title: Role of apoptosis signal-regulating kinase 1 in stress-induced neural cell apoptosis in vivo.
abstract: Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that plays an important role in oxidative stress-induced apoptosis. In the present study, we used ASK1 knockout (KO) mice to examine the possibility that ASK1 is involved in the neural cell apoptosis that occurs during retinal development and ischemic injury. ASK1 was expressed in retinal neurons, including retinal ganglion cells (RGCs), but retinal structure and extent of cell death during development were normal in ASK1 KO mice. On the other hand, the strain was less susceptible to ischemic injury, and the number of surviving retinal neurons was significantly increased compared with that in wild-type mice. Interestingly, ischemia-induced phosphorylation of p38 mitogen-activated protein kinase (p38), which mediates RGC apoptosis, was almost completely suppressed in ASK1 KO mice. In such retinas, the numbers of cleaved caspase-3- and TUNEL-positive neurons were apparently decreased compared with those in wild-type mice. Furthermore, cultured RGCs from ASK1 KO mice were resistant to H(2)O(2)-induced apoptosis. Our findings suggest that ASK1 is involved in the neural cell apoptosis after various kinds of oxidative stress. Thus, inhibition of the ASK1-p38 pathway could be useful for the treatment of neurodegenerative diseases including glaucoma.
authors.affiliation: Department of Molecular Neurobiology, Tokyo Metropolitan Institute for Neuroscience, 2-6 Musashidai, Fuchu, Tokyo 183-8526, Japan. harada@tmin.ac.jp
authors.forename: Chikako
authors.initials: C
authors.lastname: Harada
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Nakamura
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Namekata
authors.forename: Akinori
authors.initials: A
authors.lastname: Okumura
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Mitamura
authors.forename: Yoko
authors.initials: Y
authors.lastname: Iizuka
authors.forename: Kenji
authors.initials: K
authors.lastname: Kashiwagi
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yoshida
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Ohno
authors.forename: Atsushi
authors.initials: A
authors.lastname: Matsuzawa
authors.forename: Kohichi
authors.initials: K
authors.lastname: Tanaka
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ichijo
authors.forename: Takayuki
authors.initials: T
authors.lastname: Harada
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D007511:Ischemia / Q000503:physiopathology; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000502:physiology*; D012165:Retinal Ganglion Cells / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases