Reactivating the ARF-p53 axis in AML cells: By targeting ULF

Delin Chen, Jong Bok Yoon, Wei Gu

Research output: Contribution to journalReview article

13 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2946-2951
Number of pages6
JournalCell Cycle
Volume9
Issue number15
DOIs
Publication statusPublished - 2010 Aug 1

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Myeloid Cells
Ligases
Ubiquitin
Acute Myeloid Leukemia
Proteasome Endopeptidase Complex
Ubiquitin-Protein Ligases
nucleophosmin
Proteins
Mutation
Neoplasms

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

Cite this

Chen, Delin ; Yoon, Jong Bok ; Gu, Wei. / Reactivating the ARF-p53 axis in AML cells : By targeting ULF. In: Cell Cycle. 2010 ; Vol. 9, No. 15. pp. 2946-2951.
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Reactivating the ARF-p53 axis in AML cells : By targeting ULF. / Chen, Delin; Yoon, Jong Bok; Gu, Wei.

In: Cell Cycle, Vol. 9, No. 15, 01.08.2010, p. 2946-2951.

Research output: Contribution to journalReview article

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AB - 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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