p21 (WAF1, CIP1 or sdi1) is a protein induced by the tumor suppressor protein p53 and has recently been shown to have a key role in cell cycle regulation. It associates with cyclin-cdk kinases and inhibits kinase activity. In addition, p21 associates with the DNA replication factor, Proliferating Cell Nuclear Antigen (PCNA), and inhibits its function as a processivity factor for DNA polymerase delta. Since the loss of p53 function has been implicated in many human cancers, an important goal in cancer research should be to bypass the loss of p53 in cancer cells by providing the cells with effectors downstream from p53, such as p21, responsible for growth suppression. Therefore, experiments will address the following: (1) Which function of p21 will restore growth suppression to p53 negative cancer cells? (2) Do other cellular proteins interact with and regulate the function of p21? In addition, since cyclin E (a G1 cyclin) has been found to directly interact with p21, it will also be determined whether its binding to p21 can prevent p21 from inhibiting another cyclin- cdk complex. This would suggest a mechanism whereby an increase in the level of a G1 cyclin can activate another G1 cyclin-cdk complex or an S phase cyclin-cdk complex by titrating away p21.
