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lüll Novel insights into the molecular mechanisms governing Mdm2 ubiquitination and destruction Inuzuka H; Fukushima H; Shaik S; Wei WOncotarget 2010[Nov]; 1 (7): 685-90The Mdm2/p53 pathway is compromised in more than 50% of all human cancers, therefore it is an intensive area of research to understand the upstream regulatory pathways governing Mdm2/p53 activity. Mdm2 is frequently overexpressed in human cancers while the molecular mechanisms underlying the timely destruction of Mdm2 remain unclear. We recently reported that Casein Kinase I phosphorylates Mdm2 at multiple sites to trigger Mdm2 interaction with, and subsequent ubiquitination and destruction by the SCF(beta-TRCP) E3 ubiquitin ligase. We also demonstrated that the E3 ligase activity-deficient Mdm2 was still unstable in the G1 phase and could be efficiently degraded by SCF(beta-TRCP). Thus our finding expands the current knowledge on how Mdm2 is tightly regulated by both self- and SCF(beta-TRCP)-dependent ubiquitination to control p53 activity in response to stress. It further indicates that loss of beta-TRCP or Casein Kinase I function contributes to elevated Mdm2 expression that is frequently found in various types of tumors.|Animals[MESH]|Casein Kinase I/genetics/metabolism[MESH]|Humans[MESH]|Models, Biological[MESH]|Neoplasms/genetics/metabolism[MESH]|Phosphorylation/genetics[MESH]|Protein Processing, Post-Translational/*genetics[MESH]|Proto-Oncogene Proteins c-mdm2/*metabolism[MESH]|SKP Cullin F-Box Protein Ligases/genetics/metabolism[MESH]|Signal Transduction/genetics/physiology[MESH]|Tumor Suppressor Protein p53/metabolism/physiology[MESH]|Ubiquitination/*genetics[MESH] |