Dopamine induces supernumerary centrosomes and subsequent cell death through Cdk2 up-regulation in dopaminergic neuronal cells.
Aggregation of proteins in the centrosome is implicated in the pathophysiology of Parkinson's disease. However, the relevance of the centrosome in neurodegeneration is still obscure. Centrosome duplication is initiated by the cyclin E/cyclin-dependent kinase 2 (Cdk2) complex. The present study determined changes in cyclin E or Cdk2 expression and in the centrosomal structure in dopaminergic neuronal CATH.a cells exposed to 50, 100 and 150 micromolar dopamine (DA) for 24 h. DA induced significant increase in Cdk2 protein and cyclin E protein, but not cyclin e mRNA. In DA-treated cells, the intense cyclin E- and Cdk2-immunofluorescence signals were co-localized around large and supernumerary centrosomes, and these two parameters of centrosome amplification were significantly increased compared with the control. Simultaneous co-treatment with DA and a Cdk2 inhibitor blocked centrosome amplification and enhanced cell viability. Our results demonstrated that DA could lead to cyclin E accumulation and Cdk2 up-regulation triggering supernumerary centrosomes and apoptotic cell death.
Diaz-Corrales
Francisco J
FJ
Department of Brain Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
Asanuma
Masato
M
Miyazaki
Ikuko
I
Miyoshi
Ko
K
Hattori
Nobutaka
N
Ogawa
Norio
N
D000818:Animals; D018929:Cell Culture Techniques; D016923:Cell Death / Q000187:drug effects* / Q000235:genetics; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure; D002470:Cell Survival / Q000187:drug effects; D018385:Centrosome / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004298:Dopamine / Q000235:genetics / Q000633:toxicity*; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000648:ultrastructure; D012333:RNA, Messenger / Q000378:metabolism; D014463:Ultrasonography; D015854:Up-Regulation
D019927:Cyclin E; C500810:GW8510; D007211:Indoles; D012333:RNA, Messenger; D051357:Cyclin-Dependent Kinase 2; D004298:Dopamine