title: p25/cyclin-dependent kinase 5 promotes the progression of cell death in nucleus of endoplasmic reticulum-stressed neurons.
abstract: Dysregulation of cyclin-dependent kinase 5 (Cdk5) by cleavage of its activator p35 to p25 by calpain is involved in the neuronal cell death observed in neurodegenerative disorders, including Alzheimer's disease. However, it is not yet clear how p25/Cdk5 induces cell death, although its cytosolic localization or extended half life are thought to be involved. We show here that endoplasmic reticulum (ER) stress causes the calpain-dependent cleavage of p35 to p25 in primary cultured cortical neurons. Generation of p25 occurred at a cell death execution step in ER-stressed neurons. p25 translocated to the nucleus in ER-stressed neurons, whereas p35/Cdk5 was perinuclear in control neurons. Cdk5 inhibitors or dominant-negative Cdk5 suppressed ER stress-induced neuronal cell death. These findings indicate that p25/Cdk5 is a proapoptotic factor that promotes ER stress-induced neuronal cell death in nuclei.
authors.affiliation: Department of Biological Sciences, Graduate School of Science, Tokyo Metropolitan University, Hachiohji, Tokyo, Japan. tasaito@comp.metro-u.ac.jp
authors.forename: Taro
authors.initials: T
authors.lastname: Saito
authors.forename: Tsunetada
authors.initials: T
authors.lastname: Konno
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Hosokawa
authors.forename: Akiko
authors.initials: A
authors.lastname: Asada
authors.forename: Koichi
authors.initials: K
authors.lastname: Ishiguro
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Hisanaga
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002154:Calpain / Q000378:metabolism; D016923:Cell Death / Q000502:physiology*; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000201:enzymology* / Q000648:ultrastructure; D005260:Female; D005455:Fluorescent Antibody Technique; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009474:Neurons / Q000201:enzymology* / Q000648:ultrastructure; D011247:Pregnancy; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D014178:Translocation, Genetic / Q000502:physiology
chemical_list: D009419:Nerve Tissue Proteins; C089495:neuronal Cdk5 activator (p25-p35); D011494:Protein Kinases; C102333:histone H1 kinase; D051360:Cyclin-Dependent Kinase 5; D002154:Calpain