title: Cyclophilin B is involved in p300-mediated degradation of CHOP in tumor cell adaptation to hypoxia.
abstract: The regulation of CCAAT/enhancer-binding protein-homologous protein (CHOP), an endoplasmic reticulum (ER) stress-response factor, is key to cellular survival. Hypoxia is a physiologically important stress that induces cell death in the context of the ER, especially in solid tumors. Although our previous studies have suggested that Cyclophilin B (CypB), a molecular chaperone, has a role in ER stress, currently, there is no direct information supporting its mechanism under hypoxia. Here, we demonstrate for the first time that CypB is associated with p300 E4 ligase, induces ubiquitination and regulates the proteasomal turnover of CHOP, one of the well-known pro-apoptotic molecules under hypoxia. Our findings show that CypB physically interacts with the N-terminal α-helix domain of CHOP under hypoxia and cooperates with p300 to modulate the ubiquitination of CHOP. We also show that CypB is transcriptionally induced through ATF6 under hypoxia. Collectively, these findings demonstrate that CypB prevents hypoxia-induced cell death through modulation of ubiquitin-mediated CHOP protein degradation, suggesting that CypB may have an important role in the tight regulation of CHOP under hypoxia.
authors.affiliation: Department of Biochemistry and Molecular Biology (BK21 project), Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul 130-701, Korea.
authors.forename: K
authors.initials: K
authors.lastname: Jeong
authors.affiliation: Department of Biochemistry and Molecular Biology (BK21 project), Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul 130-701, Korea.
authors.forename: H
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology (BK21 project), Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul 130-701, Korea.
authors.forename: K
authors.initials: K
authors.lastname: Kim
authors.affiliation: Neurodegeneration Control Research Center, School of Medicine, Kyung Hee University, Seoul 130-701, Korea.
authors.forename: S-J
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Genetic Engineering, Kyung Hee University, Seoul, Korea.
authors.forename: B-S
authors.initials: BS
authors.lastname: Hahn
authors.affiliation: Department of Radiology, Kyung Hee University Hospital-Gangdong, School of Medicine, Kyung Hee University, Seoul 134-727, Korea.
authors.forename: G-H
authors.initials: GH
authors.lastname: Jahng
authors.affiliation: Department of Biochemistry and Molecular Biology (BK21 project), Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul 130-701, Korea.
authors.forename: K-S
authors.initials: KS
authors.lastname: Yoon
authors.affiliation: Department of Biochemistry and Molecular Biology (BK21 project), Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul 130-701, Korea.
authors.forename: S S
authors.initials: SS
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology (BK21 project), Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul 130-701, Korea.
authors.forename: J
authors.initials: J
authors.lastname: Ha
authors.affiliation: Department of Biochemistry and Molecular Biology (BK21 project), Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul 130-701, Korea.
authors.forename: I
authors.initials: I
authors.lastname: Kang
authors.affiliation: Department of Biochemistry and Molecular Biology (BK21 project), Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul 130-701, Korea.
authors.forename: W
authors.initials: W
authors.lastname: Choe
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D016923:Cell Death / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D021983:Cyclophilins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D057809:HEK293 Cells; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D051742:Transcription Factor CHOP / Q000378:metabolism*; D014162:Transfection; D054875:Ubiquitination
chemical_list: D051702:Activating Transcription Factor 6; D006360:Heat-Shock Proteins; C081786:cyclophilin B; D051742:Transcription Factor CHOP; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D021983:Cyclophilins