Phosphorylation by Casein Kinase I Promotes the Turnover of the Mdm2 Oncoprotein via the SCFβ-TRCP Ubiquitin Ligase

SummaryMdm2 is the major negative regulator of the p53 pathway. Here, we report that Mdm2 is rapidly degraded after DNA damage and that phosphorylation of Mdm2 by casein kinase I (CKI) at multiple sites triggers its interaction with, and subsequent ubiquitination and destruction, by SCFβ-TRCP. Inactivation of either β-TRCP or CKI results in accumulation of Mdm2 and decreased p53 activity, and resistance to apoptosis induced by DNA damaging agents. Moreover, SCFβ-TRCP-dependent Mdm2 turnover also contributes to the control of repeated p53 pulses in response to persistent DNA damage. Our results provide insight into the signaling pathways controlling Mdm2 destruction and further suggest that compromised regulation of Mdm2 results in attenuated p53 activity, thereby facilitating tumor progression.

► Multisite-phosphorylation by CKI triggers Mdm2 destruction via SCFβ-TRCP 4 SCFβ-TRCP controls Mdm2 stability independently of its auto-ubiquitination process ► Inactivation of β-TRCP results in elevated resistance to DNA damage-induced apoptosis ► Mdm2 turnover by SCFβ-TRCP controls p53 activity in response to genotoxic stress