Department of Anatomy and Tumor Immunity Medical Research Center, Seoul National University College of Medicine, Seoul 110-744, USA.
J Biol Chem. 2010 Mar 12;285(11):7995-8002. doi: 10.1074/jbc.M109.047985. Epub 2010 Jan 14.
The forkhead transcription factor, Foxp3, is thought to act as a master regulator that controls (suppresses) expression of the breast cancer oncogenes, SKP2 and HER-2/ErbB2. However, the mechanisms that regulate Foxp3 expression and thereby modulate tumor development remain largely unexplored. Here, we demonstrate that Foxp3 up-regulation requires p53 function, showing that Foxp3 expression is directly regulated by p53 upon DNA damage responses in human breast and colon carcinoma cells. Treatment with the genotoxic agents, doxorubicin or etoposide, induced Foxp3 expression in p53-positive carcinoma cells, but not in cells lacking p53 function. Furthermore, knock down of endogenous wild-type p53 using RNA interference abrogated Foxp3 induction by genotoxic agents, and exogenous expression of p53 in cells lacking p53 restored the responsiveness of Foxp3 to DNA-damaging stresses. In addition, Foxp3 knock down blunted the p53-mediated growth inhibitory response to DNA-damaging agents. These results suggest that induction of Foxp3 in the context of tumor suppression is regulated in a p53-dependent manner and implicate Foxp3 as a key determinant of cell fate in p53-dependent DNA damage responses.
叉头框转录因子 Foxp3 被认为是一种主控调节因子，可控制（抑制）乳腺癌致癌基因 SKP2 和 HER-2/ErbB2 的表达。然而，调节 Foxp3 表达从而调节肿瘤发展的机制在很大程度上仍未被探索。在这里，我们证明 Foxp3 的上调需要 p53 功能，表明 Foxp3 的表达在人类乳腺癌和结肠癌细胞的 DNA 损伤反应中直接受到 p53 的调控。用致瘤药物阿霉素或依托泊苷处理诱导 p53 阳性癌细 Foxp3 的表达，但缺乏 p53 功能的细胞则不会。此外，使用 RNA 干扰敲低内源性野生型 p53 可消除致瘤剂诱导的 Foxp3 诱导作用，并且在缺乏 p53 的细胞中外源表达 p53 可恢复 Foxp3 对 DNA 损伤应激的反应性。此外，Foxp3 的敲低削弱了 p53 介导的对 DNA 损伤剂的生长抑制反应。这些结果表明，在肿瘤抑制的背景下 Foxp3 的诱导是 p53 依赖性的，并且表明 Foxp3 是 p53 依赖性 DNA 损伤反应中细胞命运的关键决定因素。
