title: Hypoxia-induced β-catenin downregulation involves p53-dependent activation of Siah-1.
abstract: Solid tumors contain extensive hypoxic areas and it is of considerable importance to decipher the potential role of hypoxia in signaling pathway regulation. In the present study, we examined the impact of hypoxia on β-catenin status and the mechanisms involved. Hypoxia significantly decreased β-catenin protein, but had no effect on glycogen synthase kinase (GSK)-3β or adenomatous polyposis coli (APC) levels. However, hypoxia-induced β-catenin downregulation seemed to require APC but not GSK-3β. Further investigation revealed that hypoxia significantly upregulated Siah-1, the human homolog of Drosophila seven in absentia. In addition, hypoxia augmented the interaction between β-catenin and SIP and Skp1. Silencing of Siah-1, as well as the use of a dominant negative Siah-1 mutant, attenuated these responses to hypoxia and rescued β-catenin transactivation. The Siah-1-mediated degradation of β-catenin during hypoxia may involve p53, but not hypoxia-inducible factor-1, activation. Together, the results suggest that hypoxia downregulates β-catenin by increasing Siah-1 expression in a p53-dependent manner.
authors.affiliation: Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors.forename: Dapeng
authors.initials: D
authors.lastname: Wang
authors.forename: Yongxing
authors.initials: Y
authors.lastname: Wang
authors.forename: Tao
authors.initials: T
authors.lastname: Kong
authors.forename: Feiyue
authors.initials: F
authors.lastname: Fan
authors.forename: Yongguang
authors.initials: Y
authors.lastname: Jiang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D025601:Adenomatous Polyposis Coli Protein / Q000502:physiology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D015536:Down-Regulation; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D009687:Nuclear Proteins / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*; D019207:beta Carotene / Q000502:physiology*; D000098563:Seven in Absentia Proteins
chemical_list: C555337:APC protein, human; D048868:Adaptor Proteins, Signal Transducing; D025601:Adenomatous Polyposis Coli Protein; C484351:EFS protein, human; D009687:Nuclear Proteins; D010750:Phosphoproteins; D044786:S-Phase Kinase-Associated Proteins; C097351:SKP1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019207:beta Carotene; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3