The tumor suppressor protein p21 Waf1/Cip1 acts as an inhibitor of cell cycle progression. p21 is a potent, tight-binding inhibitor of Cdks and can inhibit the phosphorylation of Rb by cyclin A-Cdk 2, cyclin E-Cdk2, cyclin D1-Cdk4 and cyclin D2-Cdk4 complexes.The carboxy-terminal region of p21 is sufficient to bind and inhibit PCNA, a subunit of DNA polymerase, and may coordinate DNA replication with cell cycle progression. Upon UV damage or during cell cycle stages when cdc2/cyclin B or CDK2/cyclin A are active, p53 is phosphorylated and upregulates p21 transcription via a p53-responsive element . Protein levels of p21 are downregulated through ubiquitination and proteasomal degradation.
