[Identification and analysis of IRF-1 binding protein]

Interferon Regulatory Factor-1 (IRF-1) acts as a transcriptional activator in interferon system and as a tumor suppressor. The loss of functional IRF-1 has been shown in approximately 30% of patients with myelodysplastic syndrome (MDS) and overt leukemia from MDS. Here we report an alternative mechanism of inactivation of IRF-1 activity. We identified an IRF-1 binding protein (IRF-BP). Protein sequencing revealed that IRF-BP was identical to nucleophosmin (NPM), a nucleolar phosphoprotein. Functional analysis showed that IRF-BP inhibited DNA-binding and transcriptional activity of IRF-1. Moreover when we examined several leukemia samples, the level of IRF-BP mRNA was increased. These results are consistent with the hypothesis that IRF-BP binds to IRF-1, and that overexpression of IRF-BP in leukemias leads to escape from IRF-1-regulated growth control. This hypothesis was also supported by the fact that overexpression of IRF-BP in NIH 3T3 cells rendered cells transformed.