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1 Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA
* To whom correspondence should be addressed. E-mail: pricepeterm{at}uams.edu.
The p21 cyclin-dependent kinase (cdk) inhibitor protects cells from cisplatin cytotoxicity in vivo and in vitro. However, the mechanism of protection is not known. Separate p21 domains are known to interact with several different proteins having proapoptotic functions. In order to investigate the mechanism of protection by p21, we have constructed adenoviruses encoding the different domains of p21. We were able to localize the protective activity to a region of 54 amino acids containing the cyclin-cdk interacting moiety. Other protein binding domains of p21, including the N-terminal procaspase-3 interactive region and the C-terminal region containing the proliferating cell nuclear antigen (PCNA) binding domain and the nuclear localization signal, had little protective effect on cisplatin cytotoxicity. The dependence of cisplatin cytotoxicity on cdk2 activity was also demonstrated by: 1) cisplatin caused a marked increase in cdk2 activity, which was prevented by p21-expression adenovirus, and 2) a cdk2 dominant-negative adenovirus also protected from cisplatin-induced apoptosis. Thus, the data suggest that the mechanism of p21 protection is by direct inhibition of cdk2 activity, and that cisplatin-induced apoptosis is caused by a cdk2-dependent pathway.
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