A Functional Interaction Between Hippo-YAP Signalling and FoxO1 Mediates the Oxidative Stress Response

Overview

Journal Nat Commun

Specialty Biology

Date 2014 Feb 15

PMID 24525530

Citations 151

Authors

Dan Shao

Peiyong Zhai

Dominic P Del Re

Sebastiano Sciarretta

Norikazu Yabuta

Hiroshi Nojima

Dae-Sik Lim

Duojia Pan

Junichi Sadoshima

Affiliations

Soon will be listed here.

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.

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