title: ASK1 regulates influenza virus infection-induced apoptotic cell death.
abstract: Apoptosis occurs in influenza virus (IV)-infected cells. There are a number of mechanisms for the regulation of apoptosis. However, the molecular mechanism of IV infection-induced apoptosis is still controversial. Apoptosis signal-regulating kinase1 (ASK1) is a ubiquitously expressed mitogen-activated protein kinase kinase kinase (MAPKKK) that activates the SEK1-c-Jun N-terminal kinase (JNK) and MKK3/MKK6-p38 MAPK signaling cascades. ASK1 has been implicated in cytokine- and stress-induced apoptosis. Here, we show the following: (1) IV infection activated ASK1 and concomitantly phosphorylated JNK and p38 MAPK in human bronchial epithelial cells; (2) the activation of JNK and p38 MAPK but not extracellular-regulated kinase (ERK) in embryonic fibroblasts (MEFs) derived from ASK1 knockout mice (ASK1(-/-) MEFs) was depressed compared to MEFs derived from wild type mice (ASK1(+/+) MEFs); and (3) ASK1(-/-) MEFs were defective in IV infection-induced caspase-3 activation and cell death. These results indicate that apoptosis in IV-infected BEC is mediated through ASK1-dependent cascades.
authors.affiliation: First Department of Internal Medicine, Nihon University School of Medicine, 30-1 Oyaguchikamimachi, Itabashi-ku, Tokyo 173-8610, Japan.
authors.forename: Shuichiro
authors.initials: S
authors.lastname: Maruoka
authors.forename: Shu
authors.initials: S
authors.lastname: Hashimoto
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Gon
authors.forename: Hideki
authors.initials: H
authors.lastname: Nishitoh
authors.forename: Ikuko
authors.initials: I
authors.lastname: Takeshita
authors.forename: Yasukiyo
authors.initials: Y
authors.lastname: Asai
authors.forename: Kenji
authors.initials: K
authors.lastname: Mizumura
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Shimizu
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ichijo
authors.forename: Takashi
authors.initials: T
authors.lastname: Horie
mesh_terms: D000818:Animals; D017209:Apoptosis; D001980:Bronchi / Q000166:cytology; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D004285:Dogs; D000091342:Endoplasmic Reticulum Chaperone BiP; D004847:Epithelial Cells / Q000166:cytology / Q000201:enzymology / Q000821:virology; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology / Q000821:virology; D006360:Heat-Shock Proteins; D006801:Humans; D007251:Influenza, Human / Q000821:virology; D048031:JNK Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000502:physiology*; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018832:Molecular Chaperones / Q000096:biosynthesis / Q000235:genetics; D009975:Orthomyxoviridae / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D014764:Viral Proteins / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D002352:Carrier Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D012333:RNA, Messenger; D014764:Viral Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; C482858:MAP3K5 protein, human; C482859:Map3k5 protein, mouse; D020169:Caspases