title: 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.forename: Hiroyuki
authors.initials: H
authors.lastname: Inuzuka
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Fukushima
authors.forename: Shavali
authors.initials: S
authors.lastname: Shaik
authors.forename: Wenyi
authors.initials: W
authors.lastname: Wei
mesh_terms: D000818:Animals; D047389:Casein Kinase I / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000235:genetics*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology; D054875:Ubiquitination / Q000235:genetics*
chemical_list: D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D044843:SKP Cullin F-Box Protein Ligases; D047389:Casein Kinase I