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

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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.
Publisher
NATURE PUBLISHING GROUP
Issue Date
2014-02
Language
English
Article Type
Article
Keywords

TRANSCRIPTION FACTORS; TUMOR-SUPPRESSOR; CARDIOMYOCYTE PROLIFERATION; HEART SIZE; PATHWAY; CELL; CANCER; GROWTH; REGULATOR; INACTIVATION

Citation

NATURE COMMUNICATIONS, v.5

ISSN
2041-1723
DOI
10.1038/ncomms4315
URI
http://hdl.handle.net/10203/189230
Appears in Collection
BS-Journal Papers(저널논문)
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