Identification of the interleukin 4 receptor alpha gene as a direct target for p73.
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 alpha (IL-4Ralpha) gene is up-regulated by p73 but not significantly by p53 in several human cancer cell lines. IL-4Ralphatranscription 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-4Ralpha gene after cisplatin treatment. Furthermore, we identified a p73-binding site in the first intron of the IL-4Ralpha 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. p73beta promoted localized nucleosomal acetylation through recruitment of coactivator p300, indicating that p73 regulates transcription of IL-4Ralpha through the unique p73-binding site. We also found that p73beta-transfected tumor cells are sensitive to IL-4-mediated apoptosis. Our data suggest that IL-4Ralpha could mediate, in part, certain immune responses and p73-dependent cell death.
Sasaki
Yasushi
Y
Department of Molecular Biology, Cancer Research Institute, Sapporo Medical University School of Medicine, Sapporo, Japan.
Mita
Hiroaki
H
Toyota
Minoru
M
Ishida
Setsuko
S
Morimoto
Ichiro
I
Yamashita
Toshiharu
T
Tanaka
Toshihiro
T
Imai
Kohzoh
K
Nakamura
Yusuke
Y
Tokino
Takashi
T
D000107:Acetylation; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D016384:Consensus Sequence; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D016147:Genes, Tumor Suppressor; D006657:Histones / Q000378:metabolism; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology; D007438:Introns; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D019948:Receptors, Interleukin-4 / Q000096:biosynthesis / Q000235:genetics*; D015534:Trans-Activators / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins
D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D006657:Histones; D009687:Nuclear Proteins; D012333:RNA, Messenger; D019948:Receptors, Interleukin-4; C000606460:TP73 protein, human; D015534:Trans-Activators; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D015847:Interleukin-4; D002945:Cisplatin