  • Duojia Pan

    (Howard Hughes Medical Institute, Johns Hopkins University School of Medicine)

  • Junichi Sadoshima

    (Cardiovascular Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences)

Abstract

The Hippo pathway is an evolutionarily conserved regulator of organ size and tumorigenesis that negatively regulates cell growth and survival. Here we report that Yes-associated protein (YAP), the terminal effector of the Hippo pathway, interacts with FoxO1 in the nucleus of cardiomyocytes, thereby promoting survival. YAP and FoxO1 form a functional complex on the promoters of the catalase and manganese superoxide dismutase (MnSOD) antioxidant genes and stimulate their transcription. Inactivation of YAP, induced by Hippo activation, suppresses FoxO1 activity and decreases antioxidant gene expression, suggesting that Hippo signalling modulates the FoxO1-mediated antioxidant response. In the setting of ischaemia/reperfusion (I/R) in the heart, activation of Hippo antagonizes YAP-FoxO1, leading to enhanced oxidative stress-induced cell death through downregulation of catalase and MnSOD. Conversely, restoration of YAP activity protects against I/R injury. These results suggest that YAP is a nuclear co-factor of FoxO1 and that the Hippo pathway negatively affects cardiomyocyte survival by inhibiting the function of YAP-FoxO1.

Suggested Citation

  • Dan Shao & Peiyong Zhai & Dominic P. Del Re & Sebastiano Sciarretta & Norikazu Yabuta & Hiroshi Nojima & Dae-Sik Lim & Duojia Pan & Junichi Sadoshima, 2014. "A functional interaction between Hippo-YAP signalling and FoxO1 mediates the oxidative stress response," Nature Communications, Nature, vol. 5(1), pages 1-10, May.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4315
    DOI: 10.1038/ncomms4315
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    Cited by:

    1. Bayu Lestari & Ardiansah Bayu Nugroho & Thuy Anh Bui & Binh Nguyen & Nicholas Stafford & Sukhpal Prehar & Min Zi & Ryan Potter & Efta Triastuti & Florence M. Baudoin & Alicia D’Souza & Xin Wang & Eliz, 2025. "Expression of foetal gene Pontin is essential in protecting heart against pathological remodelling and cardiomyopathy," Nature Communications, Nature, vol. 16(1), pages 1-21, December.

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