Document Detail

Reactivating the ARF-p53 axis in AML cells by targeting ULF.
MedLine Citation:
PMID:  20699639     Owner:  NLM     Status:  MEDLINE    
The tumor suppressor ARF plays an essential role in the cellular response to oncogenic stress mainly through activation of p53. Nucleophosmin (NPM), a multifunctional protein, forms a stable protein complex with ARF in the nucleolus and protects ARF from the proteasome-mediated degradation. Notably, NPM is mutated in about one third of acute myeloid leukaemia (AML) patients and these mutations lead to aberrant cytoplasmic dislocation of nucleophosmin (NPM-c). Cytoplasmic NPM mutants lose their abilities to retain ARF in the nucleolus and fail to stabilize ARF. Thus, activation of the ARF-p53 axis is significantly compromised in these AML cells. We have recently identified the ubiquitin ligase of ARF (ULF) as a key factor that controls ARF turnover in human cells. Here, we found that the steady levels of both ARF and p53 are very low in human acute myeloid leukaemia OCI-AML3 cells expressing cytoplamsic dislocated nucleophosmin (NPM-c). As expected, ARF is very unstable and rapidly degraded by proteasome. Nevertheless, ULF knockdown stabilizes ARF and reactivates p53 responses in these AML cells. These results further demonstrate that ULF is a bona fide E3 ligase for ARF and also suggest that ULF is an important target for activating the ARF-p53 axis in human AML cells.
Delin Chen; Jong-Bok Yoon; Wei Gu
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-08-11
Journal Detail:
Title:  Cell cycle (Georgetown, Tex.)     Volume:  9     ISSN:  1551-4005     ISO Abbreviation:  Cell Cycle     Publication Date:  2010 Aug 
Date Detail:
Created Date:  2010-08-20     Completed Date:  2010-12-01     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  101137841     Medline TA:  Cell Cycle     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2946-51     Citation Subset:  IM    
Institute for Cancer Genetics, and Department of Pathology and Cell Biology, College of Physicians & Surgeons, Columbia University, New York, NY, USA.
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MeSH Terms
Carrier Proteins / metabolism*
Gene Expression Regulation, Leukemic
Leukemia, Myeloid, Acute / enzymology*,  genetics,  pathology
Models, Biological
Mutant Proteins / metabolism
Mutation / genetics
Nuclear Proteins / genetics,  metabolism
Protein Binding
Protein Stability
Tumor Suppressor Protein p14ARF / genetics,  metabolism*
Tumor Suppressor Protein p53 / metabolism*
Ubiquitin-Protein Ligases / metabolism*
Reg. No./Substance:
0/Carrier Proteins; 0/Mutant Proteins; 0/Nuclear Proteins; 0/Tumor Suppressor Protein p14ARF; 0/Tumor Suppressor Protein p53; 117896-08-9/nucleophosmin; EC protein, human; EC Ligases

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