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ARF impedes NPM/B23 shuttling in an Mdm2-sensitive tumor suppressor pathway
Suzanne N Brady1, Yue Yu, Leonard B Maggi
1Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, Campus Box 8069, 660 S. Euclid Ave., St. Louis, MO 63110, USA.
Abstract:
The ARF tumor suppressor is widely regarded as an upstream activator of p53-dependent growth arrest and apoptosis. However, recent findings indicate that ARF can also regulate the cell cycle in the absence of p53. In search of p53-independent ARF targets, we isolated nucleophosmin (NPM/B23), a protein we show is required for proliferation, as a novel ARF binding protein. In response to hyperproliferative signals, ARF is upregulated, resulting in the nucleolar retention of NPM and concomitant cell cycle arrest. The Mdm2 oncogene outcompetes NPM/B23 for ARF binding, and introduction of Mdm2 reverses ARF's p53-independent properties: in vitro, NPM is released from ARF-containing protein complexes, and in vivo S phase progression ensues. ARF induction by oncogenes or replicative senescence does not alter NPM/B23 protein levels but rather prevents its nucleocytoplasmic shuttling without inhibiting rRNA processing. By actively sequestering NPM in the nucleolus, ARF utilizes an additional mechanism of tumor suppression, one that is readily antagonized by Mdm2.
Insights
The ARF tumor suppressor protein sequesters nucleophosmin (NPM/B23) in the nucleolus, halting cell cycle progression independently of p53. Mdm2 oncogene binding disrupts this interaction, restoring proliferation.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- The ARF tumor suppressor is known to activate p53-dependent growth arrest and apoptosis.
- Emerging evidence suggests ARF also regulates the cell cycle independently of p53.
Purpose of the Study:
- To identify p53-independent targets of ARF.
- To elucidate the mechanism by which ARF suppresses proliferation without p53.
Main Methods:
- Protein binding assays to identify ARF interacting partners.
- Cellular localization studies (nucleolar retention) of NPM/B23.
- Analysis of cell cycle progression (S phase) in response to ARF and Mdm2.
Main Results:
- Nucleophosmin (NPM/B23), a proliferation-essential protein, was identified as a novel ARF binding protein.
- ARF upregulation leads to NPM/B23 nucleolar retention and cell cycle arrest, independent of p53.
- The Mdm2 oncogene competes with NPM/B23 for ARF binding, releasing NPM/B23 and restoring S phase progression.
Conclusions:
- ARF suppresses proliferation through p53-independent nucleolar sequestration of NPM/B23.
- Mdm2 antagonizes ARF's p53-independent tumor suppressive function by disrupting the ARF-NPM complex.
- ARF utilizes NPM/B23 sequestration as an additional tumor suppression mechanism, counteracted by Mdm2.
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