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Identification and characterization of nucleophosmin/B23/numatrin which binds the anti-oncogenic transcription factor
T Kondo1, N Minamino, T Nagamura-Inoue
1Department of Immunology, Faculty of Medicine, Tokyo University, Japan.
Abstract:
Interferon regulatory factor-1 (IRF-1) acts as a transcriptional activator in the interferon system and as a tumor suppressor. The loss of functional IRF-1 has been observed in a significant number of patients with myelodysplastic syndrome (MDS) and leukemia, suggesting a potentially critical role of IRF-1 in human oncostasis. Here we report an alternative mechanism by which IRF-1 may be inactivated. We purified an IRF-1 association molecule which was revealed to be identical to a nuclear factor nucleophosmin (NPM)/B23/numatrin. Functional analysis showed that NPM inhibited the DNA-binding and transcriptional activity of IRF-1. Moreover, NPM was overexpressed in several clinical leukemia samples and human-derived leukemia cell lines. Finally, overexpression of NPM in NIH3T3 cells resulted in malignant transformation. These results suggest the possible involvement of NPM in inactivating IRF-1-dependent anti-oncogenic surveillance in human cancer development.
Insights
Nuclear factor nucleophosmin (NPM) inactivates the tumor suppressor Interferon regulatory factor-1 (IRF-1). NPM overexpression in leukemia suggests its role in cancer development by inhibiting IRF-1
Area of Science:
- Oncology
- Molecular Biology
- Gene Regulation
Background:
- Interferon regulatory factor-1 (IRF-1) is a tumor suppressor crucial for oncostasis.
- Loss of IRF-1 function is linked to myelodysplastic syndrome (MDS) and leukemia.
- The mechanisms of IRF-1 inactivation in cancer require further elucidation.
Purpose of the Study:
- To identify novel mechanisms of IRF-1 inactivation.
- To investigate the role of nucleophosmin (NPM) in regulating IRF-1 activity.
- To explore the potential involvement of NPM in leukemia pathogenesis.
Main Methods:
- Purification of IRF-1-associated molecules.
- Assessment of NPM's effect on IRF-1 DNA-binding and transcriptional activity.
- Analysis of NPM expression in clinical leukemia samples and cell lines.
- Malignant transformation assays in NIH3T3 cells overexpressing NPM.
Main Results:
- Nucleophosmin (NPM) was identified as an IRF-1-binding protein.
- NPM inhibits the DNA-binding and transcriptional activity of IRF-1.
- NPM is overexpressed in human leukemia samples and cell lines.
- NPM overexpression induces malignant transformation in NIH3T3 cells.
Conclusions:
- NPM inactivates the tumor suppressor IRF-1 through direct inhibition.
- NPM overexpression may contribute to human cancer development by disrupting IRF-1-mediated anti-oncogenic surveillance.
- NPM represents a potential therapeutic target in leukemia and other cancers associated with IRF-1 dysfunction.