title: A functional interaction between Hippo-YAP signalling and FoxO1 mediates the oxidative stress response.
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.
authors: Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, New Jersey 07103, USA.
authors: Dan
authors: D
authors: Shao
authors: Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, New Jersey 07103, USA.
authors: Peiyong
authors: P
authors: Zhai
authors: Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, New Jersey 07103, USA.
authors: Dominic P
authors: DP
authors: Del Re
authors: Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, New Jersey 07103, USA.
authors: Sebastiano
authors: S
authors: Sciarretta
authors: Department of Molecular Genetics, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
authors: Norikazu
authors: N
authors: Yabuta
authors: Department of Molecular Genetics, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
authors: Hiroshi
authors: H
authors: Nojima
authors: Department of Biological Sciences, National Creative Research Initiatives Center, Biomedical Research Center, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
authors: Dae-Sik
authors: DS
authors: Lim
authors: Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21218, USA.
authors: Duojia
authors: D
authors: Pan
authors: Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, New Jersey 07103, USA.
authors: Junichi
authors: J
authors: Sadoshima
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D002522:Chlorocebus aethiops; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000090683:Hippo Signaling Pathway; D015151:Immunoblotting; D047468:Immunoprecipitation; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000502:physiology*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D010750:Phosphoproteins; D025521:Tumor Suppressor Proteins; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D002374:Catalase; D013482:Superoxide Dismutase; C522633:LATS2 protein, mouse; D017346:Protein Serine-Threonine Kinases