title: β-Catenin C-terminal signals suppress p53 and are essential for artery formation.
abstract: Increased activity of the tumour suppressor p53 is incompatible with embryogenesis, but how p53 is controlled is not fully understood. Differential requirements for p53 inhibitors Mdm2 and Mdm4 during development suggest that these control mechanisms are context-dependent. Artery formation requires investment of nascent endothelial tubes by smooth muscle cells (SMCs). Here, we find that embryos lacking SMC β-catenin suffer impaired arterial maturation and die by E12.5, with increased vascular wall p53 activity. β-Catenin-deficient SMCs show no change in p53 levels, but greater p53 acetylation and activity, plus impaired growth and survival. In vivo, SMC p53 inactivation suppresses phenotypes caused by loss of β-catenin. Mechanistically, β-catenin C-terminal interactions inhibit Creb-binding protein-dependent p53 acetylation and p53 transcriptional activity, and are required for artery formation. Thus in SMCs, the β-catenin C-terminus indirectly represses p53, and this function is essential for embryogenesis. These findings have implications for angiogenesis, tissue engineering and vascular disease.
authors: Department of Medicine (Cardiology Division), Department of Developmental and Molecular Biology, and Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
authors: Dario F
authors: DF
authors: Riascos-Bernal
authors: Department of Medicine (Cardiology Division), Department of Developmental and Molecular Biology, and Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
authors: Prameladevi
authors: P
authors: Chinnasamy
authors: Department of Medicine (Cardiology Division), Department of Developmental and Molecular Biology, and Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
authors: Longyue Lily
authors: LL
authors: Cao
authors: Department of Medicine (Cardiology Division), Department of Developmental and Molecular Biology, and Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
authors: Charlene M
authors: CM
authors: Dunaway
authors: Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, Zurich, CH-8057, Switzerland.
authors: Tomas
authors: T
authors: Valenta
authors: Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, Zurich, CH-8057, Switzerland.
authors: Konrad
authors: K
authors: Basler
authors: Department of Medicine (Cardiology Division), Department of Developmental and Molecular Biology, and Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
authors: Nicholas E S
authors: NE
authors: Sibinga
mesh_terms: D000107:Acetylation; D000818:Animals; D001158:Arteries / Q000196:embryology* / Q000378:metabolism*; D049109:Cell Proliferation; D002470:Cell Survival; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005838:Genotype; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism; D038081:Organogenesis; D010641:Phenotype; D011485:Protein Binding; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051176:beta Catenin / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D051176:beta Catenin