| Reactivating the ARF-p53 axis in AML cells by targeting ULF. | |
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MedLine Citation:
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PMID: 20699639 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Delin Chen; Jong-Bok Yoon; Wei Gu |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-08-11 |
Journal Detail:
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Title: Cell cycle (Georgetown, Tex.) Volume: 9 ISSN: 1551-4005 ISO Abbreviation: Cell Cycle Publication Date: 2010 Aug |
Date Detail:
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Created Date: 2010-08-20 Completed Date: 2010-12-01 Revised Date: 2011-08-03 |
Medline Journal Info:
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Nlm Unique ID: 101137841 Medline TA: Cell Cycle Country: United States |
Other Details:
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Languages: eng Pagination: 2946-51 Citation Subset: IM |
Affiliation:
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Institute for Cancer Genetics, and Department of Pathology and Cell Biology, College of Physicians & Surgeons, Columbia University, New York, NY, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Carrier Proteins / metabolism* Gene Expression Regulation, Leukemic Humans Leukemia, Myeloid, Acute / enzymology*, genetics, pathology Mice 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* |
| Chemical | |
Reg. No./Substance:
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0/Carrier Proteins; 0/Mutant Proteins; 0/Nuclear Proteins; 0/Tumor Suppressor Protein p14ARF; 0/Tumor Suppressor Protein p53; 117896-08-9/nucleophosmin; EC 6.3.2.19/TRIP12 protein, human; EC 6.3.2.19/Ubiquitin-Protein Ligases |
| Comments/Corrections | |
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