Inuzuka, HiroyukiFukushima, HidefumiShaik, ShavaliWei, Wenyi2012-08-072010Inuzuka, Hiroyuki, Hidefumi Fukushima, Shavali Shaik, and Wenyi Wei. 2010. Novel insights into the molecular mechanisms governing Mdm2 ubiquitination and destruction. Oncotarget 1(7): 685-690.1949-2553http://nrs.harvard.edu/urn-3:HUL.InstRepos:9369051The 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 β-TRCP or Casein Kinase I function contributes to elevated Mdm2 expression that is frequently found in various types of tumors.en-USJournal Article2012-08-07