Abstract
Cell cycle regulators such as cyclin-dependent kinases (Cdks) and their inhibitors (Ckis) have been reported to be involved in neuronal cell death (NCD) induced by a variety of insults such as ischemia, UV-irradiation, nerve growth factor (NGF)-withdrawal, and anticancer therapeutics. But their precise interactive regulation has still to be unveiled. In the present study, we focused on cell cycle regulators such as Cdk4, p21(WAF1) and p53 to clarify their regulatory mechanisms, using NCD induced by doxorubicin (D-NCD) in mouse cerebellar granule neurons as a model. Doxorubicin induced NCD in a dose-dependent manner, a typical feature of apoptosis as determined by TUNEL assay. Doxorubicin increased the protein expression of p53 in time- and dose-dependent manners. The protein expression of p21(WAF1), a Cki of Cdk4, was stimulated by doxorubicin at low concentrations, but it disappeared at high concentrations. Doxorubicin activated the kinase activity of Cdk4 without the enhancement of Cdk4 protein. 3-Amino-9-thio(10H)-acridone (3-ATA), the specific inhibitor of Cdk4, prevented D-NCD in a dose-dependent manner. Wortmannin, an inhibitor of ATM (ataxia telangiectasia, mutated) that has high homology with the phosphatidyl-inositol-3...Continue Reading
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