Oncotarget

Research Perspectives:

Novel Insights into the Molecular Mechanisms Governing Mdm2 Ubiquitination and Destruction

Hiroyuki Inuzuka, Hidefumi Fukushima, Shavali Shaik and Wenyi Wei _

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Oncotarget. 2010; 1:685-690. https://doi.org/10.18632/oncotarget.202

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Abstract

Received: October 9, 2010, Accepted: October 18, 2010, Published: October 20, 2010

The 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 SCFβ-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 SCFβ-TRCP. Thus our finding expands the current knowledge on how Mdm2 is tightly regulated by both self- and SCFβ-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.

 


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