Reactivating the ARF-p53 axis in AML cells by targeting ULF.

Abstract

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.

• Authors: Delin Chen, Jong-Bok Yoon, Wei Gu
• Journal: Cell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 9 Issue 15 Pg. 2946-51 (Aug 01 2010) ISSN: 1551-4005 [Electronic] United States
• PMID: 20699639 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• Mutant Proteins
• NPM1 protein, human
• Nuclear Proteins
• Tumor Suppressor Protein p14ARF
• Tumor Suppressor Protein p53
• Nucleophosmin
• TRIP12 protein, human
• Ubiquitin-Protein Ligases

Topics

• 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)
• Nucleophosmin
• Protein Binding
• Protein Stability
• Tumor Suppressor Protein p14ARF (genetics, metabolism)
• Tumor Suppressor Protein p53 (metabolism)
• Ubiquitin-Protein Ligases (metabolism)