title: Cyclophilin A regulates JNK/p38-MAPK signaling through its physical interaction with ASK1.
abstract: Cyclophilin A (CypA), a member of the immunophilin family, is predominantly localized in the cytoplasm. The peptidylprolyl isomerase (PPIase) activity of CypA has been demonstrated to be involved in diverse cellular processes, including intracellular protein trafficking, mitochondrial function, pre-mRNA processing, and maintenance of multiprotein complex stability. In this study, we have demonstrated that CypA regulates apoptosis signaling-regulating kinase 1 (ASK1) through its direct binding. ASK1 is a member of MAPK kinase kinase (MAP3K) family, and selectively activates both JNK and p38 MAPK pathways. Here, we also report that CypA negatively regulates phosphorylation of ASK1 at Ser966, and that CypA reduces ASK1 and its downstream kinases of the JNK and p38 signaling. ASK1 is known to induce caspase-3 activation and apoptosis, and CypA inhibited ASK1-mediated apoptosis by decrease in caspase-3 activity under cellular stress conditions. Overall, we conclude that CypA negatively regulates ASK1 functions by its physical interaction with ASK1.
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, Republic of Korea.
authors.forename: Hunsung
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, Republic of Korea.
authors.forename: Yoojung
authors.initials: Y
authors.lastname: Oh
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, Republic of Korea.
authors.forename: Kiyoon
authors.initials: K
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, Republic of Korea.
authors.forename: Suyun
authors.initials: S
authors.lastname: Jeong
authors.affiliation: Department of Endocrinology and Metabolism, Kyung Hee University School of Medicine, Seoul, Republic of Korea.
authors.forename: Suk
authors.initials: S
authors.lastname: Chon
authors.affiliation: Molecular Imaging & Therapy Branch, National Cancer Center, 809 Madu1dong Ilsandonggu Goyangsi, Gyeonggydo 410-769, Republic of Korea.
authors.forename: Daehong
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Physiology, College of Medicine, Kyung Hee University, Seoul 130-731, Republic of Korea.
authors.forename: Min Hyung
authors.initials: MH
authors.lastname: Jung
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors.forename: Youngmi Kim
authors.initials: YK
authors.lastname: Pak
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, Republic of Korea.
authors.forename: Joohun
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, Republic of Korea.
authors.forename: Insug
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, Republic of Korea. Electronic address: wchoe@khu.ac.kr.
authors.forename: Wonchae
authors.initials: W
authors.lastname: Choe
mesh_terms: D001665:Binding Sites; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D021984:Cyclophilin A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism*; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D010766:Phosphorylation / Q000187:drug effects; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D006861:Hydrogen Peroxide; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; D048670:MAP Kinase Kinase 4; D053148:Caspase 3; D021984:Cyclophilin A
keywords: Apoptosis; Apoptosis signal-regulating kinase 1(ASK1); Cyclophilin A (CypA); Mitogen-activated protein kinase (MAPK); Oxidative-stress