Department of Biochemistry and Molecular and Cellular Biology, Lombardi Comprehensive Center, Georgetown University, Washington, DC 20057, USA.
J Biol Chem. 2010 Feb 19;285(8):5249-57. doi: 10.1074/jbc.M109.034579. Epub 2009 Dec 10.
The nuclear factor-kappaB (NF-kappaB) family of transcription factors plays a key role in inflammation and augments the initiation, promotion, and progression of cancer. NF-kappaB activation generally leads to transcriptional enhancement of genes important in cell survival and cell growth, which is exploited in cancer cells. In this study, we identify an additional oncogene, PPM1D, which encodes for Wip1, as a transcriptional target of NF-kappaB in breast cancer cells. Inhibition of NF-kappaB or activation of NF-kappaB resulted in decreased or increased Wip1 expression, respectively, at both the mRNA and protein levels. PPM1D promoter activity was positively regulated by NF-kappaB, and this regulation was dependent on the presence of the conserved kappaB site in the PPM1D promoter region. Chromatin immunoprecipitation analysis showed basal binding of the p65 NF-kappaB subunit to the PPM1D promoter region encompassing the kappaB site, which is enhanced after NF-kappaB activation by tumor necrosis factor-alpha. Finally, we show that Wip1 expression is induced in lipopolysaccharide-stimulated mouse splenic B-cells and is required for maximum proliferation. Taken together, these data suggest an additional mechanism by which NF-kappaB may promote tumorigenesis, support the selective use of NF-kappaB inhibitors as chemotherapeutic agents for the treatment of human cancers, and further define a function for Wip1 in inflammation.
核因子-κB（NF-κB）转录因子家族在炎症中发挥关键作用，并增强癌症的起始、促进和进展。NF-κB 的激活通常导致细胞生存和细胞生长中重要基因的转录增强，这在癌细胞中得到了利用。在这项研究中，我们确定了另一个癌基因 PPM1D，其编码 Wip1，是乳腺癌细胞中 NF-κB 的转录靶点。NF-κB 的抑制或激活分别导致 Wip1 在 mRNA 和蛋白质水平上的表达减少或增加。PPM1D 启动子活性受 NF-κB 正向调节，这种调节依赖于 PPM1D 启动子区域中保守的 κB 位点的存在。染色质免疫沉淀分析显示，p65 NF-κB 亚基在 NF-κB 激活后与包含 κB 位点的 PPM1D 启动子区域有基础结合，肿瘤坏死因子-α增强了这种结合。最后，我们表明 LPS 刺激的小鼠脾 B 细胞中诱导了 Wip1 表达，并且对于最大增殖是必需的。总之，这些数据表明 NF-κB 可能促进肿瘤发生的另一种机制，支持将 NF-κB 抑制剂选择性用作人类癌症治疗的化疗药物，并进一步定义 Wip1 在炎症中的功能。
