title: Notch1 modulates oxidative stress induced cell death through suppression of apoptosis signal-regulating kinase 1.
abstract: Notch1 genes encode receptors for a signaling pathway that regulates various aspects of cell growth and differentiation; however, the role of Notch1 signaling in p38 mitogen-activated protein kinase (MAPK) signaling pathway is still not well defined. In this study, we found that Notch1 intracellular domain (Notch1-IC) prevents oxidative stress-induced cell death through the suppression of the Apoptosis signal-regulating kinase (ASK) 1 signaling pathway. Notch1-IC inhibited H2O2-induced activation of ASK1 and the activation of downstream kinases in the p38 MAPK signaling cascade. The results of both in vivo binding and kinase studies have revealed that ASK1 is the direct target of Notch1-IC, whereas it produced no effect on either MAP kinase kinase (MKK) 3 or p38 MAPK. Notch1-IC blocked both the homooligomerization of ASK1 and inhibited ASK1 activity. Furthermore, Notch1-IC facilitated the translocation of activated ASK1 toward the nucleus. Notch1 knockdown was determined to be highly susceptible to oxidative stress-induced activation of ASK1-MKK3/MKK6-p38 MAPK signaling cascade and cell death. Taken together, our findings suggest that Notch1-IC may act as a negative regulator in ASK1 signaling cascades.
authors.affiliation: Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Jung-Soon
authors.initials: JS
authors.lastname: Mo
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Yoon
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Ann
authors.forename: Ji-Seon
authors.initials: JS
authors.lastname: Ahn
authors.forename: Hyeong-Jin
authors.initials: HJ
authors.lastname: Baek
authors.forename: Hye-Jin
authors.initials: HJ
authors.lastname: Lee
authors.forename: Seol-Hee
authors.initials: SH
authors.lastname: Kim
authors.forename: Yeong-Dae
authors.initials: YD
authors.lastname: Kim
authors.forename: Mi-Yeon
authors.initials: MY
authors.lastname: Kim
authors.forename: Hee-Sae
authors.initials: HS
authors.lastname: Park
mesh_terms: D000818:Animals; D016923:Cell Death / Q000502:physiology*; D002458:Cell Fractionation; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D004926:Escherichia coli; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008156:Luciferases; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D016297:Mutagenesis, Site-Directed; D018384:Oxidative Stress / Q000502:physiology*; D011485:Protein Binding; D051881:Receptor, Notch1 / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D017931:DNA Primers; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D008156:Luciferases; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5