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An iTRAQ Proteomics Screen Reveals The Effects Of The Mdm2 Binding Ligand Nutlin-3 On Cellular Proteostasis.
MedLine Citation:
PMID:  23039052     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
MDM2 participates in protein synthesis, folding, and ubiquitin-mediated degradation and is therefore a proteostasis hub protein. The MDM2 interactome contains over 100 proteins, yet stratification of dominant MDM2-interacting proteins has not been achieved. 8-plex iTRAQ (nanoLC-MS/MS) of MCF7 cells treated with Nutlin-3 identified the most abundant protein changes over early time points, 1,323 unique proteins were identified including 35 with altered steady-state levels within 2 hours of Nutlin-3 treatment identifying a core group of MDM2 related proteins. Six of these proteins were previously identified MDM2 interactors and the effects of Nutlin-3 on the MDM2-nucleophosmin interaction (NPM), was further validated. This revealed Nutlin-3 mediates conversion of NPM from an oligomer to a monomer as an MDM2 dependent phenomenon, with Nutlin-3 stimulating MDM2 binding to a peptide derived from the oligomerization interface of NPM. These data form the first proteomic screen of Nutlin-3 in cells whereby we (i) identify the most abundant MDM2 interacting proteins whose steady-state levels change early after Nutlin-3 treatment; (ii) identify the first protein apart from p53, NPM, whose interaction with MDM2 can be stimulated allosterically by Nutlin-3 and (iii) raise the possibility that Nutlin-3 might act as a general agonist of other MDM2 protein-protein interactions.
Authors:
Judith Nicholson; Kalainanghi Neelagandan; Anne Sophie Huart; Kathryn Ball; Mark Molloy; Ted Hupp
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-10-8
Journal Detail:
Title:  Journal of proteome research     Volume:  -     ISSN:  1535-3907     ISO Abbreviation:  J. Proteome Res.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-8     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101128775     Medline TA:  J Proteome Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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