title: Calpastatin, an endogenous calpain-inhibitor protein, regulates the cleavage of the Cdk5 activator p35 to p25.
abstract: Cyclin-dependent kinase 5 (Cdk5) is a Ser/Thr kinase that is activated by binding to its regulatory subunit, p35. The calpain-mediated cleavage of p35 to p25 and the resulting aberrant activity and neurotoxicity of Cdk5 have been implicated in neurological disorders, such as Alzheimer's disease. To gain further insight into the molecular mechanisms underlying the pathological function of Cdk5, we investigated the role of the calpain inhibitor protein calpastatin (CAST), in controlling the aberrant production of p25. For this purpose, brain tissue from wild-type, CAST-over-expressing (transgenic), and CAST knockout mice were analyzed. Cleavage of p35 to p25 was increased in extracts from CAST knockout mice, compared with wild-type. Conversely, generation of p25 was not detected in brain lysates from CAST-over-expressing mice. CAST expression was 5-fold higher in mouse cerebellum than cerebral cortex. Accordingly, p25 production was lower in the cerebellum than the cerebral cortex. Furthermore, the Ca(2+) -dependent degradation of p35 by proteasome was evident when calpain was inhibited. Taken together, these results suggest that CAST is a crucial regulator of calpain activity, the production of p25, and, hence, the deregulation of Cdk5. Therefore, impairment of CAST expression and its associated mechanisms may contribute to the pathogenesis of neurodegenerative disorders.
authors.affiliation: Department of Biological Sciences, Graduate School of Science and Engineering, Tokyo Metropolitan University, Hachioji, Tokyo, Japan.
authors.forename: Ko
authors.initials: K
authors.lastname: Sato
authors.forename: Seiji
authors.initials: S
authors.lastname: Minegishi
authors.forename: Jiro
authors.initials: J
authors.lastname: Takano
authors.forename: Florian
authors.initials: F
authors.lastname: Plattner
authors.forename: Taro
authors.initials: T
authors.lastname: Saito
authors.forename: Akiko
authors.initials: A
authors.lastname: Asada
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kawahara
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Iwata
authors.forename: Takaomi C
authors.initials: TC
authors.lastname: Saido
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Hisanaga
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D015427:Reperfusion Injury / Q000201:enzymology / Q000473:pathology
chemical_list: D002135:Calcium-Binding Proteins; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; C089495:neuronal Cdk5 activator (p25-p35); C033668:calpastatin; D051360:Cyclin-Dependent Kinase 5; D046988:Proteasome Endopeptidase Complex; D002118:Calcium