Cyclin-dependent kinases as a therapeutic target for stroke.
Cyclin-dependent kinases (CDKs) are commonly known to regulate cell proliferation. However, previous reports suggest that in cultured postmitotic neurons, activation of CDKs is a signal for death rather than cell division. We determined whether CDK activation occurs in mature adult neurons during focal stroke in vivo and whether this signal was required for neuronal death after reperfusion injury. Cdk4/cyclin D1 levels and phosphorylation of its substrate retinoblastoma protein (pRb) increase after stroke. Deregulated levels of E2F1, a transcription factor regulated by pRb, are also observed. Administration of a CDK inhibitor blocks pRb phosphorylation and the increase in E2F1 levels and dramatically reduces neuronal death by 80%. These results indicate that CDKs are an important therapeutic target for the treatment of reperfusion injury after ischemia.
Osuga
H
H
Department of Molecular Neuroscience, Institute of Medical Sciences, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa, Japan 259-1193.
Osuga
S
S
Wang
F
F
Fetni
R
R
Hogan
M J
MJ
Slack
R S
RS
Hakim
A M
AM
Ikeda
J E
JE
Park
D S
DS
D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002560:Cerebrovascular Circulation / Q000187:drug effects* / Q000502:physiology; D019938:Cyclin D1 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology*; D002546:Ischemic Attack, Transient / Q000201:enzymology / Q000503:physiopathology*; D008297:Male; D009474:Neurons / Q000473:pathology / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control*; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000378:metabolism
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493755:E2f1 protein, rat; D004791:Enzyme Inhibitors; D005419:Flavonoids; D010880:Piperidines; D011518:Proto-Oncogene Proteins; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; D019938:Cyclin D1; C077990:alvocidib; C495903:Cdk4 protein, rat; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases