Cdk5 phosphorylates p53 and regulates its activity

Cyclin dependent kinase 5 (Cdk5) is a proline-direct protein kinase that is most active in the CNS, and has been implicated as a contributing factor in certain neurodegenerative diseases. Further, there is evidence to suggest that Cdk5 may facilitate the progression of apoptosis. However, the mechanisms involved have not been elucidated. The tumor suppressor protein p53, a transcription factor that is regulated by phosphorylation, increases the expression of genes that control growth arrest or cell death. To understand how Cdk5 could facilitate apoptosis, the effects of Cdk5 on p53 activity were examined. In the present study it is shown that in apoptotic PC12 cells the levels of p53 and Cdk5 increase concomitantly. Further, Cdk5/p25 effectively phosphorylates recombinant p53 in vitro. Transient transfection of Cdk5/p25 into cells results in an increase in p53 levels, as well as the expression of the p53-responsive genes p21 and Bax. Furthermore, evidence is provided that increased Cdk5 activity increases p53 transcriptional activity significantly, suggesting that p53 is modulated in situ by Cdk5. This is the first demonstration that p53 is a substrate of Cdk5, and that Cdk5 can modulate p53 levels and activity.