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Identification of the Interleukin 4 Receptor Gene as a Direct Target for p73

¹ Department of Molecular Biology, Cancer Research Institute, and
² First Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, and
³ Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

p73 has a high degree of structural homology to p53 and can activate transcription of p53-responsive genes. However, analysis of p73-deficient mice revealed a marked divergence in the physiological activities of p53 family genes and distinguishes p73 from p53. Mice deficient for p73 exhibit profound defects, including hippocampal dysgenesis, chronic infection, and inflammation, as well as abnormalities in pheromone sensory pathways. p73 plays important roles in neurogenesis, sensory pathways, and homeostatic regulation. Here, we found that the interleukin 4 receptor (IL-4R) gene is up-regulated by p73 but not significantly by p53 in several human cancer cell lines. IL-4Rtranscription is also activated in response to cisplatin, a DNA-damaging agent known to induce p73. By using small interference RNA designed to target p73, we demonstrated that silencing endogenous p73 abrogates the induction of the IL-4R gene after cisplatin treatment. Furthermore, we identified a p73-binding site in the first intron of the IL-4R gene that can directly interact with the p73 protein in vivo. This p73-binding site consists of eight copies of a 10-bp consensus p53-binding motif and is a functional response element that is relatively specific for p73 among the p53 family. p73ß promoted localized nucleosomal acetylation through recruitment of coactivator p300, indicating that p73 regulates transcription of IL-4R through the unique p73-binding site. We also found that p73ß-transfected tumor cells are sensitive to IL-4-mediated apoptosis. Our data suggest that IL-4R could mediate, in part, certain immune responses and p73-dependent cell death.

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