Figure 1. Multi-site phosphorylation of Mdm2 by Casein Kinase I triggers Mdm2 ubiquitination and destruction by SCF^β-TRCP in response to DNA damage.

A. In unstressed cells, p53 expression is maintained at basal level due to its interaction with Mdm2, which serves to promote p53 ubiquitination and subsequent destruction. In response to DNA damage, Casein Kinase I (CKI) translocates into the nucleus and phosphorylates Mdm2 at multiple sites. The phosphorylated Mdm2 species are recognized and ubiquitinated by SCF^β-TRCP, and subsequently degraded by the 26S proteasome-dependent pathway.

B. p53 phosphorylation by ATM/Chk2 and Mdm2 phosphorylation by CKI positively regulate the p53 pathway. Phosphorylation of p53 by ATM/Chk2 triggers the dissociation of p53 from Mdm2 and stabilizes p53. However, increased p53 activity induces Mdm2 transcription, which serves as a negative feedback loop to induce p53 downregulation. On the other hand, in response to the genotoxic stress, the Mdm2 oncoprotein is quickly degraded by the CKI/SCF^β-TRCP signaling pathway.