Open AccessNovel insights into the molecular mechanisms governing Mdm2 ubiquitination and destruction.
Author(s) -
Hiroyuki Inuzuka,
Hidefumi Fukushima,
Shavali Shaik,
Wenyi Wei
Publication year - 2010
Publication title -
pubmed
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.373
H-Index - 127
eISSN - 1949-2553
DOI - 10.18632/oncotarget.101011
Subject(s) - mdm2 , ubiquitin ligase , ubiquitin , phosphorylation , microbiology and biotechnology , kinase , cancer research , casein kinase 2 , biology , medicine , genetics , protein kinase a , cell culture , cyclin dependent kinase 2 , gene
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 SCF(β-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(β-TRCP). Thus our finding expands the current knowledge on how Mdm2 is tightly regulated by both self- and SCF(β-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.