TY - JOUR
T1 - A functional interaction between Hippo-YAP signalling and FoxO1 mediates the oxidative stress response
AU - Shao, Dan
AU - Zhai, Peiyong
AU - Del Re, Dominic P.
AU - Sciarretta, Sebastiano
AU - Yabuta, Norikazu
AU - Nojima, Hiroshi
AU - Lim, Dae Sik
AU - Pan, Duojia
AU - Sadoshima, Junichi
N1 - Funding Information:
We thank D. Zablocki and C.D. Brady for critical reading of the manuscript. This work was supported in part by the United States Public Health Service grants HL67724, HL91469, HL102738, HL112330 and AG23039 (J.S.), the Foundation of Leducq Transatlantic Network of Excellence (J.S.) and the National Creative Research Program (2010-001827) (D.-S.L.).
PY - 2014/2/14
Y1 - 2014/2/14
N2 - 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.
AB - 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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U2 - 10.1038/ncomms4315
DO - 10.1038/ncomms4315
M3 - Article
C2 - 24525530
AN - SCOPUS:84894057702
SN - 2041-1723
VL - 5
JO - Nature communications
JF - Nature communications
M1 - 3315
ER -