Aqeilan Rami I, Pekarsky Yuri, Herrero Juan J, Palamarchuk Alexey, Letofsky Jean, Druck Teresa, Trapasso Francesco, Han Shuang-Yin, Melino Gerry, Huebner Kay, Croce Carlo M
Kimmel Cancer Institute, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107, USA.
Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4401-6. doi: 10.1073/pnas.0400805101.
The WWOX gene is a recently cloned tumor suppressor gene that spans the FRA16D fragile region. Wwox protein contains two WW domains that are generally known to mediate protein-protein interaction. Here we show that Wwox physically interacts via its first WW domain with the p53 homolog, p73. The tyrosine kinase, Src, phosphorylates Wwox at tyrosine 33 in the first WW domain and enhances its binding to p73. Our results further demonstrate that Wwox expression triggers redistribution of nuclear p73 to the cytoplasm and, hence, suppresses its transcriptional activity. In addition, we show that cytoplasmic p73 contributes to the proapoptotic activity of Wwox. Our findings reveal a functional cross-talk between p73 and Wwox tumor suppressor protein.
WWOX基因是最近克隆出的一种肿瘤抑制基因，它跨越FRA16D脆性区域。Wwox蛋白包含两个WW结构域，一般认为这两个结构域介导蛋白质-蛋白质相互作用。在此我们表明，Wwox通过其第一个WW结构域与p53同源物p73发生物理相互作用。酪氨酸激酶Src使Wwox第一个WW结构域中的酪氨酸33磷酸化，并增强其与p73的结合。我们的结果进一步证明，Wwox的表达会引发核p73向细胞质的重新分布，从而抑制其转录活性。此外，我们表明细胞质中的p73有助于Wwox的促凋亡活性。我们的发现揭示了p73与Wwox肿瘤抑制蛋白之间的功能性相互作用。
