Reactivating the ARF-p53 axis in AML cells by targeting ULF.
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.
Chen
Delin
D
Institute for Cancer Genetics, and Department of Pathology and Cell Biology, College of Physicians & Surgeons, Columbia University, New York, NY, USA.
Yoon
Jong-Bok
JB
Gu
Wei
W
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D000090243:Nucleophosmin; D011485:Protein Binding; D055550:Protein Stability; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
D002352:Carrier Proteins; D050505:Mutant Proteins; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D000090243:Nucleophosmin; C530813:TRIP12 protein, human; D044767:Ubiquitin-Protein Ligases