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Abstract
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.
Highlights
Recent scientific advances clearly demonstrated that tumors arise in a progressive fashion through overexpression of certain set of oncogenes, concomitantly with loss of function mutations in key tumor suppressor proteins
We obtained experimental evidence showing that the ring-finger mutant Mdm2, which is defective in its E3 ligase activity, is still unstable in the early G1 phase and is quickly degraded after DNA damage. These results strongly suggest that the destruction of the Mdm2 protein, which is central in regulating the p53 pathway, is tightly controlled by a foreign E3 ligase
We demonstrated that this mechanism operates both in response to DNA damage stress and in normal cell cycle progression, tightly controlling the abundance of Mdm2
Summary
Recent scientific advances clearly demonstrated that tumors arise in a progressive fashion through overexpression of certain set of oncogenes, concomitantly with loss of function mutations in key tumor suppressor proteins. In response to stresses such as DNA damage, activation of the ATM/ATR/CHK kinase pathway results in p53 phosphorylation at the Ser15 and In response to the genotoxic stress, the Mdm2 oncoprotein is quickly degraded by the CKI/SCFβ-TRCP signaling pathway.
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