Novel insights into the molecular mechanisms governing Mdm2 ubiquitination and destruction.

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.

• Authors: Hiroyuki Inuzuka, Hidefumi Fukushima, Shavali Shaik, Wenyi Wei
• Journal: Oncotarget (Oncotarget) Vol. 1 Issue 7 Pg. 685-90 (Nov 2010) ISSN: 1949-2553 [Electronic] United States
• PMID: 21317463 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Review)

Chemical References

• Tumor Suppressor Protein p53
• MDM2 protein, human
• Proto-Oncogene Proteins c-mdm2
• SKP Cullin F-Box Protein Ligases
• Casein Kinase I

Topics

• Animals
• Casein Kinase I (genetics, metabolism)
• Humans
• Models, Biological
• Neoplasms (genetics, metabolism)
• Phosphorylation (genetics)
• Protein Processing, Post-Translational (genetics)
• Proto-Oncogene Proteins c-mdm2 (metabolism)
• SKP Cullin F-Box Protein Ligases (genetics, metabolism)
• Signal Transduction (genetics, physiology)
• Tumor Suppressor Protein p53 (metabolism, physiology)
• Ubiquitination (genetics)