Nuclear factor-kappaB (NF-kappaB) is a novel positive transcriptional regulator of the oncogenic Wip1 phosphatase.
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.
Lowe
Julie M
JM
Department of Biochemistry and Molecular and Cellular Biology, Lombardi Comprehensive Center, Georgetown University, Washington, DC 20057, USA.
Cha
Hyukjin
H
Yang
Qian
Q
Fornace
Albert J
AJ
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D051379:Mice; D015513:Oncogene Proteins / Q000096:biosynthesis*; D010749:Phosphoprotein Phosphatases / Q000096:biosynthesis*; D000071636:Protein Phosphatase 2C; D020218:Response Elements; D013154:Spleen / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D015513:Oncogene Proteins; C498143:RELA protein, human; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; C000607468:Ppm1d protein, mouse; D000071636:Protein Phosphatase 2C