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

Dan Shao, Peiyong Zhai, Dominic P. Del Re, Sebastiano Sciarretta, Norikazu Yabuta, Hiroshi Nojima, Dae Sik Lim, Duojia Pan, Junichi Sadoshima

Research output: Contribution to journalArticle

117 Scopus citations

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.

Original languageEnglish (US)
Article number3315
JournalNature communications
Volume5
DOIs
StatePublished - Feb 14 2014

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Shao, D., Zhai, P., Del Re, D. P., Sciarretta, S., Yabuta, N., Nojima, H., Lim, D. S., Pan, D., & Sadoshima, J. (2014). A functional interaction between Hippo-YAP signalling and FoxO1 mediates the oxidative stress response. Nature communications, 5, [3315]. https://doi.org/10.1038/ncomms4315