Interaction of the Tumor Suppressor p53 With Replication Protein A

摘要

In order to understand how the tumor suppressor p53 blocks the cell- cycle at the G1-S transition we studied how p21, a transcription target of p53, interacts with and inhibits cyclin-dependent kinases (cdk). We identified specific cyclin-binding Cy motifs on the p21 molecule that were essential for docking p21 on cyclin-cdks and discovered that such Cy motifs were present and functional on substrates and activators of cdks. This year we discovered the presence of a Cy motif on a newly identified human DNA replication initiation factor, Cdc18. This Cy motif is required for the stable association of Cdc18 with cyclin A-cdk2 in vivo. Wild type Cdc18 is in the nucleus at G1 and removed from the nucleus at S phase once cyclin-cdks are activated. The Cy motif of Cdc18 is necessary for this S phase specific removal of nuclear Cdc18 implying that Cdc18 is a physiological substrate of cyclin-cdks at the G1-S transition.