Nuclear Factor-κB (NF-κB) Is a Novel Positive Transcriptional Regulator of the Oncogenic Wip1 Phosphatase

The nuclear factor-kappa B (NF-kappa B) family of transcription factors plays a key role in inflammation and augments the initiation, promotion, and progression of cancer. NF-kappa B 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-kappa B in breast cancer cells. Inhibition of NF-kappa B or activation of NF-kappa B resulted in decreased or increased Wip1 expression, respectively, at both the mRNA and protein levels. PPM1D promoter activity was positively regulated by NF-kappa B, and this regulation was dependent on the presence of the conserved kappa B site in the PPM1D promoter region. Chromatin immunoprecipitation analysis showed basal binding of the p65 NF-kappa B subunit to the PPM1D promoter region encompassing the kappa B site, which is enhanced after NF-kappa B activation by tumor necrosis factor-kappa. 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-kappa B may promote tumorigenesis, support the selective use of NF-kappa B inhibitors as chemotherapeutic agents for the treatment of human cancers, and further define a function for Wip1 in inflammation.